Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Atlas Journal
Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS
Volume 12, Number 2, Mar-Apr Previous Issue / Next Issue 2008 Genes PLAGL1 (Pleomorphic adenoma gene-like 1) (6q24.2). Abbas Abdollahi. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 164-171. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PLAGL1ID41737ch6q24.html PDCD4 (Programmed Cell Death 4) (10q24). Nancy H Colburn. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 172-177. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PDCD4ID41675ch10q24.html PAWR (PRKC apoptosis WT1 regulator protein) (12q21.2). Yanming Zhao, Vivek Rangnekar. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 178-183. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PAWRID41641ch12q21.html NOTCH3 (Notch homolog 3 (Drosophila)) (19p13.12). Tian-Li Wang. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 184-188. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/NOTCH3ID41557ch19p13.html NOTCH1 (Notch homolog 1, translocation-associated (Drosophila)) (9q34.3). Max Cayo, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 189-205. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/NOTCH1ID30ch9q34.html KLK10 (Kallikrein-related peptidase 10) (19q13.41). Liu-Ying Luo, Eleftherios P Diamandis. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 206-211. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/KLK10ID41076ch19q13.html
Atlas Genet Cytogenet Oncol Haematol 2008; 2 I HDAC3 (Histone deacetylase 3) (5q31.3). Fabrice Escaffit. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 212-217. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/HDAC3ID40804ch5q31.html FOXP1 (Forkhead box P1) (3p14.1). Iwona Wlodarska. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 218-224. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/FOXP1ID40632ch3p14.html ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7) (17q25.3). Rui-Dong Duan. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 225-231. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ENPP7ID44055ch17q25.html DMBT1 (Deleted in malignant brain tumors 1) (10q26.13). Jan Mollenhauer, Annemarie Poustka. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 232-241. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/DMBT1ID309ch10q26.html CDKN2a, cyclin dependent kinase 2a / p16 (9p21.3) - updated. Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 242-247. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CDKN2aID146.html BAG3 (Bcl-2 associated athanogene 3) (10q26.11). Arturo Leone, Alessandra Rosati, Massimo Ammirante, Maria Caterina Turco. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 248-252. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/BAG3ID43160ch10q26.html SPA17 (sperm autoantigenic protein 17) (11q24.2). Leri S. Faried, Ahmad Faried. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 253-257. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/SPA17ID42360ch11q24.html SOCS1 (Suppressor of cytokine signaling 1) (16p13.13). Liang-In Lin, Hwei-Fang Tien. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 258-265. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/SOCS1ID42350ch16p13.html SEPT2 (septin 2) (2q37.3). Nuno Cerveira, Manuel R Teixeira. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 266-270. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/SEPT2ID44125ch2q37.html PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit) (12q24.1). Monserrat Sanchez-Cespedes. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 271-275. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PRKAB1ID44100ch12q24.html GNB2L1 (guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1) (5q35.3). Mirna Mourtada-Maarabouni. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 276-280. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/GNB2L1ID43285ch5q35.html
Atlas Genet Cytogenet Oncol Haematol 2008; 2 II ERVWE1 (Endogenous Retroviral family W, Env(C7), member 1) (7q21.2). Juliette Gimenez, François Mallet. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 281-305. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ERVWE1ID40497ch7q21.html CTSH (cathepsin H) (15q25.1). Zala Jevnikar, Janko Kos. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 306-314. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CTSHID40206ch15q25.html Leukaemias t(3;3)(p24;q26). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12(2): 315. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0303p24q26ID1277.html inv(3)(q23q26). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12(2): 316. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/inv3q23q26ID1276.html inv(3)(p12q26). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12(2): 317. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/inv3p12q26ID1275.html inv(11)(q21;q23) in therapy related leukemias. Kazumi Suzukawa. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12(2): 318-320. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/inv11q21q23ID1471.html Solid Tumours Digestive organs: Carcinoma of the gallbladder and extrahepatic bile ducts. Munechika Enjoji, Toyoma Kaku. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 321-327. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Tumors/GallbladderID5275.html Cancer Prone Diseases Currarino Syndrome. Sally Ann Lynch. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 328-335. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Kprones/CurrarinoID10082.html Deep Insights Case Reports A t(4;12)(q11;p13) in a patient with coincident CLL at the same time of AML diagnosis. Paola Dal Cin, Daniel J DeAngelo, Richard M Stone. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 336-337. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0412DalCinID100023.html t(3;5)(q25;q35) as a sole anomaly in acute myeloid leukemia patient. Adriana Zamecnikova. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 338-341. [Full Text] [PDF]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 III URL : http://atlasgeneticsoncology.org/Reports/0305ZamecnikovaID100025.html t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient. Adriana Zamecnikova. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 342-345. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0304ZamecnikovaID100026.html t(1;16)(q11-12;q11) presented as a der(16)t(1;16) in a patient with acute lymphoblastic leukemia.. Adriana Zamecnikova. Atlas Genet Cytogenet Oncol Haematol 2008; Vol 12 (2): 346-350. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0116ZamecnikovaID100024.html Educational Items
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Atlas Genet Cytogenet Oncol Haematol 2008; 2 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology
PLAGL1 (Pleomorphic adenoma gene-like 1)
Identity Other names DKFZp781P1017 LOT1 MGC126275 MGC126276 ZAC ZAC1 Hugo PLAGL1 Location 6q24.2 DNA/RNA
Schematic view of the PLAGL1 gene. A. The six exons, shown in red, are 326; 72; 1443; 75; 475; 2380 bp, respectively. The introns are approximately 39; 2.6; 4.2; 12.5; 5.5 kbp in size, respectively. B. The figure shows three splice variants of PLAGL1; the exons are shown as a box. Description The genome is about 64 kbp with six exons and five introns. The major mRNA transcript is about 4.7 kb in size. Transcription At least three splicing variants (See Figure, above) Protein Description The PLAGL1 protein is a seven C2H2-type zinc finger protein. The seven zinc finger domain is located at the amino terminal region, from the amino acid residue 1 to 210. Additional features of note are proline and glutamine rich regions at the carboxyl terminal portion (residues 220 to 444). There are two nuclear localization signals at the amino terminal region. Expression Ovary, breast, brain, liver, spleen, thymus, prostate, uterus, testis, intestine, colon, leukocytes. Localisation Nuclear Function The PLAGL1 protein is a candidate tumor suppressor gene and has been shown to have transactivation and DNA-binding activity and to exhibit antiproliferative activities. Homology Homologous to the mouse and Rat plagl1 and to the human PLAG1 and PLAGL2 proteins. Mutations Note Mutation has not been found in the PLAGL1 coding region. Implicated in Entity Carcinogenicity Note Alteration of the gene expression was found to be a potential genetic event silencing the PLAGL1 gene in cancers such as breast primary tumors, ovarian primary tumors and tumor-derived cell lines, basal cell carcinoma, head and neck squamous cell carcinoma (HNSCC), and extraskeletal myxoid chondrosarcoma (EMC). Several mechanisms have been shown to regulate the PLAGL1 gene expression, including growth factor receptor activation, epigenetic factors, maternal imprinting, and loss of heterozygosity (LOH). Allelic deletion of 6q24-q25, the PLAGL1 locus, in the tumor tissues has been shown in the cancers of ovarian, breast, HNSCC, and
Atlas Genet Cytogenet Oncol Haematol 2008; 2 164 pheochromocytomas (PCCs). Disease Cancer Entity Transient Neonatal Diabetes (TNDM) Note Initial reports suggested that transient neonatal diabetes mellitus (TNDM), a rare condition characterized in the patients by intrauterine growth retardation, dehydration, failure to thrive, and hyperglycemia due to a lack of normal insulin secretion, is associated with paternal uniparental disomy (UPD) of chromosome 6 (UPD 6). Later studies showed the involvement of an imprinted gene in this disease within the chromosomal region 6q24.1-q24.3 between markers D6S1699 and D6S1010. Analysis of the CpG islands in the TNDM critical region, using DNA from TNDM patients with paternal UPD 6 and normal controls, suggested PLAGL1/LOT1/ZAC1 as a candidate imprinted gene for this disease. Disease Diabetes mellitus To be noted PLAGL1 has been implicated in embryonic development. The gene is variably expressed in different tissues and stages during development. Inactivation of this maternally repressed gene resulted in intrauterine growth restriction, altered bone formation, and neonatal lethality. External links Nomenclature Hugo PLAGL1 GDB PLAGL1 Entrez_Gene PLAGL1 5325 pleiomorphic adenoma gene-like 1 Cards Atlas PLAGL1ID41737ch6q24 GeneCards PLAGL1 Ensembl PLAGL1 [Search_View] ENSG00000118495 [Gene_View] Genatlas PLAGL1 GeneLynx PLAGL1 eGenome PLAGL1 euGene 5325 Genomic and cartography GoldenPath PLAGL1 - 6q24.2 chr6:144303130-144371234 - 6q24-q25 (hg18-Mar_2006) Ensembl PLAGL1 - 6q24-q25 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PLAGL1 Gene and transcription Genbank AI741398 [ ENTREZ ] Genbank AJ006354 [ ENTREZ ] Genbank AJ303119 [ ENTREZ ] Genbank AJ311395 [ ENTREZ ] Genbank AK091707 [ ENTREZ ] RefSeq NM_001080951 [ SRS ] NM_001080951 [ ENTREZ ] RefSeq NM_001080952 [ SRS ] NM_001080952 [ ENTREZ ] RefSeq NM_001080953 [ SRS ] NM_001080953 [ ENTREZ ] RefSeq NM_001080954 [ SRS ] NM_001080954 [ ENTREZ ] RefSeq NM_001080955 [ SRS ] NM_001080955 [ ENTREZ ] RefSeq NM_001080956 [ SRS ] NM_001080956 [ ENTREZ ] RefSeq NM_002656 [ SRS ] NM_002656 [ ENTREZ ] RefSeq NM_006718 [ SRS ] NM_006718 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_025741 [ SRS ] NT_025741 [ ENTREZ ] RefSeq NW_923184 [ SRS ] NW_923184 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 165 AceView PLAGL1 AceView - NCBI Unigene Hs.444975 [ SRS ] Hs.444975 [ NCBI ] HS444975 [ spliceNest ] Fast-db 16730 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9UM63 [ SRS] Q9UM63 [ EXPASY ] Q9UM63 [ INTERPRO ] PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 Prosite [ Expasy ] PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 Prosite [ Expasy ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] Interpro IPR015880 Znf_C2H2-like [ SRS ] IPR015880 Znf_C2H2-like [ EBI ] IPR013087 Znf_C2H2/integrase_DNA-bd [ SRS ] IPR013087 Interpro Znf_C2H2/integrase_DNA-bd [ EBI ] CluSTr Q9UM63 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00355 ZnF_C2H2 [EMBL] Prodom PD000003 Znf_C2H2[INRA-Toulouse] Q9UM63 PLAL1_HUMAN [ Domain structure ] Q9UM63 PLAL1_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks Q9UM63 HPRD 16010 Protein Interaction databases DIP Q9UM63 IntAct Q9UM63 Polymorphism : SNP, mutations, diseases OMIM 601410;603044 [ map ] GENECLINICS 601410;603044 SNP PLAGL1 [dbSNP-NCBI] SNP NM_001080951 [SNP-NCI] SNP NM_001080952 [SNP-NCI] SNP NM_001080953 [SNP-NCI] SNP NM_001080954 [SNP-NCI] SNP NM_001080955 [SNP-NCI] SNP NM_001080956 [SNP-NCI] SNP NM_002656 [SNP-NCI] SNP NM_006718 [SNP-NCI] SNP PLAGL1 [GeneSNPs - Utah] PLAGL1] [HGBASE - SRS] HAPMAP PLAGL1 [HAPMAP] HGMD PLAGL1 General knowledge Family Browser PLAGL1 [UCSC Family Browser] SOURCE NM_001080951 SOURCE NM_001080952 SOURCE NM_001080953 SOURCE NM_001080954 SOURCE NM_001080955 SOURCE NM_001080956 SOURCE NM_002656 SOURCE NM_006718 SMD Hs.444975 SAGE Hs.444975 GO nucleic acid binding [Amigo] nucleic acid binding GO DNA binding [Amigo] DNA binding GO intracellular [Amigo] intracellular
Atlas Genet Cytogenet Oncol Haematol 2008; 2 166 GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO induction of apoptosis [Amigo] induction of apoptosis GO cell cycle arrest [Amigo] cell cycle arrest GO zinc ion binding [Amigo] zinc ion binding positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter GO metal ion binding [Amigo] metal ion binding PubGene PLAGL1 Other databases Probes Probe PLAGL1 Related clones (RZPD - Berlin) PubMed PubMed 29 Pubmed reference(s) in LocusLink Bibliography Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors. Abdollahi A, Roberts D, Godwin AK, Schultz DC, Sonoda G, Testa JR, Hamilton TC. Oncogene 1997; 14(16): 1973-1979. PMID 9150364
Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells. Abdollahi A, Godwin AK, Miller PD, Getts LA, Schultz DC, Taguchi T, Testa JR, Hamilton TC. Cancer Res 1997; 57(10): 2029-2034. PMID 9158001
Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain. Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L. EMBO J 1997; 16(10): 2814-2825. PMID 9184226
Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice. Gillardon F, Hata R, Hossmann KA. Brain Res Mol Brain Res 1998; 61(1-2): 207-210. PMID 9795221
Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ. J Biol Chem 1998; 273(36): 23026-23032. PMID 9722527 hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. Varrault A, Ciani E, Apiou F, Bilanges B, Hoffmann A, Pantaloni C, Bockaert J, Spengler D, Journot L. Proc Natl Acad Sci U S A 1998; 95(15): 8835-8840. PMID 9671765
LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor receptor ligands and encodes a nuclear zinc-finger protein. Abdollahi A, Bao R, Hamilton TC. Oncogene 1999; 18(47): 6477-6487. PMID 10597250
Atlas Genet Cytogenet Oncol Haematol 2008; 2 167 Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors. Bilanges B, Varrault A, Basyuk E, Rodriguez C, Mazumdar A, Pantaloni C, Bockaert J, Theillet C, Spengler D, Journot L. Oncogene 1999; 18(27): 3979-3988. PMID 10435621
Inhibition of Zac1, a new gene differentially expressed in the anterior pituitary, increases cell proliferation. Pagotto U, Arzberger T, Ciani E, Lezoualc'h F, Pilon C, Journot L, Spengler D, Stalla GK. Endocrinology 1999; 140(2): 987-996. PMID 9927333
A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC. Arima T, Drewell RA, Oshimura M, Wake N, Surani MA. Genomics 2000; 67(3): 248-255. PMID 10936046
Mouse Zac1, a transcriptional coactivator and repressor for nuclear receptors. Huang SM, Stallcup MR. Mol Cell Biol 2000; 20(5): 1855-1867. PMID 10669760
The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes. Kamiya M, Judson H, Okazaki Y, Kusakabe M, Muramatsu M, Takada S, Takagi N, Arima T, Wake N, Kamimura K, Satomura K, Hermann R, Bonthron DT, Hayashizaki Y. Hum Mol Genet 2000; 9(3): 453-460. PMID 10655556
The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas. Pagotto U, Arzberger T, Theodoropoulou M, Grübler Y, Pantaloni C, Saeger W, Losa M, Journot L, Stalla GK, Spengler D. Cancer Res 2000; 60(24): 6794-6799. PMID 11156367
Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines. Piras G, El Kharroubi A, Kozlov S, Escalante-Alcalde D, Hernandez L, Copeland NG, Gilbert DJ, Jenkins NA, Stewart CL. Mol Cell Biol 2000; 20(9): 3308-3315. PMID 10757814
Alternative splicing of the imprinted candidate tumor suppressor gene ZAC regulates its antiproliferative and DNA binding activities. Bilanges B, Varrault A, Mazumdar A, Pantaloni C, Hoffmann A, Bockaert J, Spengler D, Journot L. Oncogene 2001; 20(10): 1246-1253. PMID 11313869
Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1. Huang SM, Schonthal AH, Stallcup MR. Oncogene 2001; 20(17): 2134-2143. PMID 11360197
Expression pattern of Zac1 mouse gene, a new zinc-finger protein that regulates apoptosis and cellular cycle arrest, in both adult brain and along development. Valente T, Auladell C.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 168 Mech Dev 2001; 108(1-2): 207-211. PMID 11578877
Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus. Varrault A, Bilanges B, Mackay DJ, Basyuk E, Ahr B, Fernandez C, Robinson DO, Bockaert J, Journot L. J Biol Chem 2001; 276(22): 18653-18656. PMID 11297535
The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities. Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML. Cancer Res 2002; 62(5): 1510-1517. PMID 11888928
Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus. Mackay DJ, Coupe AM, Shield JP, Storr JN, Temple IK, Robinson DO. Hum Genet 2002; 110(2): 139-144. PMID 11935319
The mouse Zac1 locus: basis for imprinting and comparison with human ZAC. Smith RJ, Arnaud P, Konfortova G, Dean WL, Beechey CV, Kelsey G. Gene 2002; 292(1-2): 101-112. PMID 12119104
LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer. Abdollahi A, Pisarcik D, Roberts D, Weinstein J, Cairns P, Hamilton TC. J Biol Chem 2003; 278(8): 6041-6049. PMID 12473647
Developmental expression of the cell cycle and apoptosis controlling gene, Lot1, in the rat cerebellum and in cultures of cerebellar granule cells. Ciani E, Frenquelli M, Contestabile A. Brain Res Dev Brain Res 2003; 142(2): 193-202. PMID 12711370
Transcriptional activities of the zinc finger protein Zac are differentially controlled by DNA binding. Hoffmann A, Ciani E, Boeckardt J, Holsboer F, Journot L, Spengler D. Mol Cell Biol 2003; 23(3): 988-1003. PMID 12529403
Altered expression and loss of heterozygosity of the LOT1 gene in ovarian cancer. Cvetkovic D, Pisarcik D, Lee C, Hamilton TC, Abdollahi A. Gynecol Oncol 2004; 95(3): 449-455. PMID 15581945
Loss of expression of ZAC/LOT1 in squamous cell carcinomas of head and neck. Koy S, Hauses M, Appelt H, Friedrich K, Schackert HK, Eckelt U. Head Neck 2004; 26(4): 338-344. PMID 15054737
Zac1 is up-regulated in neural cells of the limbic system of mouse brain following seizures that provoke strong cell activation. Valente T, Dominguez MI, Bellmann A, Journot L, Ferrer I, Auladell C. Neuroscience 2004; 128(2): 323-336. PMID 15350644
Atlas Genet Cytogenet Oncol Haematol 2008; 2 169
ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome. Arima T, Kamikihara T, Hayashida T, Kato K, Inoue T, Shirayoshi Y, Oshimura M, Soejima H, Mukai T, Wake N. Nucleic Acids Res 2005; 33(8): 2650-2660. PMID 15888726
The candidate tumor suppressor gene ZAC is involved in keratinocyte differentiation and its expression is lost in basal cell carcinomas. Basyuk E, Coulon V, Le Digarcher A, Coisy-Quivy M, Moles JP, Gandarillas A, Journot L. Mol Cancer Res 2005; 3(9): 483-492. PMID 16179495
Cyclic AMP-mediated regulation of transcription factor Lot1 expression in cerebellar granule cells. Contestabile A, Fila T, Bartesaghi R, Ciani E. J Biol Chem 2005; 280(39): 33541-33551. PMID 16061485
Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer. Kamikihara T, Arima T, Kato K, Matsuda T, Kato H, Douchi T, Nagata Y, Nakao M, Wake N. Int J Cancer 2005; 115(5): 690-700. PMID 15751035
The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors. Poulin H, Labelle Y. Cancer Lett 2005; 227(2): 185-191. PMID 16112421
Zac1 is expressed in progenitor/stem cells of the neuroectoderm and mesoderm during embryogenesis: differential phenotype of the Zac1-expressing cells during development. Valente T, Junyent F, Auladell C. Dev Dyn 2005; 233(2): 667-679. PMID 15844099
The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice. Arima T, Yamasaki K, John RM, Kato K, Sakumi K, Nakabeppu Y, Wake N, Kono T. Genomics 2006; 88(5): 650-658. PMID 16928428
Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region during oogenesis. Arima T, Wake N. Cytogenet Genome Res 2006; 113(1-4): 247-252. PMID 16575187
Peroxisome proliferator-activated receptor gamma is a Zac target gene mediating Zac antiproliferation. Barz T, Hoffmann A, Panhuysen M, Spengler D. Cancer Res 2006; 66(24): 11975-11982. PMID 17178896
Multitasking C2H2 zinc fingers link Zac DNA binding to coordinated regulation of p300-histone acetyltransferase activity. Hoffmann A, Barz T, Spengler D. Mol Cell Biol 2006; 26(14): 5544-5557. PMID 16809786
Atlas Genet Cytogenet Oncol Haematol 2008; 2 170
Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C, Severac D, Chotard L, Kahli M, Le Digarcher A, Pavlidis P, Journot L. Dev Cell 2006; 11(5): 711-722. PMID 17084362
LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions. Abdollahi A. J Cell Physiol 2007; 210(1): 16-25. Review. PMID 17063461
Zac1 functions through TGFbetaII to negatively regulate cell number in the developing retina. Ma L, Cantrup R, Varrault A, Colak D, Klenin N, Gotz M, McFarlane S, Journot L, Schuurmans C. Neural Develop 2007; 2: 11. PMID 17559664
Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. Valleley EM, Cordery SF, Bonthron DT. Hum Mol Genet 2007; 16(8): 972-981. PMID 17341487
Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators. Wu MH, Huang CJ, Liu ST, Liu PY, Ho CL, Huang SM. Biochem Biophys Res Commun 2007; 356(3): 523-528. PMID 17376404
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Contributor(s) Written 08-2007 Abbas Abdollahi Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, BioLife Sciences Building, Suite 446, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA Citation This paper should be referenced as such : Abdollahi A . PLAGL1 (Pleomorphic adenoma gene-like 1). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PLAGL1ID41737ch6q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 171 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PDCD4 (Programmed Cell Death 4)
Identity Other names TIS H731 DUG MA3 Hugo PDCD4 Location 10q24 DNA/RNA Description Single gene of 11 exons spanning 21 Kbp. Transcription 2.4 Kb mRNA; PDCD4 mRNA levels modulated by apoptosis inducers, retinoids, and other extracellular signals. Pseudogene None. Protein
Description 469 amino acids; 52 kDa predicted; found to be 50-64 kDa in mouse and human tissues and cell lines; contains two highly conserved helical MA3 domains each about 130 amino acids long; contains two Akt/S6K phosphorylation sites, one N-terminal and one C-terminal; contains two nuclear export signals. Expression PDCD4 expressed in all tissues tested. Shows inverse expression with proliferation marker PCNA, higher expression in differentiated areas. Protein expression is regulated by PI3K/Akt/S6K and MEK/ERK signaling that programs PDCD4 for ubiquitylation and proteasome degradation. Localisation Nuclear and cytoplasmic. Inhibits translation in cytoplasm. Function PDCD4 inhibits translation initiation mRNA-specifically by interacting with translation initiation factor eIF4A and competing with eIF4Gc for binding to eIF4A. As a consequence of inhibiting translation initiation, inhibits AP-1 dependent transcription via targeting Jun kinase signaling. Found to be a tumor suppressor in PDCD4 transgenic and deficient mice. Homology Conserved MA3 domain also found in translation initiation factor eIF4G, a scaffold protein; death associated protein DAP5; and NOM 1, a nucleolar protein. Mutations Note No evidence for mutational inactivation in cancer. Implicated in Entity Human tumors Disease PDCD4 expression attenuated with progression in human tumors of the lung, colon, prostate and breast; diagnostic and prognostic for colon cancer staging with decreased expression in adenomas and a further decrease in stage 1 adenocarcinomas. Transgenic PDCD4 expression attenuates skin tumorigenesis and tumor progression in transgenic mice; PDCD4 deficiency increases tumor multiplicity and tumor incidence. External links Nomenclature Hugo PDCD4 GDB PDCD4 Entrez_Gene PDCD4 27250 programmed cell death 4 (neoplastic transformation inhibitor) Cards Atlas PDCD4ID41675ch10q24
Atlas Genet Cytogenet Oncol Haematol 2008; 2 172 GeneCards PDCD4 Ensembl PDCD4 [Search_View] ENSG00000150593 [Gene_View] Genatlas PDCD4 GeneLynx PDCD4 eGenome PDCD4 euGene 27250 Genomic and cartography GoldenPath PDCD4 - 10q24 chr10:112621586-112649753 + 10q24 (hg18-Mar_2006) Ensembl PDCD4 - 10q24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PDCD4 Gene and transcription Genbank AK223623 [ ENTREZ ] Genbank AL049932 [ ENTREZ ] Genbank BC015036 [ ENTREZ ] Genbank BC026104 [ ENTREZ ] Genbank BC031049 [ ENTREZ ] RefSeq NM_014456 [ SRS ] NM_014456 [ ENTREZ ] RefSeq NM_145341 [ SRS ] NM_145341 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_030059 [ SRS ] NT_030059 [ ENTREZ ] RefSeq NW_924884 [ SRS ] NW_924884 [ ENTREZ ] AceView PDCD4 AceView - NCBI Unigene Hs.232543 [ SRS ] Hs.232543 [ NCBI ] HS232543 [ spliceNest ] Fast-db 16753 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q53EL6 [ SRS] Q53EL6 [ EXPASY ] Q53EL6 [ INTERPRO ] Interpro IPR003891 IF_eIF4G_MA3 [ SRS ] IPR003891 IF_eIF4G_MA3 [ EBI ] CluSTr Q53EL6 Pfam PF02847 MA3 [ SRS ] PF02847 MA3 [ Sanger ] pfam02847 [ NCBI-CDD ] Smart SM00544 MA3 [EMBL] Blocks Q53EL6 PDB 2GGF [ SRS ] 2GGF [ PdbSum ], 2GGF [ IMB ] 2GGF [ RSDB ] HPRD 10549 Protein Interaction databases DIP Q53EL6 IntAct Q53EL6 Polymorphism : SNP, mutations, diseases OMIM 608610 [ map ] GENECLINICS 608610 SNP PDCD4 [dbSNP-NCBI] SNP NM_014456 [SNP-NCI] SNP NM_145341 [SNP-NCI] SNP PDCD4 [GeneSNPs - Utah] PDCD4] [HGBASE - SRS] HAPMAP PDCD4 [HAPMAP] COSMIC PDCD4 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PDCD4 General knowledge Family Browser PDCD4 [UCSC Family Browser] SOURCE NM_014456 SOURCE NM_145341
Atlas Genet Cytogenet Oncol Haematol 2008; 2 173 SMD Hs.232543 SAGE Hs.232543 GO RNA binding [Amigo] RNA binding GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO cytosol [Amigo] cytosol GO apoptosis [Amigo] apoptosis GO cell cycle [Amigo] cell cycle GO cell aging [Amigo] cell aging GO negative regulation of transcription [Amigo] negative regulation of transcription GO negative regulation of transcription [Amigo] negative regulation of transcription GO negative regulation of JNK activity [Amigo] negative regulation of JNK activity GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle PubGene PDCD4 Other databases Probes Probe PDCD4 Related clones (RZPD - Berlin) PubMed PubMed 26 Pubmed reference(s) in LocusLink Bibliography Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P, Perussia B. J Immunol 1998; 161(7): 3493-3500. PMID 9759869
Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S, Colburn NH. Proc Natl Acad Sci U S A 1999; 96(24): 14037-14042. PMID 10570194
The chicken Pdcd4 gene is regulated by v-Myb. Schlichter U, Burk O, Worpenberg S, Klempnauer KH. Oncogene 2001; 20(2): 231-239. PMID 11313950
A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, Colburn NH. Oncogene 2001; 20(6): 669-676. PMID 11314000
Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Zhang Z, DuBois RN. Oncogene 2001; 20(33): 4450-4456. PMID 11494140
Targeted disruption of c-myb in the chicken pre B-cell line DT40. Appl H, Klempnauer KH. Oncogene 2002; 21(19): 3076-3081. PMID 12082539
The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 174 Bohm M, Sawicka K, Siebrasse JP, Brehmer-Fastnacht A, Peters R, Klempnauer KH. Oncogene 2003; 22(31): 4905-4910. PMID 12894233
Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. Chen Y, Knosel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, Ozaki I, Petersen I. J Pathol 2003; 200(5): 640-646. PMID 12898601
The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, Lockett SJ, Sonenberg N, Colburn NH. Mol Cell Biol 2003; 23(1): 26-37. PMID 12482958
Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Yang HS, Knies JL, Stark C, Colburn NH. Oncogene 2003; 22(24): 3712-3720. PMID 12802278
Promising molecular targets for cancer prevention: AP-1, NF-kappa B and Pdcd4. Young MR, Yang HS, Colburn NH. Trends Mol Med 2003; 9(1): 36-41. Review. PMID 12524209
Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. Jansen AP, Camalier CE, Stark C, Colburn NH. Mol Cancer Ther 2004; 3(2): 103-110. PMID 14985450
A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N, Colburn NH. Mol Cell Biol 2004; 24(9): 3894-3906. PMID 15082783
Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Jansen AP, Camalier CE, Colburn NH. Cancer Res 2005; 65(14): 6034-6041. PMID 16024603
Akt phosphorylates and regulates Pdcd4 tumor suppressor protein. Palamarchuk A, Efanov A, Maximov V, Aqeilan RI, Croce CM, Pekarsky Y. Cancer Res 2005; 65(24): 11282-11286. PMID 16357133
S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. Science 2006; 314(5798): 467-471. PMID 17053147
Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, Goke R, Chen YH. J Immunol 2006; 177(11): 8095-8102.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 175 PMID 17114484
Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice. Jin H, Kim TH, Hwang SK, Chang SH, Kim HW, Anderson HK, Lee HW, Lee KH, Colburn NH, Yang HS, Cho MH, Cho CS. Mol Cancer Ther 2006; 5(4): 1041-1049. PMID 16648576
Signal transduction. Protein synthesis and oncogenesis meet again. Sonenberg N, Pause A. Science 2006; 314(5798): 428-429. PMID 17053135
Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC, Tan TH, Colburn NH. Mol Cell Biol 2006; 26(4): 1297-1306. PMID 16449643
Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, Ideguchi H, Yamamoto K, Matsuhashi S. Oncogene 2006; 25(45): 6101-6112. PMID 16682950
Structural basis for inhibition of translation by the tumor suppressor Pdcd4. LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH. Mol Cell Biol 2007; 27(1): 147-156. PMID 17060447
Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u- PAR) gene expression via Sp-transcription factors. Leupold JH, Yang HS, Colburn NH, Asangani I, Post S, Allgayer H. Oncogene 2007; 26(31): 4550-4562. PMID 17297470
Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. Ozpolat B, Akar U, Steiner M, Zorrilla-Calancha I, Tirado-Gomez M, Colburn N, Danilenko M, Kornblau S, Berestein GL. Mol Cancer Res 2007; 5(1): 95-108. PMID 17259349
Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterization of its interaction with eIF4A. Waters LC, Veverka V, Bohm M, Schmedt T, Choong PT, Muskett FW, Klempnauer KH, Carr MD. Oncogene 2007; 26(34): 4941-4950. PMID 17310995
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Contributor(s) Written 08-2007 Nancy H Colburn Laboratory of Cancer Prevention, National Cancer Institute, Bldg. 576, Rm.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 176 101, Frederick, MD 21702-1201, USA Citation This paper should be referenced as such : Colburn NH . PDCD4 (Programmed Cell Death 4). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PDCD4ID41675ch10q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 177 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PAWR (PRKC apoptosis WT1 regulator protein)
Identity Other names Par-4 (Prostate apoptosis gene 4) PAR4 Hugo PAWR Location 12q21.2 Synaptotagmin I 12q21.2 on plus strand protein phosphatase 1, regulatory (inhibitor) Local_order subunit 12A 12q21.2 on minus strand PAWR 12q21.2 on minus strand protein tyrosine phosphatase, receptor type, Q 12q21.2 on plus strand DNA/RNA Description Genomic regions: Par-4/PAWR gene is encoded by the minus strand of chromosome 12q21.2. The gene encompasses 99.064 kb of DNA; 7 exons and 6 introns. ATG is located on exon 2. Transcription 2.2 kb nucleotides mRNA. 1.02 kb open reading frame. Pseudogene Not known Protein Description Human Par-4/PAWR is a about 40 kDa protein containing 340 amino acids. Rat Par-4 has 332 amino acids whereas mouse Par-4 has 333 amino acids. Par-4/PAWR has two putative nuclear localization sequences in the N-terminal region and a leucine zipper domain and a nuclear export sequence in the C-terminal portion. There is a SAC domain (147-206 amino acids), selective for apoptosis induction in cancer cells. SAC domain is the effecter domain of Par-4/PAWR. These domains are 100% conserved in human, rat and mouse homologs. Expression Par-4/PAWR is ubiquitously expressed in normal mammalian tissues. However, Par-4/ PAWR is diminished in a majority (>75% specimens) of renal cell carcinoma specimens. Par-4/PAWR expression is also decreased in endometrial tumors, neuroblastoma and in cells of patients with acute lymphatic leukemia and chronic lymphocytic leukemia. Localisation Immonocytochemical analysis indicates that Par-4/PAWR is predominantly localized in cytoplasm in normal cells and is strongly localized in cytoplasm and nucleus in most cancer cell lines. However, Western blot analysis indicates that Par-4/PAWR is also in the nuclear fraction of normal cells implying it is masked in the nucleus. Function Par-4/PAWR, a pro-apoptotic protein, was first identified in prostate cancer cells that were induced to undergo apoptosis. Par-4 knockout mice spontaneously develop tumors of the liver, lung, and endometrium; prostatic intraepithelial neoplasia, and an increased frequency of estrogen-inducible tumors in the endometrium and BBN- inducible tumors in the bladder. Endogenous Par-4/PAWR expressed in normal and cancer cells does not, by itself, causes apoptosis, yet is essential for apoptosis via diverse cell death pathways. Par-4/PAWR sensitizes cells to apoptosis by wide variety of pro-apoptotic stimuli, such as growth factor withdrawal, agents that elevate intracellular Ca2+, TNF, TRAIL, UV, X-ray and gamma irradiation, or IFN-gamma. Ectopic Par-4/PAWR over-expression is by itself sufficient to induce apoptosis in most cancer cells, but not in normal or immortalized cells. The cancer selective pro-apoptotic function of Par-4/PAWR is localized in its central core SAC (Selective for Apoptosis- induction in Cancer cells) domain (amino acids 147-206 in human Par-4/PAWR; or 137-195 in rat Par-4) which is 100% conserved in human, mouse and rat. Apoptosis by ectopic Par-4/PAWR requires Par-4/PAWR nuclear translocation and involves both activation of the Fas death receptor signaling pathway and NF-kappaB inhibition. Par-4/PAWR also inhibits the prosurvival protein Bcl-2 and down regulates ERK-2 expression. Neither p53 nor PTEN are directly required for apoptosis by Par-4/PAWR or the SAC domain. Par-4/PAWR has been shown to be i nvolved in suppression of transformation by down-regulation of Ras. Overexpression of Par-4/PAWR results in
Atlas Genet Cytogenet Oncol Haematol 2008; 2 178 apoptosis of cells expressing oncogenic Ras. Several partner proteins of Par-4/PAWR have been identified and partner interaction requires an intact Par-4/PAWR leucine zipper domain. Par-4/PAWR associates with aPKC resulting in inhibition of NF-kappaB activity, interaction with WT1 results in transcriptional repression of Bcl-2, whereas binding to and phosphorylation by Akt1 results in Par-4/PAWR cytoplasm retention by 14-3-3, thus isolating Par-4/PAWR from its nuclear targets. Par-4/PAWR also binds to DLK/ZIP kinase (ZIPK) and induces DAAX/ZIPK-mediated apoptosis. In addition, THAP1 (a novel nuclear pro-apoptotic factor) interacts with Par-4/PAWR and potentiates both serum withdrawal and TNF- induced apoptosis in endothelial cells. Par-4/PAWR is also involved in sensitization of neurons to apoptosis. Endogenous Par-4/PAWR is reported to be up-regulated in different neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's diseases and amyotrophic lateral sclerosis. Post-translational modifications: The apoptosis of Par-4/PAWR requires phosphorylation of the threonine residue (T155 in rat Par-4/PAWR) in the SAC domain by PKA, which is elevated in cancer cells. Amino acid S249 in rat Par-4/PAWR is phosphorylated by AKT for Par-4/PAWR cytoplasm retention and inactivation. Homology The Par-4/PAWR gene has been identified in various organisms, including mammals (Pan Troglodytes), rodents (mouse, rat), chicken (Gallus gallus), fish(Zebrafish and Pufferfish) and tadpole. The nuclear localization, leucine zipper, nuclear export and SAC domain sequences are highly conserved. Mutations Note Par-4/PAWR mutations are uncommon although a single base mutation (Arg (CGA) 189 (TGA) Stop) localized in exon 3 or the SAC domain has been found in endometrial carcinoma. Implicated in Entity renal cell carcinoma, and endometrial tumors Note Par-4/PAWR is down regulated in over 75% of clear cell type of renal cell carcinoma, and in endometrial tumors. It is mutated within its effector SAC domain in endometrial tumors. External links Nomenclature Hugo PAWR GDB PAWR Entrez_Gene PAWR 5074 PRKC, apoptosis, WT1, regulator Cards Atlas PAWRID41641ch12q21 GeneCards PAWR Ensembl PAWR [Search_View] ENSG00000177425 [Gene_View] Genatlas PAWR GeneLynx PAWR eGenome PAWR euGene 5074 Genomic and cartography GoldenPath PAWR - 12q21.2 chr12:78509878-78608921 - 12q21 (hg18-Mar_2006) Ensembl PAWR - 12q21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PAWR Gene and transcription Genbank BC007018 [ ENTREZ ] Genbank CA313080 [ ENTREZ ] Genbank CN280333 [ ENTREZ ] Genbank CR536549 [ ENTREZ ] Genbank U63809 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 179 RefSeq NM_002583 [ SRS ] NM_002583 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_019546 [ SRS ] NT_019546 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView PAWR AceView - NCBI Unigene Hs.643130 [ SRS ] Hs.643130 [ NCBI ] HS643130 [ spliceNest ] Fast-db 10974 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q96IZ0 [ SRS] Q96IZ0 [ EXPASY ] Q96IZ0 [ INTERPRO ] CluSTr Q96IZ0 Blocks Q96IZ0 HPRD 09051 Protein Interaction databases DIP Q96IZ0 IntAct Q96IZ0 Polymorphism : SNP, mutations, diseases OMIM 601936 [ map ] GENECLINICS 601936 SNP PAWR [dbSNP-NCBI] SNP NM_002583 [SNP-NCI] SNP PAWR [GeneSNPs - Utah] PAWR] [HGBASE - SRS] HAPMAP PAWR [HAPMAP] HGMD PAWR General knowledge Family Browser PAWR [UCSC Family Browser] SOURCE NM_002583 SMD Hs.643130 SAGE Hs.643130 negative regulation of transcription from RNA polymerase II promoter GO [Amigo] negative regulation of transcription from RNA polymerase II promoter
GO transcription corepressor activity [Amigo] transcription corepressor activity GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO apoptosis [Amigo] apoptosis GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO enzyme binding [Amigo] enzyme binding GO positive regulation of apoptosis [Amigo] positive regulation of apoptosis PubGene PAWR Other databases Probes Probe PAWR Related clones (RZPD - Berlin) PubMed PubMed 38 Pubmed reference(s) in LocusLink Bibliography Apoptosis in androgen-dependent and -independent prostate cells. Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, Crist SA, Humphreys S, Rangnekar VM. Cell Growth Differ 1994; 5: 457-466. PMID 8043520
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The product of Par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Diaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J. Cell 1996; 86: 777-786. PMID 8797824
A novel repressor, Par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y. Mol Cell Biol 1996; 16(12): 6945-6956. PMID 8943350
Expression and function of the leucine zipper protein Par-4 in apoptosis. Sells SF, Han SS, Muthukkumar S, Maddiwar N, Johnstone R, Boghaert E, Gillis D, Liu G, Nair P, Monnig S, Collini P, Mattson MP, Sukhatme VP, Zimmer SG, Wood DP Jr, McRoberts JW, Shi Y, Rangnekar VM. Mol Cell Biol 1997; 17: 3823-3832. PMID 9199316
Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP. Nat Med 1998; 4: 957-996 PMID 9701251
Mapping of the human PAWR (Par-4) gene to chromosome 12q21. Johnstone RW, Tommerup N, Hansen C, Vissing H, Shi Y. Genomics 1998; 53(2): 241-243. PMID 9790775
Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis. Diaz-Meco MT, Lallena MJ, Monjas A, Frutos S, Moscat J. Bio l Chem 1999; 274(28): 19606-19612. PMID 10391896
Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: Evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration. Duan W, Rangnekar VM, Mattson MP. J Neurochem 1999; 72: 2312-232 PMID 10349840
Oncogenic Ras sensitizes cells to apoptosis by Par-4. Nalca A, Qiu SG, El-Guendy N, Krishnan S, Rangnekar VM. J Biol Chem 1999; 274(42): 29976-29983. PMID 10514481
Participation of Par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. Duan W, Guo Z, Mattson MP. Exp Neurol 2000; 165: 1-11. PMID 10964480
The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis. Pedersen WA, Luo H, Kruman I, Kasarskis E, Mattson MP. FASEB J 2000; 14: 913-924.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 181 PMID 10783145
Par-4 drives trafficking and activation of Fas and FasL to induce prostate cancer cell apoptosis and tumor Regression. Chakraborty M, Qiu SG, Vasudevan KM, Rangnekar VM. Cancer Research 2001; 61: 7255-7263. PMID 11585763
Regulation of apoptosis in prostate cancer. Gurumurthy S, Vasudevan KM, Rangnekar VM. Cancer Metastasis Rev. 2001; 20(3-4): 225-243. PMID 12085964
Apoptosis by Par-4 in cancer and neurodegenerative diseases. El-Guendy N, Rangnekar VM. Exp Cell Res 2003; 283: 51-66. (Review) PMID 12565819
Identification of a unique core domain of Par-4 sufficient for selective apoptosis-induction in cancer cells. El-Guendy N, Zhao Y, Gurumurthy S, Burikhanov R, Rangnekar VM. Mol Cell Biol 2003; 23: 5516-5525. PMID 12897127
ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Kawai T, Akira S, Reed JC. Mol Cell Biol 2003; 23(17): 6174-6186 PMID 12917339
Regulation of mature T lymphocyte proliferation and differentiation by Par-4. Lafuente MJ, Martin P, Garcia-Cao I, Diaz-Meco MT, Serrano M, Moscat J. EMBO J 2003; 22(18): 4689-4698 PMID 12970181
Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival. Goswami A, Burikhanov R, de Thonel A, Fujita N, Goswami M, Zhao Y, Eriksson JE, Tsuruo T, Rangnekar VM. Mol. Cell 2005; 20(1): 33-44. PMID 16209943
Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM. Mol Cell Biol 2005; 25: 1146-1161. PMID 15657440
Inactivation of the candidate tumor suppressor Par-4 in endometrial cancer. Moreno-Bueno G, Fernandez-Marcos PJ, Collado M, Tendero MJ, Rodriguez-Pinilla SM, Garcia-Cao I, Hardisson D, Diaz-Meco MT, Moscat J, Serrano M, Palacios J. Cancer Res 2007; 67(5): 1927-1934. PMID 17332319
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Contributor(s) Written 08-2007 Yanming Zhao, Vivek Rangnekar Markey Cancer Center University of Kentucky Combs Research Building,
Atlas Genet Cytogenet Oncol Haematol 2008; 2 182 Room 309 800 Rose Street Lexington, KY 40536, USA Citation This paper should be referenced as such : Zhao Y, Rangnekar V . PAWR (PRKC apoptosis WT1 regulator protein). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PAWRID41641ch12q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 183 Atlas of Genetics and Cytogenetics in Oncology and Haematology
NOTCH3 (Notch homolog 3 (Drosophila))
Identity Other names CADASIL CASIL Hugo NOTCH3 Location 19p13.12 Local_order Gene orientation: telomere-3¹ NOTCH3 5¹-centromere. DNA/RNA Description The Notch3 gene is encoded by 33 exons spanning 41.35 kb that are located on Chromosome 19p13.12. Transcription 8.089 Kb mRNA, the coding sequence is from 77 bp-7042 bp. Protein Note 2321 amino acids with a predicted molecular mass of 243.66 Kd. Single-pass type I membrane protein. Contain 1 signal peptide, 36 extracellular EGF repeats, 1 single transmembrane domain, and 2 PEST domains. Synthesized in the endoplasmic reticulum as an inactive form, which is cleaved by a furin-like convertase in the trans-Golgi complex before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a transmembrane Notch subunit (NTM) and an extracellular Notch subunit (ECN). Description Notch3 is a cell surface receptor for membrane-bound ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4. It is activated by ligand-receptor interaction, which triggers two successive proteolytic cleavages that release the active intracellular domain of Notch (NICD). The NICD translocates to the nucleus, where it interacts with CSL (CBF1/RBP-J kappa, Suppressor of Hairless, LAG-1). Binding of NICD to CSL displaces corepressor complexes and recruits coactivators, leading to transcription from promoters containing CSL-binding elements. The Notch3 target genes participate in wide spectrum of biological processes such as differentiation, proliferation and apoptosis. Expression Expressed in certain types of fetal and adult tissues. Localisation Mainly located at cell membrane. Following proteolytic events upon ligand binding, its intracellular domain is translocated into the nuclei. Function Notch3 is a membrane receptor that mediates cell-cell interactions to facilitate cell differentiation, growth and cell death. Mutations Germinal Mutation in NOTCH3 is associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is an adult-onset disorder characterized by recurrent ischemic strokes, dementia, and premature death. It affects predominantly the small cerebral arteries, leads to progressive degeneration of vasculature smooth-muscle cells. Disease-associated mutations are distributed throughout the epidermal growth factor- like repeats (EGFRs) that compose the extracellular domain of the Notch3 receptor and result in a loss or a gain of a cysteine residue in one of these EGFRs. Mutation hotspots were located at the two exons encoding the first five EGFRs. The findings suggested that aberrant dimerization of NOTCH3, due to abnormal disulfide bridging with NOTCH3 molecule or another protein, may be involved in the pathogenesis of CADASIL. Somatic Somatic sequence mutations, gene translocation and amplification of chromosomal locus involved Notch3 gene were identified in T-cell lymphoma, non-small-cell lung cancer and ovarian cancer, respectively. Implicated in Entity Non-small-cell lung cancer
Atlas Genet Cytogenet Oncol Haematol 2008; 2 184 Cytogenetics t(15;19)(q11;p13) Hybrid/Mutated A breakpoint was localized to the cosmid R31546. The breakpoint was found about 50 Gene kilobases (kb) upstream of the Notch3 and within the 3' untranslated region of a putative gene, Hunk1, on 19p. Translocation of chromosome 19p was also found in several other chromosomes, including chromosomes 12q, 14q, 17q, 4q, and 6q. Overexpression of Notch3 full-length mRNA is associated with a 19p translocation. Oncogenesis The translocation is associated with Notch3 over-expression. Transgenic mouse study by constitutive expression of intracellular domain of Notch3 in lung epithelium using surfactant protein C promoter/enhancer resulted in inhibited differentiation of epithelial lung cell, altered lung morphology, and perinatal lethality in the transgenic mice. Entity Ovarian cancer-serous type Cytogenetics Chromosome 19p13.12 amplification harboring the Notch3 gene is frequently identified in ovarian cancer. Oncogenesis In vitro study demonstrated that cell lines with Notch3 over-expression are more sensitive to the anti-proliferative effect of Notch3 signaling pathway inhibitors including gamma-secretase inhibitor and Notch3-specific siRNA. External links Nomenclature Hugo NOTCH3 GDB NOTCH3 Entrez_Gene NOTCH3 4854 Notch homolog 3 (Drosophila) Cards Atlas NOTCH3ID41557ch19p13 GeneCards NOTCH3 Ensembl NOTCH3 [Search_View] ENSG00000074181 [Gene_View] Genatlas NOTCH3 GeneLynx NOTCH3 eGenome NOTCH3 euGene 4854 Genomic and cartography NOTCH3 - 19p13.12 chr19:15131444-15172792 - 19p13.2-p13.1 (hg18- GoldenPath Mar_2006) Ensembl NOTCH3 - 19p13.2-p13.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene NOTCH3 Gene and transcription Genbank AB209447 [ ENTREZ ] Genbank CR611252 [ ENTREZ ] Genbank DQ156540 [ ENTREZ ] Genbank DQ156541 [ ENTREZ ] Genbank DQ156542 [ ENTREZ ] RefSeq NM_000435 [ SRS ] NM_000435 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView NOTCH3 AceView - NCBI Unigene Hs.8546 [ SRS ] Hs.8546 [ NCBI ] HS8546 [ spliceNest ] Fast-db 8129 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9UM47 [ SRS] Q9UM47 [ EXPASY ] Q9UM47 [ INTERPRO ] Prosite PS50297 ANK_REP_REGION [ SRS ] PS50297 ANK_REP_REGION [ Expasy ] Prosite PS50088 ANK_REPEAT [ SRS ] PS50088 ANK_REPEAT [ Expasy ] Prosite PS00010 ASX_HYDROXYL [ SRS ] PS00010 ASX_HYDROXYL [ Expasy ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 185 Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Prosite PS01187 EGF_CA [ SRS ] PS01187 EGF_CA [ Expasy ] Prosite PS50258 LNR [ SRS ] PS50258 LNR [ Expasy ] Interpro IPR002110 ANK [ SRS ] IPR002110 ANK [ EBI ] Interpro IPR000152 Asx_hydroxyl_S [ SRS ] IPR000152 Asx_hydroxyl_S [ EBI ] Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ] Interpro IPR001438 EGF_2 [ SRS ] IPR001438 EGF_2 [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR001881 EGF_Ca_bd [ SRS ] IPR001881 EGF_Ca_bd [ EBI ] Interpro IPR013091 EGF_Ca_bd_2 [ SRS ] IPR013091 EGF_Ca_bd_2 [ EBI ] Interpro IPR013111 EGF_extracell [ SRS ] IPR013111 EGF_extracell [ EBI ] Interpro IPR006209 EGF_like [ SRS ] IPR006209 EGF_like [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR008297 Notch [ SRS ] IPR008297 Notch [ EBI ] Interpro IPR010660 Notch_NOD [ SRS ] IPR010660 Notch_NOD [ EBI ] Interpro IPR011656 Notch_NODP [ SRS ] IPR011656 Notch_NODP [ EBI ] Interpro IPR000800 Notch_region [ SRS ] IPR000800 Notch_region [ EBI ] CluSTr Q9UM47 Pfam PF00023 Ank [ SRS ] PF00023 Ank [ Sanger ] pfam00023 [ NCBI-CDD ] Pfam PF00008 EGF [ SRS ] PF00008 EGF [ Sanger ] pfam00008 [ NCBI-CDD ] Pfam PF07974 EGF_2 [ SRS ] PF07974 EGF_2 [ Sanger ] pfam07974 [ NCBI-CDD ] Pfam PF07645 EGF_CA [ SRS ] PF07645 EGF_CA [ Sanger ] pfam07645 [ NCBI-CDD ] Pfam PF06816 NOD [ SRS ] PF06816 NOD [ Sanger ] pfam06816 [ NCBI-CDD ] Pfam PF07684 NODP [ SRS ] PF07684 NODP [ Sanger ] pfam07684 [ NCBI-CDD ] Pfam PF00066 Notch [ SRS ] PF00066 Notch [ Sanger ] pfam00066 [ NCBI-CDD ] Smart SM00248 ANK [EMBL] Smart SM00181 EGF [EMBL] Smart SM00179 EGF_CA [EMBL] Smart SM00004 NL [EMBL] Blocks Q9UM47 HPRD 02607 Protein Interaction databases DIP Q9UM47 IntAct Q9UM47 Polymorphism : SNP, mutations, diseases OMIM 125310;600276 [ map ] GENECLINICS 125310;600276 SNP NOTCH3 [dbSNP-NCBI] SNP NM_000435 [SNP-NCI] SNP NOTCH3 [GeneSNPs - Utah] NOTCH3] [HGBASE - SRS] HAPMAP NOTCH3 [HAPMAP] COSMIC NOTCH3 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD NOTCH3 General knowledge Family Browser NOTCH3 [UCSC Family Browser] SOURCE NM_000435 SMD Hs.8546 SAGE Hs.8546 GO receptor activity [Amigo] receptor activity GO calcium ion binding [Amigo] calcium ion binding GO protein binding [Amigo] protein binding
Atlas Genet Cytogenet Oncol Haematol 2008; 2 186 GO nucleus [Amigo] nucleus GO plasma membrane [Amigo] plasma membrane GO integral to plasma membrane [Amigo] integral to plasma membrane GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO Notch signaling pathway [Amigo] Notch signaling pathway GO multicellular organismal development [Amigo] multicellular organismal development GO anatomical structure morphogenesis [Amigo] anatomical structure morphogenesis GO integral to membrane [Amigo] integral to membrane GO cell differentiation [Amigo] cell differentiation GO forebrain development [Amigo] forebrain development negative regulation of neuron differentiation [Amigo] negative regulation of neuron GO differentiation GO neuron fate commitment [Amigo] neuron fate commitment GO regulation of developmental process [Amigo] regulation of developmental process KEGG Dorso-ventral axis formation KEGG Notch signaling pathway PubGene NOTCH3 Other databases Probes Probe NOTCH3 Related clones (RZPD - Berlin) PubMed PubMed 57 Pubmed reference(s) in LocusLink Bibliography Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP. J Natl Cancer Inst 2000; 92: 1355-1357. PMID 10944559
Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. Dang TP, Eichenberger S, Gonzalez A, Olson S, Carbone DP. Oncogene 2003; 22: 1988-1997. PMID 12673204
Notch3 gene amplification in ovarian cancer. Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL. Cancer Res 2006; 66: 6312-6318. PMID 16778208
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Contributor(s) Written 08-2007 Tian-Li Wang Departments of Gynecology/Obstetrics and Oncology Johns Hopkins Medical Institutions CRBII, Rm: 306 1550 Orleans Street Baltimore, MD 21231, USA Citation This paper should be referenced as such : Wang TL . NOTCH3 (Notch homolog 3 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. August
Atlas Genet Cytogenet Oncol Haematol 2008; 2 187 2007 . URL : http://AtlasGeneticsOncology.org/Genes/NOTCH3ID41557ch19p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 188 Atlas of Genetics and Cytogenetics in Oncology and Haematology
NOTCH1 (Notch homolog 1, translocation-associated (Drosophila))
Identity Other names TAN1 hN1 notch1 Notch1 Hugo NOTCH1 Location 9q34.3 DNA/RNA Note History and Nomenclature: The notch1 gene, previously referred to as TAN1, was first described in 1917 by American giant of genetics and embryology Thomas Hunt Morgan in a strain of the fruit fly Drosophila melanogaster with "notches" apparent in their wings. Molecular study of the notch1 gene product and sequencing was carried out in the 1980s. The following discussion will refer to the notch1 gene as "notch1" and the functional gene product (protein) as "NOTCH1". Description Notch1 encompasses 51,418 bp of DNA on chromosome 9 (9q34.3) between 138,508,717 and 138,508,135 bp from pter. Transcription The notch1 RNA transcript contains 34 exons and is 9,371 bp in length. Protein Description The notch1 gene product NOTCH1 (2,556 amino acids; 272,500 Da) consists of a large extracellular unit which associates in a calcium-dependent, non-covalent interaction with a second unit consisting of the following: a small extracellular region, a single transmembrane spanning region, and a small intracellular region. The NOTCH1 extracellular domain is composed primarily of 36 small cysteine knot motifs called EGF-like repeats. Each EGF-like repeat is approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. This feature is critical in ligand binding. The extracellular domain also contains three cysteine-rich Notch/Lin12 (LN) repeats required for the blockage of signaling in the absence of ligand. The NOTCH1 intracellular domain (NICD) contains a RAM23 domain, six ankyrin/cdc10 repeats involved in protein-protein interactions, two nuclear localization signals (N1 and N2), a transcriptional activation domain (TAD), and a PEST (proline-, glutamic acid-, serine-, and threonine- rich) sequence that negatively regulates protein stability. NOTCH1 undergoes an initial proteolytic cleavage by furin (PACE1) in the Golgi during trafficking to the cell surface. NOTCH1 is subject to several important post-translational modifications. An O-glucose sugar may be added between the first and second conserved cysteine, and an O- fucose may be added between the second and third conserved cysteine. These sugars are added by an as yet unidentified O-glucosyltransferase, and GDP-fucose protein O- fucosyltransferase 1 (POFUT1) respectively. The addition of O-fucose by POFUT1 is crucial for NOTCH1 function, and without its addition NOTCH1 proteins fail to function properly. As yet, the manner in which the glycosylation of NOTCH1 affects function is not completely understood. The O-glucose on NOTCH1 can be further elongated to a trisaccharide with the addition of two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a galactosyltransferase, and the addition of a sialic acid by a sialyltransferase. The NOTCH1 ligands are single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila there are two involved ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like
Atlas Genet Cytogenet Oncol Haematol 2008; 2 189 and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as probably a variety of other ligands, such as F3/contactin. Localisation NOTCH1: Cell membrane. Single pass type I membrane protein. NICD: Internal surface of cell membrane translocating to the nucleus upon ligand binding. Function The NOTCH1 cell signaling mechanism is conserved in most multicellular organisms including all metazoans (and thus vertebrates). NOTCH1 functions as a receptor for membrane-bound ligands Jagged1, Jagged2, and Delta1 in regulation of cell-fate determination. Once the NOTCH1 extracellular domain interacts with a ligand, an ADAM-family metalloprotease called TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the NOTCH1 protein just outside the membrane. Consequently, the extracellular portion of NOTCH1 is released and continues to interact with the ligand. The ligand plus the NOTCH1 extracellular domain is then endocytosed by the ligand- expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis, however currently these effects are not well understood. Upon ligand activation and cleavage via gamma secretase, the released notch intracellular domain (NICD) forms a transcriptional activator complex via its RAM23 domain with the transcription factor CSL (CBF1 in humans, RBP-JK in mice, Suppressor of Hairless in Drosophila, LAG in Caenorhabditis elegans). In the absence of NOTCH1, CSL proteins bind to promoters of target genes and recruit histone deacetylases and corepressors (CoR) that inhibit transcription of these genes. Among known corepressor molecules are SMRT/NcoR and SHARP/MINT/SPEN. The NICD/CSL interaction converts CSL from a transcriptional repressor into a transcriptional activator (CBF1 binding complex in humans) by displacing the corepressor complex and recruiting coactivators such as Mastermind-Like 1 (MAM) and histone acetyltransferase. Several other proteins are known to affect NOTCH1 signaling, including the RING-domain E3 ubiquitin ligase deltex and the phosphotyrosine binding domain (PTB)-containing proteins numb and numblike, which act as context-dependent negative or positive Notch1 regulators. In mammals there are three Fringe N-acetylglucosamine (GlcNAc)-transferase enzymes named Lunatic Fringe, Manic Fringe, and Radical Fringe, which are responsible for something called the "Fringe Effect" on NOTCH1 signaling. If Fringe adds a GlcNAc to the O-fucose sugar, then addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, NOTCH1 signals strongly when it interacts with the Delta ligand, but is inhibited when interacting with the Jagged ligand. The means by which this addition of sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood. Known target genes of NOTCH1 signaling include: members of the basic helix-loop- helix (bHLH) hairy/enhancer of split (Hes) family, the related HRT/Herp (Hes-related repressor protein) transcription factor family, the cell cycle regulator p21, the Notch pathway element Notch-regulated ankyrin repeat protein (Nrarp), deltex1, and the pre- T cell receptor-alpha gene. The NOTCH1 signaling pathway is important for cell-cell communication, involving gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. NOTCH1 signaling is known to play a role in the following processes: Neuronal function and development: Via lateral inhibition, NOTCH1 in the embryo generates molecular differences between adjacent cells. In the central nervous system, NOTCH1 activity maintains the neural progenitor state and inhibits differentiation. During gliogenesis, NOTCH1 has an instructive role, directly promoting the differentiation of different glial subtypes. More detailed analyses have also revealed that Notch regulates progenitor pool diversification and neuronal maturation. New data suggests that NOTCH1 activity has a role in neuronal function of the adult brain. Modulating arterial endothelial fate and angiogenesis: Expression of NOTCH1 and its ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the NOTCH1 pathway suggest a critical role for NOTCH1 signaling in vasculogenesis and angiogenesis. Vascular endothelial growth factor (VEGF) can induce gene expression of NOTCH1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 (FLT1/VEGFR1 and KDR/VEGFR2) and is transmitted via the
Atlas Genet Cytogenet Oncol Haematol 2008; 2 190 phosphatidylinositol 3-kinase/Akt pathway. Constitutive activation of NOTCH1 signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model. Blocking Notch signaling can inhibit network formation. Regulating cell communication events between endocardium and myocardium during ventricular chamber formation: Ventricular chamber morphogenesis is critical for proper cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. Ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, weakened EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses have shown that Notch1 inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch1 target acting upstream of NRG1 in the ventricles. Cell lineage specification of both endocrine and exocrine pancreas: Multiple cell types of the pancreas appear asynchronously during embryogenesis, which requires that pancreatic progenitor cell potential changes over time. Loss-of-function studies have shown that NOTCH1 signaling modulates the differentiation of these progenitors. It has been demonstrated that misexpression of activated NOTCH1 in Pdx1-expressing progenitor cells prevents differentiation of both exocrine and endocrine lineages. Progenitors remained trapped in an undifferentiated state even if notch1 activation occurred long after the pancreas was specified. Endocrine differentiation is associated with escape from this activity, as Ngn3-expressing endocrine precursors were susceptible to notch1 inhibition, whereas fully differentiated endocrine cells were resistant. Notch1-dependent bone morphogenic protein (BMP) signaling: NOTCH1 enhances BMP2-induced commitment to the osteoblastic lineage during bone development. Regulation of cell-fate decision in the mammary gland: It has been suggested that Notch1 signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Notch signaling can act on mammary stem cells to promote self renewal and on early progenitor cells to promote their proliferation, as demonstrated in one study by a 10-fold increase in secondary mammosphere formation upon addition of a Notch activating DSL peptide. The same study showed that in addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. Notch1 signaling has no such effect on fully committed, differentiated, mammary epithelial cells. Cytoskeletal component formation: It has been suggested that NOTCH1 signaling, via some non-nuclear mechanisms, controls the actin cytoskeleton through the tyrosine kinase Abl. Normal lymphocyte function: NOTCH1 signaling is involved in the maturation of both CD4+ and CD8+ cells in the thymus. In altered form, NOTCH1 may contribute to transformation or progression in some T-cell neoplasms. NOTCH1 may be important for follicular differentiation and possibly cell fate selection within the follicle. Regulation of fate choices in the inner ear. Induction of left-right asymmetry. Regulation of limb bud development. Regulation of kidney development. Mutations Note Notch1 mutant mice display defects in somite morphology. Mutations in the NOTCH1 ligand affect the development of many organs, including that of the liver, skeleton, heart and eye. Mutations in the NOTCH1 ligand DLL3 result in rib fusions and trunk dwarfism. Notch1 mutations play a dual role in carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1 within and between cells depends on signal strength, timing, cell type, and context. Notch1 mutant cells infected with a retrovirus transducing the ras oncogene and injected subcutaneously into nude mice form aggressive squamous cell carcinoma (SCC), whereas wild-type cells do not. Loss of notch1 activity may thus cooperate with
Atlas Genet Cytogenet Oncol Haematol 2008; 2 191 ras oncogene transformation in keratinocyte tumor development. In humans, aberrant NOTCH1 expression has been identified as a causative factor in the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). Recurrent t(7;9) translocation that involves the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1 is associated with T-ALL. The t (7; 9) translocation in T-ALL patients is characterized by juxtaposition of the 3' portion of the human notch1 gene with the T cell receptor beta (TCRB) locus. This leads to expression of truncated NOTCH1 transcripts and consequent production of dominant active, ligand-independent forms of the NOTCH1 receptor, causing T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however, activating mutations in notch1 independent of t(7;9) have been identified in more than 50% of human T-ALL. Cells that are mutant for notch1 form skin and corneal tumors in mice, indicating that Notch1 signaling suppresses tumorigenesis in these instances. Notch1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease. Many other human and murine cancers, including certain neuroblastomas, mammary, skin, cervical and prostate cancers are correlated with alterations in expression of Notch proteins and/or ligands. These cases await better characterization, but these observations suggest broad roles for Notch dysfunction in a wide range of neoplasms. Based on analysis of neuroendocrine tumors and cell lines, NOTCH1 appears to be absent in this type of cancer. Expression of ectopic NOTCH1 in human medullary thyroid carcinoma and carcinoid tumor cell lines resulted in suppression of cancer cell growth. These data suggest that in neuroendocrine malignancies notch1 may act as a tumor suppressor. Implicated in Entity Medullary Thyroid Cancer (MTC) Disease A neuroendocrine tumor (NET) derived from parafollicular C cells of the thyroid, MTC is the third most common form of thyroid cancer accounting for 3-5% of all thyroid cancers. Symptoms include airway obstruction and diarrhea. MTC typically secretes the bioactive hormone calcitonin. Currently, surgery is the only curative therapy for these patients, consisting of total thyroidectomy with lymph node dissection. 50% of these patients suffer persistent disease. Oncogenesis 20% of patients with MTC have an autosomal dominant inherited form of the disease, which has been shown to be the result of well-characterized point mutations in the RET- protooncogene. The results of human MTC tissue sample analysis revealed an absence of active NOTCH1 protein in all tumors tested whereas NET markers such as chromogranin A (CgA) and ASCL1 were highly expressed. Activation of doxycycline- inducible notch1 in MTC cells by varying concentrations of doxycycline led to a dose- dependent increase in NOTCH1 protein and HES-1 protein expression. The level of ASCL1 was reduced with increase in NOTCH1. Further, it was observed that activation of notch1 significantly reduced the growth of MTC cells and the reduction in growth was dependent on the level of active NOTCH1 protein. NOTCH1 also down-regulates aberrant calcitonin secretion in a dose-dependent manner. Entity Gastrointestinal (GI) Carcinoid Tumors Disease GI carcinoids are rare tumors that arise from the diffuse neuroendocrine tissue of the gut with a reported incidence of 1-8 per 100,000. They frequently metastasize to the liver and are the second most common source of isolated liver metastases. GI carcinoids secrete various bioactive hormones such as 5-HT (serotonin) and CgA. Patients with hepatic metastases suffer debilitating symptoms such as abdominal pain, flushing, bronchoconstriction, and diarrhea. Standard palliative treatment for these hormone- induced symptoms includes somatostatin analogs (such as octeotride). Oncogenesis RT-PCR reactions for various Notch receptors and ligands showed the presence of transcripts for notch1, notch2, notch3 and DLL1 in all carcinoid tumors tested. The human pancreatic carcinoid BON cell line also showed detectable amounts all three NOTCH receptors (1-3). An absence of active NOTCH1 intracellular domain (NICD) protein in BON cells was noted, suggesting that the NOTCH1 signaling pathway is inactive in carcinoids. Transient expression of active NOTCH1 via adenoviral vector in BON cells resulted in growth suppression and significant reduction in NET markers such as 5-HT, CgA, synaptophysin, neuron specific enolase (NSE), and ASCL1, confirming
Atlas Genet Cytogenet Oncol Haematol 2008; 2 192 the tumor suppressor role of Notch1 signaling in carcinoid tumors. Further, it was shown that the reduction in serotonin is at the level of transcription of tryptophan hydroxylase 1 mRNA suggesting that NOTCH1 signaling regulates tryptophan hydroxylase 1, a rate- limiting enzyme in 5-HT biosynthesis. In addition, stable expression of a NOTCH1 fusion protein in BON cells also resulted in high levels of functional NOTCH1 that led to an increase in the level of HES-1, an immediate downstream NOTCH1 effector. Increases in the level of HES-1 significantly reduced the level of ASCL1 protein. Similar to transient adenoviral NOTCH1 activation, the stable expression of NOTCH1 in BON cells also caused reductions in the levels of serotonin, CgA, NSE, and synaptophysin. Treatment of human carcinoid cancer cells with histone deacetylase (HDAC) inhibitors resulted in activation of NOTCH1 signaling and inhibition of carcinoid cell growth in vitro and in vivo. These findings suggest that NOTCH1 activation with HDAC inhibitors may be an attractive approach for the treatment of these tumors. Entity Small-Cell Lung Cancer (SCLC) Disease SCLC tends to present with metastatic and regional spread. SCLC is extremely aggressive and is characterized by rapid growth and early metastases. SCLC arises from major bronchi, and expresses NSE, CgA, and synaptophysin. Oncogenesis Similar to the observations in other neuroendocrine tumors such as carcinoids and MTC, neither the Notch1 nor the raf-1 pathway is active in SCLC cells. In addition, these tumors express high levels of ASCL1. Inhibition of ASCL1 expression by anti sense or RNA interference has been shown to suppress the growth of SCLC cells and reduce expression of NET markers, furthering the idea that ASCL1 plays a critical role in SCLC development. RNA interference against ASCL1 significantly inhibited growth both in vitro and in vivo xenograft model. It was also demonstrated that the growth inhibition by suppression of ASCL1 is mediated by cell cycle arrest and apoptotic cell death. It is also known that NOTCH1 is a negative regulator of ASCL1 and it is inactive in various SCLC cell lines tested. Adenoviral mediated expression of active NOTCH1 in these cell lines resulted in both NET marker reduction and growth suppression. Furthermore, the reduction in ASCL1 by Notch1 is achieved both at the level of transcription and post-translational degradation of the ASCL1 protein. These results further confirm that the Notch1 pathway is not active in SCLC at baseline. Activation of NOTCH1 signaling in SCLC led to growth inhibition and NET marker reduction, suggesting a tumor suppressor role for notch1 in SCLC. Entity T Cell Malignancies. Disease Human acute T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is the prototypical notch1-associated cancer. The disease constitutes approximately 15 or 20% of ALL in children and adults. Oncogenesis Oncogenesis is attributed to constitutively active notch1 due to t(7;9) (q34:q34.3) activating mutations. This leads to expression of NICD in a T cell receptor-beta- regulated manner. Although the t(7; 9) mutation is rare (less that 1% of T-ALL), the majority of human T-ALL have gain-of-function mutations in notch1, leading to aberrant increases in downstream signaling. Entity B-Cell Malignancies Disease Several mature B-cell and therapy-resistant B-cell malignancies have been shown to be susceptible to NOTCH1-mediated growth inhibition/apoptosis including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)-translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies. In direct contrast to the previously mentioned studies, several groups have reported NOTCH1-mediated growth proliferation in such B cell malignancies as multiple myeloma and Hodgkin and anaplastic large cell lymphoma. Oncogenesis Several studies support the existence of a dual-role for NOTCH1 signaling as either a tumor suppressor or oncogene in malignant B cells. These studies conflict, indicating that more definitive research is needed. A reasonably comprehensive study targeted the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. They found that expression of constitutively active, truncated forms of several mammalian Notch receptors (including NOTCH1) inhibited growth and induced apoptosis in both murine and human B-cell lines. Similar results
Atlas Genet Cytogenet Oncol Haematol 2008; 2 193 were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. Truncated NOTCH1 receptors, as well as the Jagged ligands, induced HES-1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (HES-1) recapitulated the NOTCH1 effects, suggesting that HES-1 is an important mediator of NOTCH1-induced growth arrest and apoptosis in B cells. Entity Breast Cancer Disease Breast cancer is the most commonly diagnosed malignancy in women after skin cancer, and is a leading cause of cancer death in women from western countries. Oncogenesis NOTCH1 is over-expressed in solid tumors of the breast in the human model. Moreover, NOTCH1 expression isincreased in poorly differentiated tumors. A separate study found that elevated coexpression of the NOTCH1 ligand Jagged1 and NOTCH1 is characteristic of a subclass of breast cancer with a very poor outcome. Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes (5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1(High vs. Low) (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1(High vs. Low) (P = 0.02)). Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). Entity Skin Cancer Disease In basal cell carcinoma (BCC), the most common non-melanocytic human skin cancer, hyperplasic cell division may lead to invasion of the dermis by epidermal tissues. NOTCH1 signaling has been linked to BCC. NOTCH1 signaling has also been linked to primary melanoma. Melanomas originate from pigment-producing melanocytes. In human skin, melanocytes are positioned at the epidermal-dermal junction and are interspersed every 5 to 10 basal keratinocytes. Oncogenesis Notch1 is implicated differentially as an oncogene in melanocyte-derived carcinoma and as a tumor suppressor gene in keratinocyte-derived carcinoma. Notch1 may act as a tumor suppressor gene in basal cell carcinoma (BCC). This conclusion was drawn from the observation that when keratinocytes were hyperproliferating, as in BCC, notch1 expression was essentially absent. A study showed that blocking NOTCH1 signaling suppressed, whereas constitutive activation of the NOTCH1 pathway enhanced, primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of NOTCH1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of notch1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following notch1 activation. Inhibiting beta-catenin expression reversed notch1-enhanced tumor growth and metastasis. Another study continued, finding that NOTCH1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of NOTCH1 by ectopic expression of the NICD enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor-independent manner in vitro and to grow more aggressively with metastatic activity in vivo. They show that notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of NOTCH1 signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the NOTCH1 signaling- induced tumor cell growth. Entity Cervical Cancer Disease Cervical carcinomas are a major type of epithelial keratinocyte-derived tumors. Infection with human papillomaviruses (HPVs), more specifically the high-risk HPV16 and HPV18, is associated with most cervical cancer and is thought to have a causal link with the disease. Oncogenesis NOTCH1 signaling is believed to play an oncogenic role in early disease stages and a tumor suppressive role in late disease stages. Immunohistochemical data have indicated that notch1 expression is elevated in squamous metaplasia of the columnar epithelium, and in early HPV-induced lesions
Atlas Genet Cytogenet Oncol Haematol 2008; 2 194 (CINI-III) and well-differentiated superficial carcinomas of the cervix. A study shows that in invasive cervical cancers, notch1 expression is substantially reduced. This dual-role pattern of notch1 expression suggests that the protein may play an oncogenic function in the early stages of cervical carcinogenesis, and a tumor suppressive function in the later stages. Entity Epithelial-mesenchymal transition (EMT) Disease EMT occurs during tumor progression when cells from a primary epithelial tumor change phenotype, become mesenchymal, and disseminate as single carcinoma cells, invading other organs as metastases. EMT may also be involved in the dedifferentiation program that leads to malignant carcinoma. Oncogenesis Jagged1 activation of endogenous Notch receptors in human endothelial cells promotes EMT in endothelial cells. NICD induction in the human adenocarcinoma cell line MCF7 promotes migratory behavior associated with E-CADHERIN loss. TGFb is another well-known inducer of EMT during embryonic development and the later stages of tumor progression. One possible mechanism of Notch-induced tumor development and progression may involve modulation of the TGFb signaling pathway, as it has been suggested that TGFb may be Notch-dependent. External links Nomenclature Hugo NOTCH1 GDB NOTCH1 Entrez_Gene NOTCH1 4851 Notch homolog 1, translocation-associated (Drosophila) Cards Atlas NOTCH1ID30ch9q34 GeneCards NOTCH1 Ensembl NOTCH1 [Search_View] ENSG00000148400 [Gene_View] Genatlas NOTCH1 GeneLynx NOTCH1 eGenome NOTCH1 euGene 4851 Genomic and cartography GoldenPath NOTCH1 - 9q34.3 chr9:138508717-138560059 - 9q34.3 (hg18-Mar_2006) Ensembl NOTCH1 - 9q34.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene NOTCH1 Gene and transcription Genbank AB209873 [ ENTREZ ] Genbank AF308602 [ ENTREZ ] Genbank AK000012 [ ENTREZ ] Genbank BC013208 [ ENTREZ ] Genbank BC039147 [ ENTREZ ] RefSeq NM_017617 [ SRS ] NM_017617 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_024000 [ SRS ] NT_024000 [ ENTREZ ] RefSeq NW_924573 [ SRS ] NW_924573 [ ENTREZ ] AceView NOTCH1 AceView - NCBI Unigene Hs.698674 [ SRS ] Hs.698674 [ NCBI ] HS698674 [ spliceNest ] Fast-db 16508 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P46531 [ SRS] P46531 [ EXPASY ] P46531 [ INTERPRO ] Prosite PS50297 ANK_REP_REGION [ SRS ] PS50297 ANK_REP_REGION [ Expasy ] Prosite PS50088 ANK_REPEAT [ SRS ] PS50088 ANK_REPEAT [ Expasy ] Prosite PS00010 ASX_HYDROXYL [ SRS ] PS00010 ASX_HYDROXYL [ Expasy ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 195 Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Prosite PS01187 EGF_CA [ SRS ] PS01187 EGF_CA [ Expasy ] Prosite PS50258 LNR [ SRS ] PS50258 LNR [ Expasy ] Interpro IPR002110 ANK [ SRS ] IPR002110 ANK [ EBI ] Interpro IPR000152 Asx_hydroxyl_S [ SRS ] IPR000152 Asx_hydroxyl_S [ EBI ] Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR001881 EGF_Ca_bd [ SRS ] IPR001881 EGF_Ca_bd [ EBI ] Interpro IPR013091 EGF_Ca_bd_2 [ SRS ] IPR013091 EGF_Ca_bd_2 [ EBI ] Interpro IPR006209 EGF_like [ SRS ] IPR006209 EGF_like [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR008297 Notch [ SRS ] IPR008297 Notch [ EBI ] Interpro IPR010660 Notch_NOD [ SRS ] IPR010660 Notch_NOD [ EBI ] Interpro IPR011656 Notch_NODP [ SRS ] IPR011656 Notch_NODP [ EBI ] Interpro IPR000800 Notch_region [ SRS ] IPR000800 Notch_region [ EBI ] CluSTr P46531 Pfam PF00023 Ank [ SRS ] PF00023 Ank [ Sanger ] pfam00023 [ NCBI-CDD ] Pfam PF00008 EGF [ SRS ] PF00008 EGF [ Sanger ] pfam00008 [ NCBI-CDD ] Pfam PF07645 EGF_CA [ SRS ] PF07645 EGF_CA [ Sanger ] pfam07645 [ NCBI-CDD ] Pfam PF06816 NOD [ SRS ] PF06816 NOD [ Sanger ] pfam06816 [ NCBI-CDD ] Pfam PF07684 NODP [ SRS ] PF07684 NODP [ Sanger ] pfam07684 [ NCBI-CDD ] Pfam PF00066 Notch [ SRS ] PF00066 Notch [ Sanger ] pfam00066 [ NCBI-CDD ] Smart SM00248 ANK [EMBL] Smart SM00181 EGF [EMBL] Smart SM00179 EGF_CA [EMBL] Smart SM00004 NL [EMBL] Blocks P46531 PDB 1PB5 [ SRS ] 1PB5 [ PdbSum ], 1PB5 [ IMB ] 1PB5 [ RSDB ] PDB 1TOZ [ SRS ] 1TOZ [ PdbSum ], 1TOZ [ IMB ] 1TOZ [ RSDB ] PDB 1YYH [ SRS ] 1YYH [ PdbSum ], 1YYH [ IMB ] 1YYH [ RSDB ] PDB 2F8X [ SRS ] 2F8X [ PdbSum ], 2F8X [ IMB ] 2F8X [ RSDB ] PDB 2F8Y [ SRS ] 2F8Y [ PdbSum ], 2F8Y [ IMB ] 2F8Y [ RSDB ] PDB 2HE0 [ SRS ] 2HE0 [ PdbSum ], 2HE0 [ IMB ] 2HE0 [ RSDB ] HPRD 01827 Protein Interaction databases DIP P46531 IntAct P46531 Polymorphism : SNP, mutations, diseases OMIM 109730;190198 [ map ] GENECLINICS 109730;190198 SNP NOTCH1 [dbSNP-NCBI] SNP NM_017617 [SNP-NCI] SNP NOTCH1 [GeneSNPs - Utah] NOTCH1] [HGBASE - SRS] HAPMAP NOTCH1 [HAPMAP] COSMIC NOTCH1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD NOTCH1 General knowledge Family Browser NOTCH1 [UCSC Family Browser] SOURCE NM_017617 SMD Hs.698674 SAGE Hs.698674
Atlas Genet Cytogenet Oncol Haematol 2008; 2 196 GO receptor activity [Amigo] receptor activity GO calcium ion binding [Amigo] calcium ion binding GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO plasma membrane [Amigo] plasma membrane regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO immune response [Amigo] immune response GO Notch signaling pathway [Amigo] Notch signaling pathway GO multicellular organismal development [Amigo] multicellular organismal development GO integral to membrane [Amigo] integral to membrane GO cell differentiation [Amigo] cell differentiation negative regulation of myoblast differentiation [Amigo] negative regulation of myoblast GO differentiation GO regulation of developmental process [Amigo] regulation of developmental process BIOCARTA Segmentation Clock [Genes] BIOCARTA Proteolysis and Signaling of Notch [Genes] BIOCARTA Presenilin action in Notch and Wnt signaling [Genes] KEGG Dorso-ventral axis formation KEGG Notch signaling pathway PubGene NOTCH1 Other databases Probes Probe NOTCH1 Related clones (RZPD - Berlin) PubMed PubMed 177 Pubmed reference(s) in LocusLink Bibliography The theory of the gene. Morgan TH. The American Naturalist 1917; (609): 513-544.
The theory of the gene, revised. Morgan TH. Yale University Press 1938; 77-81.
Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S. Cell 1985; 43(3 Pt 2): 567-581. PMID 3935325
Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Kidd S, Kelley MR, Young MW. Mol Cell Biol 1986; 6(9): 3094-3108. PMID 3097517
Regulation of enzyme levels by proteolysis: the role of pest regions. Rechsteiner M. Adv Enzyme Regul 1988; 27: 135-151. PMID 2907964
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. Cell 1991; 66(4): 649-661. PMID 1831692
Atlas Genet Cytogenet Oncol Haematol 2008; 2 197
NF-kappa B and related proteins: Rel/dorsal homologies meet ankyrin-like repeats. Blank V, Kourilsky P, Israel A. Trends Biochem Sci 1992; 17(4): 135-140. PMID 1533967
Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T. Curr Biol 1995; 5(12): 1416-1423. PMID 8749394
Alterations in Notch signaling in neoplastic lesions of the human cervix. Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Proc Natl Acad Sci U S A 1995; 92(14): 6414-6418. PMID 7604005
Tissue-specific expression of human achaete-scute homolog-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions Chen H, Biel MA, Borges MW, Thiagalingam A, Nelkin BD, Baylin SB, Ball DW. Cell Growth Differ 1997; 8(6): 677-686. PMID 9186001
Conservation of the lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW. Proc Natl Acad Sci U S A 1997; 94(10): 5355-5360. PMID 9144241
Human achaete-scute homolog-1 is highly expressed in a subset of neuroendocrine tumors. Chen H, Udelsman R, Zeiger MA, Ball DW. Oncol Rep 1997.
The link between integration and expression of human papillomavirus type 16 genomes and cellular changes in the evolution of cervical intraepithelial neoplastic lesions. Daniel B, Rangarajan A, Mukherjee G, Vallikad E, Krishna S. J Gen Virol 1997; 78 ( Pt 5): 1095-1101. PMID 9152428
Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB. Nat Genet 1997; 16(3): 243-251. PMID 9207788
Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Nat Genet 1997; 16(3): 235-242. PMID 9207787
A role for Abl in Notch signaling. Giniger E. Neuron 1998; 20(4): 667-681. PMID 9581760
A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T. Genes Dev 1998; 12(15): 2269-2277.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 198 PMID 9694793
Human ligands of the Notch receptor. Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S. Am J Pathol 1999; 154(3): 785-794. PMID 10079256
Cytogenetics and molecular genetics of childhood leukemia. Ma SK, Wan TS, Chan LC. Hematol Oncol 1999; 17(3): 91-105. PMID 10641030
A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin- metalloprotease TACE. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. Mol Cell 2000; 5(2): 207-216. PMID 10882063
Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD. Nat Genet 2000; 24(4): 438-441. PMID 10742114
Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. Kurooka H, Honjo T. J Biol Chem 2000; 275(22): 17211-17220. PMID 10747963
Cell cycle arrest and apoptosis induced by Notch1 in B cells. Morimura T, Goitsuka R, Zhang Y, Saito I, Reth M, Kitamura D. J Biol Chem 2000; 275(47): 36523-36531. PMID 10967117
Notch signaling: from the outside in. Mumm JS, Kopan R. Dev Biol 2000; 228(2): 151-165. PMID 11112321
MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. Nat Genet 2000; 26(4): 484-489. PMID 11101851
Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. zur Hausen H. J Natl Cancer Inst 2000; 92(9): 690-698. PMID 10793105
The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Krebs LT, Deftos ML, Bevan MJ, Gridley T. Dev Biol 2001; 238(1): 110-119. PMID 11783997
Atlas Genet Cytogenet Oncol Haematol 2008; 2 199 Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F. Curr Biol 2001; 11(10): 789-792. PMID 11378391
Notch signaling induces cell cycle arrest in small cell lung cancer cells. Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, Ball DW. Cancer Res 2001; 61(7): 3200-3205. PMID 11306509
Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals. Cayouette M, Raff M. Nat Neurosci 2002; 5(12): 1265-1269. PMID 12447381
Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Fortini ME. Nat Rev Mol Cell Biol 2002; 3(9): 673-684. PMID 12209127
Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B. Blood 2002; 99(9): 3398-3403. PMID 11964309
Aph-2/Nicastrin: an essential component of gamma-secretase and regulator of Notch signaling and Presenilin localization. Kopan R, Goate A. Neuron 2002; 33(3): 321-324. PMID 11832221
Notch signaling induces rapid degradation of achaete-scute homolog 1. Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW. Mol Cell Biol 2002; 22(9): 3129-3139. PMID 11940670
Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Talora C, Sgroi DC, Crum CP, Dotto GP. Genes Dev 2002; 16(17): 2252-2263. PMID 12208848
Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. Thelu J, Rossio P, Favier B. BMC Dermatol 2002; 2: 7. PMID 11978185
Epithelial-mesenchymal transitions in tumour progression. Thiery JP. Nat Rev Cancer 2002; 2(6): 442-454. PMID 12189386 p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Wallberg AE, Pedersen K, Lendahl U, Roeder RG.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 200 Mol Cell Biol 2002; 22(22): 7812-7819. PMID 12391150
An overview of the Notch signalling pathway. Baron M. Semin Cell Dev Biol 2003; 14(2): 113-119. PMID 12651094
Learning and memory deficits in Notch mutant mice. Costa RM, Honjo T, Silva AJ. Curr Biol 2003; 13(15): 1348-1354. PMID 12906797
HES and HERP families: multiple effectors of the Notch signaling pathway. Iso T, Kedes L, Hamamori Y. J Cell Physiol 2003; 194(3): 237-255. PMID 12548545
The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. LaVoie MJ, Selkoe DJ. J Biol Chem 2003; 278(36): 34427-34437. PMID 12826675
Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M. Mol Cell Biol 2003; 23(1): 14-25. PMID 12482957
Notch signaling controls multiple steps of pancreatic differentiation. Murtaugh LC, Stanger BZ, Kwan KM, Melton DA. Proc Natl Acad Sci U S A 2003; 100(25): 14920-14925. PMID 14657333
Notch1 functions as a tumor suppressor in mouse skin. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, Hui CC, Clevers H, Dotto GP, Radtke F. Nat Genet 2003; 33(3): 416-421. PMID 12590261
Notch1 enhances B-cell receptor-induced apoptosis in mature activated B cells without affecting cell cycle progression and surface IgM expression Romer S, Saunders U, Jack HM, Jehn BM. Cell Death Differ 2003; 10(7): 833-844. PMID 12815466
The Role of Human Achaete-Scute Homolog-1 in Medullary Thyroid Cancer Cells. Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H. Surgery 2003; 134(6): 866-871; discussion 871-873. PMID 14668716
The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA. J Biol Chem 2003; 278(24): 21930-21937. PMID 12670957
Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Breast Cancer Res 2004; 6(6): R605-R615.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 201 PMID 15535842
Drosophila deltex mediates suppressor of Hairless-independent and late-endosomal activation of Notch signaling. Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H, Baron M, Matsuno K. Development 2004; 131(22): 5527-5537. PMID 15496440
Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Jundt F, Probsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S, Bargou RC, Manz R, Stein H, Dorken B. Blood 2004; 103(9): 3511-3515. PMID 14726396
Notch signaling: control of cell communication and cell fate. Lai EC. Development 2004; 131(5): 965-973. PMID 14973298
Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Blood 2004; 103(9): 3503-3510. PMID 14670925
Notch activation results in phenotypic and functional changes consistent with endothelial-to- mesenchymal transformation. Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, Shahidi R, Dorovini-Zis K, Li L, Beckstead B, Durand RE, Hoodless PA, Karsan A. Circ Res 2004; 94(7): 910-917. PMID 14988227
The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Parr C, Watkins G, Jiang WG. Int J Mol Med 2004; 14(5): 779-786. PMID 15492845
Notch regulation of lymphocyte development and function. Radtke F, Wilson A, Mancini SJ, MacDonald HR. Nat Immunol 2004; 5(3): 247-253. PMID 14985712
Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Science 2004; 306(5694): 269-271. PMID 15472075
Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M, Liu ZJ. J Clin Invest 2005; 115(11): 3166-3176. PMID 16239965 p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP. Genes Dev 2005; 19(12): 1485-1495. PMID 15964998
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Conservation of the Notch1 Signaling Pathway in Gastrointestinal Carcinoid Cells. Kunnimalaiyaan M, Traeger K, Chen H. Am J Physiol Gastrointest Liver Physiol 2005; 289(4): G636-G642. PMID 16160079
Hairy Enhancer-of-Split (HES-1), a Notch1 Effector, Inhibits the Growth of Carcinoid Tumor Cells. Kunnimalaiyaan M, Yan S, Wong F, Zhang YW, Chen H. Surgery 2005; 138(6): 1137-1142; discussion 1142. PMID 16360401
Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K, Kurokawa M, Hayashi Y, Ogawa S, Chiba S. Leukemia 2005; 19(10): 1841-1843. PMID 16079893
Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling Nakakura EK, Sriuranpong VR, Kunnimalaiyaan M, Hsiao EC, Schuebel KE, Borges MW, Jin N, Collins BJ, Nelkin BD, Chen H, Ball DW. J Clin Endocrinol Metab 2005; 90(7): 4350-4356. PMID 15870121
Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. Nobta M, Tsukazaki T, Shibata Y, Xin C, Moriishi T, Sakano S, Shindo H, Yamaguchi A. J Biol Chem 2005; 280(16): 15842-15848. PMID 15695512
ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Osada H, Tatematsu Y, Yatabe Y, Horio Y, Takahashi T. Cancer Res 2005; 65(23): 10680-10685. PMID 16322211
RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Knochel W, Borggrefe T. Mol Cell Biol 2005; 25(23): 10379-10390. PMID 16287852
High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR, Lockwood G, Egan SE. Cancer Res 2005; 65(18): 8530-8537. PMID 16166334
Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways. Talora C, Cialfi S, Segatto O, Morrone S, Kim Choi J, Frati L, Paolo Dotto G, Gulino A, Screpanti I. Exp Cell Res 2005; 305(2): 343-354. PMID 15817159
Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC, Aster JC, Allman D, Pear WS. Blood 2005; 106(12): 3898-3906. PMID 16118316
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Notch signalling: a simple pathway becomes complex. Bray SJ. Nat Rev Mol Cell Biol 2006; 7(9): 678-689. PMID 16921404
Overexpression of the NOTCH1 intracellular domain inhibits cell proliferation and alters the neuroendocrine phenotype of medullary thyroid cancer cells. Kunnimalaiyaan M, Vaccaro AM, Ndiaye MA, Chen H. J Biol Chem 2006; 281(52): 39819-3930. PMID 17090547
Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression Liu ZJ, Xiao M, Balint K, Smalley KS, Brafford P, Qiu R, Pinnix CC, Li X, Herlyn M. Cancer Res 2006; 66(8): 4182-4190. PMID 16618740
Roles of O-fucose glycans in notch signaling revealed by mutant mice. Lu L, Stanley P. Methods Enzymol 2006; 417: 127-136. PMID 17132502
Complex networks orchestrate epithelial-mesenchymal transitions. Thiery JP, Sleeman JP. Nat Rev Mol Cell Biol 2006; 7(2): 131-142. PMID 16493418
Notch signaling in development and cancer. Bolos V, Grego-Bessa J, de la Pompa JL. Endocr Rev 2007; 28(3): 339-363. PMID 17409286
Notch signaling is essential for ventricular chamber development. Grego-Bessa J, Luna-Zurita L, del Monte G, Bolos V, Melgar P, Arandilla A, Garratt AN, Zang H, Mukouyama YS, Chen H, Shou W, Ballestar E, Esteller M, Rojas A, Perez-Pomares JM, de la Pompa JL. Dev Cell 2007; 12(3): 415-429. PMID 17336907
Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Kunnimalaiyaan M, Chen H. Oncologist 2007; 12(5): 535-542. PMID 17522241
Tumor Suppressor Role of Notch1 and Raf-1 Signaling in Medullary Thyroid Cancer Cells. Kunnimalaiyaan M, Haymart MR. Chen H. Translational Oncogenomics 2007
Suberoyl bis hydroxamic acid (SBHA) inhibits cellular proliferation by inducing cell cycle arrest in carcinoid cancer cells. Greenblatt DY, Cayo MA, Ning L, Jaskula-Sztul R, Haymart M, Kunnimalaiyaan M, Chen H. J Gastrointest Surg; In Press.
Valproic acid activates Notch1 signaling and regulates the neuroendocrine phenotype in carcinoid cancer cells. Greenblatt DY, Vaccaro A, Jaskula-Sztul R, Ning L, Haymart M, Kunnimalaiyaan M, Chen H. Oncologist; In Press.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 204 The HDAC Inhibitor Trichostatin A Inhibits Growth of Small Cell Lung Cancer Cells. Platta CS, Greenblatt DY, Kunnimalaiyaan M, Chen H. Journal of Surgical Research; In Press.
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Contributor(s) Written 08-2007 Max Cayo, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen Endocrine Cancer Disease Group, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. Citation This paper should be referenced as such : Cayo M, Greenblatt DY, Kunnimalaiyaan M, Chen H . NOTCH1 (Notch homolog 1, translocation- associated (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/NOTCH1ID30ch9q34.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 205 Atlas of Genetics and Cytogenetics in Oncology and Haematology
KLK10 (Kallikrein-related peptidase 10)
Identity Other names NES1 PRSSL1 Hugo KLK10 Location 19q13.41 Local_order Telomere to centromere. DNA/RNA Description Spanning 5.7 kb of genomic DNA, the KLK10 gene consists of 5 introns and six exons. Transcription The KLK10 gene has several splice variants with different lengths of the first exon. The predominant form is 1443 bp. Since the first exon is untranslated, all splice variants encode the same protein. Pseudogene Not identified so far. Protein Description KLK10 is a 30 kDa serine protease containing 276 amino acids. It consists of a signal peptide (aa 1-33), an activation peptide (aa 34-42), and a mature chain (aa 43-276). Expression High levels of KLK10 expression are typically found in glandular epithelia in a wide variety of organs, such as salivary gland, gastrointestinal tract, prostate, lung, breast, and ovary. Localisation KLK10 is synthesized as a precursor protein of 276 amino acids. Within the secretary pathway, its signal peptide is cleaved and it is secreted into the extracellular milieu as an inactive zymogen. KLK10 has been identified in many biological fluids, such as blood, amniotic fluid, cerebrospinal fluid, milk, and nipple aspirate. Function How KLK10 is activated remains undetermined. It is expected that upon activation, the peptide bond between arginine42 and lysine43 is proteolysed to release the mature chain. Mature KLK10 exhibits some typical characteristics of a trypsin-like serine protease, such as the catalytic triad (Histidine86, serine229, and aspartic acid137) and an aspartic acid in its substrate-binding pocket. However, its enzymatic activity has not been experimentally confirmed so far. Consequently, its potential physiologic substrates have not been identified. Homology Human KLK10 shares 98.2% and 69% identity with chimpanzee and mouse/rat klk10, respectively. Mutations Note No germinal or somatic mutations are identified to be associated with cancer so far. Implicated in Entity Various cancers with upragulated KLK10. Disease Epithelial ovarian carcinoma, uterine serous papillary carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and gastrointestinal tract cancer. Prognosis In these malignancies, KLK10 has been reported to be upregulated. Among them, epithelial ovarian carcinoma is by far studied the most. KLK10 is overexpressed in ovarian tumor tissue than in normal epithelium and stromal tissues both at the mRNA and protein levels. Due to increased leakage of KLK10 into the circulation, serum concentrations of KLK10 in ovarian cancer patients are elevated. High levels of KLK10 in tumor tissue or in serum are associated with more advanced disease stages and poor survival. In particular, preoperative serum KLK10 levels can serve as a complimentary biomarker for CA125, a well-established tumor marker routinely used in ovarian cancer. It has been demonstrated that nearly all CA125-negative tumors show KLK10 immunostaining positivity and that about 35% of CA125-negative patients have increased serum levels of KLK10. In combination with CA125, KLK10 can improve the
Atlas Genet Cytogenet Oncol Haematol 2008; 2 206 diagnostic sensitivity by about 20% compared to that of CA125 alone. Cytogenetics No cytogenetic abnormalities are identified so far. Hybrid/Mutated Not identified so far. Gene Entity Various cancers with down regulated KLK10. Disease Breast cancer, testicular cancer, leukemia, and prostate cancer. Prognosis In contrast to ovarian cancer, KLK10 is down regulated in these malignancies, with breast cancer as a prototype. Several lines of evidence have demonstrated that KLK10 is progressively down regulated during breast cancer development. In a clinical study, it is observed that essentially all normal breast specimens had KLK10 expression, whereas about 46% of ductal carcinoma in situ (DCIS) and the majority of infiltrating ductal carcinoma (IDC) had no detectable KLK10 expression. More importantly, the KLK10 negative-DCIS was found to subsequently develop to IDC. In in vitro studies, it has been shown that KLK10 is expressed in normal breast epithelial cells but dramatically reduced in breast cancer cell lines. Moreover, reintroduction of KLK10 expression into these cancer cells can suppress their tumorigenecity in nude mice. KLK10 was thus considered to function as a tumor suppressor in breast cancer. The mechanisms governing the down regulation of KLK10 in breast cancer is not clear. One explanation is CpG island hypermethylation of exon 3, as demonstrated in a number of cancer cell lines. Noteworthy, expression of KLK10 is modulated by some steroid hormones and retinoid acid. They may, under certain conditions, also contribute to the aberrant expression of KLK10 in tumor tissues. However, the paradoxical expression of KLK10 in different types of tumors remains obscure. External links Nomenclature Hugo KLK10 GDB KLK10 Entrez_Gene KLK10 5655 kallikrein-related peptidase 10 Cards Atlas KLK10ID41076ch19q13 GeneCards KLK10 Ensembl KLK10 [Search_View] ENSG00000129451 [Gene_View] Genatlas KLK10 GeneLynx KLK10 eGenome KLK10 euGene 5655 Genomic and cartography GoldenPath KLK10 - 19q13.41 chr19:56207812-56215094 - 19q13.3-q13.4 (hg18-Mar_2006) Ensembl KLK10 - 19q13.3-q13.4 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene KLK10 Gene and transcription Genbank AF024605 [ ENTREZ ] Genbank AY561635 [ ENTREZ ] Genbank BC002710 [ ENTREZ ] Genbank BM830577 [ ENTREZ ] Genbank BU685208 [ ENTREZ ] RefSeq NM_001077500 [ SRS ] NM_001077500 [ ENTREZ ] RefSeq NM_002776 [ SRS ] NM_002776 [ ENTREZ ] RefSeq NM_145888 [ SRS ] NM_145888 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011109 [ SRS ] NT_011109 [ ENTREZ ] RefSeq NW_927284 [ SRS ] NW_927284 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 207 AceView KLK10 AceView - NCBI Unigene Hs.275464 [ SRS ] Hs.275464 [ NCBI ] HS275464 [ spliceNest ] Fast-db 14737 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O43240 [ SRS] O43240 [ EXPASY ] O43240 [ INTERPRO ] Prosite PS50240 TRYPSIN_DOM [ SRS ] PS50240 TRYPSIN_DOM [ Expasy ] Prosite PS00134 TRYPSIN_HIS [ SRS ] PS00134 TRYPSIN_HIS [ Expasy ] Prosite PS00135 TRYPSIN_SER [ SRS ] PS00135 TRYPSIN_SER [ Expasy ] Interpro IPR001254 Peptidase_S1_S6 [ SRS ] IPR001254 Peptidase_S1_S6 [ EBI ] Interpro IPR001314 Peptidase_S1A [ SRS ] IPR001314 Peptidase_S1A [ EBI ] CluSTr O43240 Pfam PF00089 Trypsin [ SRS ] PF00089 Trypsin [ Sanger ] pfam00089 [ NCBI-CDD ] Smart SM00020 Tryp_SPc [EMBL] Blocks O43240 HPRD 04054 Protein Interaction databases DIP O43240 IntAct O43240 Polymorphism : SNP, mutations, diseases OMIM 602673 [ map ] GENECLINICS 602673 SNP KLK10 [dbSNP-NCBI] SNP NM_001077500 [SNP-NCI] SNP NM_002776 [SNP-NCI] SNP NM_145888 [SNP-NCI] SNP KLK10 [GeneSNPs - Utah] KLK10] [HGBASE - SRS] HAPMAP KLK10 [HAPMAP] COSMIC KLK10 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD KLK10 General knowledge Family Browser KLK10 [UCSC Family Browser] SOURCE NM_001077500 SOURCE NM_002776 SOURCE NM_145888 SMD Hs.275464 SAGE Hs.275464 Enzyme 3.4.21.- [ Enzyme-SRS ] 3.4.21.- [ Brenda-SRS ] 3.4.21.- [ KEGG ] 3.4.21.- [ WIT ] GO serine-type endopeptidase activity [Amigo] serine-type endopeptidase activity GO extracellular region [Amigo] extracellular region GO proteolysis [Amigo] proteolysis GO cell cycle [Amigo] cell cycle GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle PubGene KLK10 Other databases Probes Probe KLK10 Related clones (RZPD - Berlin) PubMed PubMed 30 Pubmed reference(s) in LocusLink Bibliography Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Liu XL, Wazer DE, Watanabe K, Band V. Cancer Res 1996; 56: 3371-3379. PMID 8764136
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The role for NES1 serine protease as a novel tumor suppressor. Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V. Cancer Res 1998; 58: 4782-4786. PMID 9809976
Structural characterization and mapping of the normal epithelial cell-specific 1 gene. Luo L, Herbrick JA, Scherer SW, Beatty B, Squire J, Diamandis EP. Biochem Biophys Res Commun 1998; 247: 580-586. PMID 9647736
Analysis of normal epithelial cell specific-1 (NES1)/kallikrein 10 mRNA expression by in situ hybridization, a novel marker for breast cancer. Dhar S, Bhargava R, Yunes M, Li B, Goyal J, Naber SP, Wazer DE, Band V. Clin Cancer Res 2001; 7: 3393-3398. PMID 11705853
CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Li B, Goyal J, Dhar S, Dimri G, Evron E, Sukumar S, Wazer DE, Band V. Cancer Res 2001; 61: 8014-8021. PMID 11691827
Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues. Luo LY, Grass L, Howarth DJ, Thibault P, Ong H, Diamandis EP. Clin Chem 2001; 47: 237-246. PMID 11159772
Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Luo LY, Rajpert-De Meyts ER, Jung K, Diamandis EP. Br J Cancer 2001; 85: 220-224. PMID 11461080
Human kallikrein 10 expression in normal tissues by immunohistochemistry. Petraki CD, Karavana VN, Luo LY, Diamandis EP. J Histochem Cytochem 2002; 50: 1247-1261. PMID 12185203
Steroid hormone regulation of the human kallikrein 10 (KLK10) gene in cancer cell lines and functional characterization of the KLK10 gene promoter. Luo LY, Grass L, Diamandis EP. Clin Chim Acta 2003; 337: 115-126. PMID 14568187
The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Luo LY, Katsaros D, Scorilas A, Fracchioli S, Bellino R, van Gramberen M, de Bruijn H, Henrik A, Stenman UH, Massobrio M, van der Zee AG, Vergote I, Diamandis EP. Cancer Res 2003; 63: 807-811. PMID 12591730
Overexpression of kallikrein 10 in epithelial ovarian carcinomas. Shvartsman HS, Lu KH, Lee J, Lillie J, Deavers MT, Clifford S, Wolf JK, Mills GB, Bast RC Jr, Gershenson DM, Schmandt R. Gynecol Oncol 2003; 90: 44-50. PMID 12821340
Loss of expression of the putative tumor suppressor NES1 gene in biopsy-proven ductal carcinoma in situ predicts for invasive carcinoma at definitive surgery.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 209 Yunes MJ, Neuschatz AC, Bornstein LE, Naber SP, Band V, Wazer DE. Int J Radiat Oncol Biol Phys 2003; 56: 653-657. PMID 12788170
The normal epithelial cell-specific 1 (NES1) gene, a candidate tumor suppressor gene on chromosome 19q13.3-4, is downregulated by hypermethylation in acute lymphoblastic leukemia. Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Barrios M, Andreu EJ, Prosper F, Heiniger A, Torres A. Leukemia 2004; 18: 362-365. PMID 14628074
Potential markers that complement expression of CA125 in epithelial ovarian cancer. Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, Hellstrom I, Mok SC, Liu J, Bast RC Jr. Gynecol Oncol 2005; 99: 267-277. PMID 16061277
Downregulation of human kallikrein 10 (KLK10/NES1) by CpG island hypermethylation in breast, ovarian and prostate cancers. Sidiropoulos M, Pampalakis G, Sotiropoulou G, Katsaros D, Diamandis EP. Tumour Biol 2005; 26: 324-336. PMID 16254462
Identification of new splice variants and differential expression of the human kallikrein 10 gene, a candidate cancer biomarker. Yousef GM, White NM, Michael IP, Cho JC, Robb JD, Kurlender L, Khan S, Diamandis EP. Tumour Biol 2005; 26: 227-235. PMID 16103744
Identification of molecular targets for immunotherapy of patients with head and neck squamous cell carcinoma. Dasgupta S, Tripathi PK, Qin H, Bhattacharya-Chatterjee M, Valentino J, Chatterjee SK. Oral Oncol 2006; 42: 306-316. PMID 16321566
Clinical significance of human kallikrein 10 gene expression in colorectal cancer and gastric cancer. Feng B, Xu WB, Zheng MH, Ma JJ, Cai Q, Zhang Y, Ji J, Lu AG, Qu Y, Li JW, Wang ML, Hu WG, Liu BY, Zhu ZG. J Gastroenterol Hepatol 2006; 21: 1596-1603. PMID 16928223
Overexpression of kallikrein 10 (hK10) in uterine serous papillary carcinomas. Santin AD, Diamandis EP, Bellone S, Marizzoni M, Bandiera E, Palmieri M, Papasakelariou C, Katsaros D, Burnett A, Pecorelli S. Am J Obstet Gynecol 2006; 194: 1296-1302. PMID 16647913
The human kallikrein 10 promoter contains a functional retinoid response element. Zeng M, Zhang Y, Bhat I, Wazer DE, Band H, Band V. Biol Chem 2006; 387: 741-747. PMID 16800735
Downregulation and CpG island hypermethylation of NES1/hK10 gene in the pathogenesis of human gastric cancer. Huang W, Zhong J, Wu LY, Yu LF, Tian XL, Zhang YF, Li B. Cancer Lett 2007; 251: 78-85. PMID 17182177
A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung
Atlas Genet Cytogenet Oncol Haematol 2008; 2 210 squamous cell carcinoma. Vachani A, Nebozhyn M, Singhal S, Alila L, Wakeam E, Muschel R, Powell CA, Gaffney P, Singh B, Brose MS, Litzky LA, Kucharczuk J, Kaiser LR, Marron JS, Showe MK, Albelda SM, Showe LC. Clin Cancer Res 2007; 13: 2905-2915. PMID 17504990
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Contributor(s) Written 08-2007 Liu-Ying Luo, Eleftherios P Diamandis R and D Systems, Inc. 614 McKinley Pl. N. E. Minneapolis, MN 55413, USA (LYL); Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada (EPD) Citation This paper should be referenced as such : Luo LY, Diamandis EP . KLK10 (Kallikrein-related peptidase 10). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/KLK10ID41076ch19q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 211 Atlas of Genetics and Cytogenetics in Oncology and Haematology
HDAC3 (Histone deacetylase 3)
Identity Other names HDAC3 HD3 RPD3-2 RPD3 SMAP45 Hugo HDAC3 Location 5q31.3 Local_order 140,980,626 pb to 140,996,596 bp in minus strand orientation DNA/RNA
Description The HDAC3 gene consists of 15 exons and spans 15.97 kb of genomic sequence on chromosome 5 (from position 140,980,626 pb to 140,996,596 bp, in minus strand orientation). Transcription The mRNA transcribed from this gene is 1,934 nucleotides long. There are actually two described isoforms resulting from an alternative splicing in the 5' region. Pseudogene No pseudogene have been described. Protein
Note HDAC3 interacts with other proteins, such as HDAC1, HDAC7, HDAC10, DACH1, YY1, DAXX, PML, RB1, RELA, JUN, SIN3A, BCOR, JMJD2A/JHDM3A, AKAP95, KLF6, DLK1, TR2, NRIP1 and SRY. Also described as a component of the N- CoR/SMRT repressor complexes by interacting with NCOR1/NCOR2. Description The HDAC3 protein is 428 amino acids long (isoelectric point: 4.98) and belongs to the class I histone deacetylase subfamily. In spite of the presence of a sequence ressembling the canonical NES at the position 29-41, CRM1 binding is observed in the region 180-313 and these residues act as a NES (or as a binding site for a NES-containing protein) that uses CRM1 export pathway. A NLS has been characterised in the C-terminal region (313-428). Another important sequence, required for oligomerisation of HDAC3 with itself and for the cell viability, is present in the N-terminal part (1-122) of the protein. The HDAC3 protein can be phosphorylated on Ser424 by Caseine Kinase 2 and the same residue is dephosphorylated by protein serine/threonine phosphatase 4 (PP4). HDAC3 can also be symoylated in vitro. Expression Like the other members of class I HDACs, HDAC3 is widely expressed in organisms, whereas HDACs of other classes are tissue-specific. Two different isoforms of HDAC3 are expressed depending on an alternative splicing of the mRNA. The resulting proteins differ in their first 15 N-terminal amino acids
Atlas Genet Cytogenet Oncol Haematol 2008; 2 212 (MAKTVAYFYDPDVGN -> MIVFKPYQASQHDMCR). Localisation As opposed to other class I HDACs that have been found predominantly nuclear, HDAC3 is located in both nuclear and cytoplasmic compartments as well as at the plasma membrane. Function In accordance to the limited homology of HDAC3 with the other HDACs (particularly in the C-terminal part of the protein) and its specific subcellular localisation, HDAC3 plays specific roles in the cell physiology and has substrates in the various cell compartments. Thus, unlike HDAC1/HDAC2, HDAC3 is required for cell growth and is involved in the apoptotic process of almost all cell types via the regulation of pro- apoptotic genes. Moreover, HDAC3 has been suggested to have a role in the cytoplasm, notably in signal transduction since it is a substrate of the membrane associated tyrosine kinase Src. So, in organisms, this protein plays a critical role in development, inflammation and metabolism. As the other histone deacetylases, HDAC3 acts on the chromatin via the formation of large multiprotein complexes. But unlike HDAC1/2, that are implicated in the formation of Sin3, NuRD and CoREST complexes, HDAC3 is present in specific complexes containing members of the nuclear receptor co-repressor family N-CoR/SMRT (Silencing Mediator of Retinoid acid and Thyroid hormone receptor). HDAC3 is responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) that correlates with epigenetic repression. This deacetylation is involved in transcriptional regulation of genes important for cell cycle progression and development. Thus, HDAC3 has been implicated to play roles in governing cell proliferation via the inhibition of p15(INK4b) and p21(WAF1/cip1). Many transcription factors can directly interact with HDAC3 and thus, may target the histone deacetylase to specific promoters. Thus, HDAC3 is able to regulate osteoblast differentiation and bone formation via its association with the osteoblast master protein, Runx2, and the inhibition of the trans-activity of Runx2. Likewise, in hematopoietic stem cells, HDAC3, but not other class I HDACs, directly associates with GATA-2 and suppresses its key transcriptional potential. The deacetylase activity of HDAC-3 can also target non-histone proteins: for example, HDAC3 is responsible in the inhibition of the myogenesis via its association with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation and thus, to repress the p300/PCAF/MEF2-dependent transcription. So, HDAC3 regulates many biological processes in a complex multi-levels manner. The activity of HDAC3 is regulated by the phosphorylation of the Ser424 residue of the protein (see protein description above) and CK2 and PP4 are responsible for this regulation. Interaction with the other members within multiprotein complexes also regulates the deacetylase activity of HDAC3 (the nuclear receptor corepressor SMRT stimulated this activity towards MEF2 and PCAF). HDAC3 activity can also be indirectly regulated by post-translational modification of its associated proteins (for example, the phosphorylation of SMRT induces the disruption of the complex and the de-repression of the target promoter). The cleavage of the HDAC3 protein is another type of regulation affecting this enzyme: thus, during apoptosis, removal of the C-terminal part of HDAC3 results in accumulation of the cleaved protein in the cytoplasm and so, in its inactivation towards nuclear histones (but a possible role of the cleaved protein in the cytoplasm cannot be excluded). Homology HDAC3 is very tightly conserved from plants to human. The histone deacetylase domain of HDAC3 (amino acids 3 to 316) is partly homologous to the other class I HDACs (HDAC1, HDAC2 and HDAC8) whereas C-terminal part of the protein is highly divergent. So, the HDAC3 protein is about 50% identical compared with other class I HDACs. Mutations Note No mutation is actually known for HDAC3 but Single Nucleotide Polymorphisms have been described in mRNA UTR (TGGGGG/TTCACC), introns (GATCTA/GTATTA; AAGGAA/CACAAT; GAAGGA/GCCCAT; AAACTA/GTAAAA) or in exons where it induces synonymous (TCATGT/CTGGGA (Q/Q)) or non-synonymous (ACCCAA/GTGAGT (N/S); CCAATC/GGATCA (R/P)) coding (non-exhaustive list). Implicated in Entity Cancers
Atlas Genet Cytogenet Oncol Haematol 2008; 2 213 Note Phase I/II clinical trials are actually conducted in north America with isoselective inhibitors of class I HDACs for the treatment of the Hodgkin lymphoma (HDACs inhibitors alone), of the acute myeloid leukemia and myelodysplastic syndrome (in association with DNA methylation inhibitors) or of pancreatic cancers (in association with antimetabolites). Disease Histone Deacetylase 3 and other class I HDACs, that regulate cell maturation and p21 expression, are deregulated in numerous cancers such as colon, ovary, lung, stomach, muscle, bone or skin cancers. The overexpression of HDAC3 is observed in almost tumoral pathologies. The downregulation of HDAC3 in colon cancer cells, in which the enzyme is normally overexpressed, results in cell growth inhibition, differentiation and increased apoptosis. Prognosis HDAC3 in combination with other antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients. There is no correlation between HDAC3 polymorphism and the risk of lung cancer . Oncogenesis HDAC3 was shown to be recruited by the tumor antigen MAGE-A to block the activation of the tumor suppressor p53. In leukaemia, the generation of oncogenic fusion proteins (TEL-AML1, ETO-AML1, MTG16a-AML1, PLZF-RARalpha) causes aberrant recruitment of N-CoR/SMRT-HDAC3 repressor complexes on promoters. Moreover, nuclear HDAC3 plays an anti-apoptotic role that is important for cancer cell growth. Entity Neurodegenerative and neuromuscular diseases Note Clinical trials are conducted with class I HDACs isoselective inhibitors for the treatment of Spinal Muscular Atrophy. HDAC inhibitors are also tested to enhance neuronal survival in both in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis. External links Nomenclature Hugo HDAC3 GDB HDAC3 Entrez_Gene HDAC3 8841 histone deacetylase 3 Cards Atlas HDAC3ID40804ch5q31 GeneCards HDAC3 Ensembl HDAC3 [Search_View] ENSG00000171720 [Gene_View] Genatlas HDAC3 GeneLynx HDAC3 eGenome HDAC3 euGene 8841 Genomic and cartography GoldenPath HDAC3 - 5q31.3 chr5:140980627-140996607 - 5q31 (hg18-Mar_2006) Ensembl HDAC3 - 5q31 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene HDAC3 Gene and transcription Genbank AF005482 [ ENTREZ ] Genbank AF039703 [ ENTREZ ] Genbank AY429538 [ ENTREZ ] Genbank BC000614 [ ENTREZ ] Genbank BM461585 [ ENTREZ ] RefSeq NM_003883 [ SRS ] NM_003883 [ ENTREZ ] RefSeq AC_000048 [ SRS ] AC_000048 [ ENTREZ ] RefSeq NC_000005 [ SRS ] NC_000005 [ ENTREZ ] RefSeq NT_029289 [ SRS ] NT_029289 [ ENTREZ ] RefSeq NW_922784 [ SRS ] NW_922784 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 214 AceView HDAC3 AceView - NCBI Unigene Hs.519632 [ SRS ] Hs.519632 [ NCBI ] HS519632 [ spliceNest ] Fast-db 11282 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O15379 [ SRS] O15379 [ EXPASY ] O15379 [ INTERPRO ] Interpro IPR000286 His_deacetylse [ SRS ] IPR000286 His_deacetylse [ EBI ] Interpro IPR003084 His_deacetylse_1 [ SRS ] IPR003084 His_deacetylse_1 [ EBI ] CluSTr O15379 PF00850 Hist_deacetyl [ SRS ] PF00850 Hist_deacetyl [ Sanger ] pfam00850 Pfam [ NCBI-CDD ] Blocks O15379 HPRD 08950 Protein Interaction databases DIP O15379 IntAct O15379 Polymorphism : SNP, mutations, diseases OMIM 605166 [ map ] GENECLINICS 605166 SNP HDAC3 [dbSNP-NCBI] SNP NM_003883 [SNP-NCI] SNP HDAC3 [GeneSNPs - Utah] HDAC3] [HGBASE - SRS] HAPMAP HDAC3 [HAPMAP] COSMIC HDAC3 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD HDAC3 General knowledge Family Browser HDAC3 [UCSC Family Browser]
SOURCE NM_003883
SMD Hs.519632 SAGE Hs.519632 GO histone deacetylase complex [Amigo] histone deacetylase complex GO histone deacetylase activity [Amigo] histone deacetylase activity GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO anti-apoptosis [Amigo] anti-apoptosis GO transcription factor binding [Amigo] transcription factor binding GO chromatin modification [Amigo] chromatin modification GO histone deacetylation [Amigo] histone deacetylation GO hydrolase activity [Amigo] hydrolase activity BIOCARTA Acetylation and Deacetylation of RelA in The Nucleus [Genes] Nuclear receptors coordinate the activities of chromatin remodeling complexes and BIOCARTA coactivators to facilitate initiation of transcription in carcinoma cells [Genes] PubGene HDAC3 Other databases Probes Probe HDAC3 Related clones (RZPD - Berlin) PubMed PubMed 103 Pubmed reference(s) in LocusLink Bibliography Characterization of a human RPD3 ortholog, HDAC3.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 215 Emiliani S, Fischle W, Van Lint C, Al-Abed Y, Verdin E. Proc Natl Acad Sci U S A 1998; 95(6): 2795-2800. PMID 9501169
The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Guenther MG, Barak O, Lazar MA. Mol Cell Biol 2001; 21(18): 6091-6101. PMID 11509652
Histone deacetylase 3 associates with and represses the transcription factor GATA-2. Ozawa Y, Towatari M, Tsuzuki S, Hayakawa F, Maeda T, Miyata Y, Tanimoto M, Saito H. Blood 2001; 98(7): 2116-2123. PMID 11567998
Functional domains of histone deacetylase-3. Yang WM, Tsai SC, Wen YD, Fejer G, Seto E. J Biol Chem 2002; 277(11): 9447-9454. PMID 11779848
Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. Schroeder TM, Kahler RA, Li X, Westendorf JJ. J Biol Chem 2004; 279(40): 41998-42007. PMID 15292260
Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients. Shebzukhov YV, Koroleva EP, Khlgatian SV, Belousov PV, Kuz'mina KE, Radko BV, Longpre F, Lagarkova MA, Kadachigova TS, Gurova OV, Meshcheryakov AA, Lichinitser MR, Knuth A, Jager E, Kuprash DV, Nedospasov SA. Int J Cancer 2005; 117(5): 800-806. PMID 15981215
Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Zhang X, Ozawa Y, Lee H, Wen YD, Tan TH, Wadzinski BE, Seto E. Genes Dev 2005; 19(7): 827-839. PMID 15805470
Epigenetics of lung cancer. Bowman RV, Yang IA, Semmler AB, Fong KM. Respirology 2006; 11(4): 355-365. PMID 16771905
Histone deacetylase 3 represses p15(INK4b) and p21(WAF1/cip1) transcription by interacting with Sp1. Huang W, Tan D, Wang X, Han S, Tan J, Zhao Y, Lu J, Huang B. Biochem Biophys Res Commun 2006; 339(1): 165-171. PMID 16298343
Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src. Longworth MS, Laimins LA. Oncogene 2006; 25(32): 4495-4500. PMID 16532030
Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. Wilson AJ, Byun DS, Popova N, Murray LB, L'Italien K, Sowa Y, Arango D, Velcich A, Augenlicht LH, Mariadason JM. J Biol Chem 2006; 281(19): 13548-13558.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 216 PMID 16533812
Cleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progression. Escaffit F, Vaute O, Chevillard-Briet M, Segui B, Takami Y, Nakayama T, Trouche D. Mol Cell Biol 2007; 27(2): 554-567. PMID 17101790
Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2. Gregoire S, Xiao L, Nie J, Zhang X, Xu M, Li J, Wong J, Seto E, Yang XJ. Mol Cell Biol 2007; 27(4): 1280-1295. PMID 17158926
HDAC3: taking the SMRT-N-CoRrect road to repression. Karagianni P, Wong J. Oncogene 2007; 26(37): 5439-5449. PMID 17694085
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Contributor(s) Written 08-2007 Fabrice Escaffit Chromatin and Cell Proliferation group, LBCMCP-UMR 5088 CNRS, Université Paul Sabatier, Bât 4R3B1, 118, route de Narbonne, 31062 TOULOUSE Cedex 9, France Citation This paper should be referenced as such : Escaffit F . HDAC3 (Histone deacetylase 3). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HDAC3ID40804ch5q31.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 217 Atlas of Genetics and Cytogenetics in Oncology and Haematology
FOXP1 (Forkhead box P1)
Identity Other names 12CC4 FLJ23741 hFKH1B HSPC215 MGC12942 MGC88572 MGC9551 QRF1 (Glutamine-Rich Factor 1) Hugo FOXP1 Location 3p14.1 Local_order 3ptelomere-3' FOXP1 5'-centromere
FOXP1 (3p14.1): RP11-154H23 (Spectrum0range) and RP11-79P21 (SpectrumGreen) covering the 5' and the 3'end of FOXP1, respectively. Note chr3: 71087426-71715830 bps DNA/RNA Description 21 exons; the first 5 exons, the 5' part of exon 6 and the 3' part of exon 21 are non- coding. Transcription 628405 bps mRNA; transcribed in a centromeric to telomeric orientation. Alternative splicing; 4 named isoforms (Q9H334-1,-2,-3,-4) recognized. Protein
Schematic diagram of the Foxp1 protein indicating the localization of predicted domains and motifs. Modified from Banham AH et al., Cancer Res 61, 8820-8820, 2001. Note Forkhead box P1 Description The FOXP1 protein is 677-amino acid long and its molecular weight is 75317 Da. It
Atlas Genet Cytogenet Oncol Haematol 2008; 2 218 contains two potential nucleic acid-binding motifs, including a forkhead (winged-helix) domain and C2H2 zinc finger domain. Other regions that may regulate transcription and mediate protein-protein interaction include coiled-coil, glutamine rich, S/T-rich, S/T/ P-rich and acidic rich domains. Two potential nuclear localization signals (NLS) were identified at amino acid434-440 and amino acid543-546. Two potential PEST motifs are predicted in the acidic region near its COOH terminus. The FOXP1 protein contains a number potential of cyclin-cdk phosphorylation sites and a recognition site for the p70S6-kinase which is itself regulated by the PI(3)K. The FOXP1 protein forms homodimers and heterodimers with FOXP2 and FOXP4. Dimerization is required for DNA-binding. Expression Ubiquitous expression in normal adult and fetal human tissues; highest expression in lymphoid and gastrointestinal tissues. Within the B lineage, FOXP1 is expressed modestly in progenitors, with highest levels in activated B cells and mantle zone B cells. Localisation Predominantly nuclear Function FOXP1 can act as a transcriptional repressor. The gene has a broad range of functions and plays an important role in cardiac and lung development, B-cell development and macrophage differentiation. FOXP1 is implicated in malignancy. Homology Member of the broadly expressed FOXP subfamily which itself is a part of the FOX gene family of transcription factors, characterized by sharing a common DNA binding domain termed forkhead or a winged-helix domain. FOXP proteins (FOXP1, -2, -3, -4) play important roles in immune responses, organ development and cancer pathogenesis. Implicated in Entity t(3;9)(p14;p13) --> PAX5-FOXP1 in childhood ALL Disease B-progenitor ALL (single case) Cytogenetics Unknown Abnormal Contains the NH2 terminus of PAX5 with the DNA-binding paired, octapeptide and Protein homeodomain-like domains and the COOH-terminus of FOXP1 containing its DNA- binding (Zn and FH) and transcriptional regulatory domains. Oncogenesis The fusion protein is predicted to retain the ability to bind to PAX5 and FOXP1 transcriptional targets, but no longer provide normal transcriptional regulatory functions of both genes. Entity t(3;14)(p14;q32)/B-cell malignancies IGH-FOXP1 Disease t(3;14)(p14;q32) resulting in upregulated expression of FOXP1, is a rare aberration in B-NHL. The translocation occurs recurrently in MALT-type of marginal zone B-cell lymphomas (MZBCL) and diffuse large B cell lymphoma (DLBCL). Single cases with variant FOXP1 translocations involving unknown non-IG loci have been reported. Of note, a significant number of DLBCL (with a predominantly ABC-like phenotype) and extranodal MZBCL displayed a strong expression of FOXP1 which is independent of genomic rearrangements of the FOXP1 locus. FOXP1-positivity was also found in numerous cases of cutaneous B-cell lymphomas and follicular lymphomas. Prognosis High expression of FOXP1 in DLBCL is associated with poor prognosis. Deregulation of FOXP1 in MALT lymphomas possibly leads to transformation to a more aggressive DLBCL. Cytogenetics t(3;14) was recorded as a sole aberration and as a part of complex karyotypes. In MALT lymphomas, translocations involving FOXP1, MALT1 and BCL10 are mutually exclusive. Hybrid/Mutated No hybrid gene; 5' FOXP1 juxtaposed with 3' IGH enhancer. Molecular characteristics Gene of FOXP1 variant translocations are unknown. Oncogenesis The occurrence of activated FOXP1 translocations in lymphoma indicates that FOXP1 functions as an oncogene. So far, mechanisms and molecular consequences of aberrant expression of FOXP1 in lymphomas not harboring 3p14/FOXP1 rearrangements are unknown. The preliminary data suggest that not the full-length protein, but smaller FOXP1 isoforms are atypically highly expressed in ABC-DLBCL cell lines. Their role in the disease process is currently investigated. Entity Solid tumors Disease FOXP1 abnormalities (overexpression, mislocalization or loss of FOXP1) are observed
Atlas Genet Cytogenet Oncol Haematol 2008; 2 219 in a wide variety of cancers, particularly of epithelial origin. FOXP1 located in the 3p region frequently deleted in multiple types of cancers is one of a few potential tumor suppressor genes. Genomic loss of FOXP1 correlates with a decrease in FOXP1 mRNA and/or a decrease in FOXP1 protein levels in a significant number of analyzed lung cancers and head and neck cancers. In addition, an aberrant cytoplasmic localization of FOXP1 has been observed in a number of epithelial malignancies. Whether that aberrant localization may be a mechanism for inactivation of FOXP1 remains to be determined. So far, the direct evidence that FOXP1 functions as a tumor suppressor gene is limited. In contrast, increased nuclear expression of FOXP1 has been detected in renal cell carcinoma, some prostate cancers, endometrial cancers and breast cancers. The mechanisms leading to altered expression of FOXP1 in cancer are elusive. Breakpoints
Recurrent (14q32/IGH) and non-recurrent chromosomal breakpoints/partners involved in the FOXP1 rearrangements in hematological malignancies. External links Nomenclature Hugo FOXP1 GDB FOXP1 Entrez_Gene FOXP1 27086 forkhead box P1 Cards Atlas FOXP1ID40632ch3p14 GeneCards FOXP1 Ensembl FOXP1 [Search_View] ENSG00000114861 [Gene_View] Genatlas FOXP1 GeneLynx FOXP1 eGenome FOXP1 euGene 27086 Genomic and cartography GoldenPath FOXP1 - 3p14.1 chr3:71087427-71715830 - 3p14.1 (hg18-Mar_2006) Ensembl FOXP1 - 3p14.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene FOXP1 Gene and transcription Genbank AB052767 [ ENTREZ ] Genbank AF146696 [ ENTREZ ] Genbank AF151049 [ ENTREZ ] Genbank AF250920 [ ENTREZ ] Genbank AF275309 [ ENTREZ ] RefSeq NM_001012505 [ SRS ] NM_001012505 [ ENTREZ ] RefSeq NM_032682 [ SRS ] NM_032682 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022459 [ SRS ] NT_022459 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 220 AceView FOXP1 AceView - NCBI Unigene Hs.431498 [ SRS ] Hs.431498 [ NCBI ] HS431498 [ spliceNest ] Fast-db 9747 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9H334 [ SRS] Q9H334 [ EXPASY ] Q9H334 [ INTERPRO ] Prosite PS00657 FORK_HEAD_1 [ SRS ] PS00657 FORK_HEAD_1 [ Expasy ] Prosite PS00658 FORK_HEAD_2 [ SRS ] PS00658 FORK_HEAD_2 [ Expasy ] Prosite PS50039 FORK_HEAD_3 [ SRS ] PS50039 FORK_HEAD_3 [ Expasy ] PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 Prosite [ Expasy ] PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 Prosite [ Expasy ] Interpro IPR001766 TF_Fork_head [ SRS ] IPR001766 TF_Fork_head [ EBI ] Interpro IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Wing_hlx_DNA_bd [ EBI ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] Interpro IPR015880 Znf_C2H2-like [ SRS ] IPR015880 Znf_C2H2-like [ EBI ] CluSTr Q9H334 PF00250 Fork_head [ SRS ] PF00250 Fork_head [ Sanger ] pfam00250 [ NCBI- Pfam CDD ] Smart SM00339 FH [EMBL] Smart SM00355 ZnF_C2H2 [EMBL] Prodom PD000425 TF_Fork_head[INRA-Toulouse] Q9H334 FOXP1_HUMAN [ Domain structure ] Q9H334 FOXP1_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks Q9H334 HPRD 18518 Protein Interaction databases DIP Q9H334 IntAct Q9H334 Polymorphism : SNP, mutations, diseases OMIM 605515 [ map ] GENECLINICS 605515 SNP FOXP1 [dbSNP-NCBI] SNP NM_001012505 [SNP-NCI] SNP NM_032682 [SNP-NCI] SNP FOXP1 [GeneSNPs - Utah] FOXP1] [HGBASE - SRS] HAPMAP FOXP1 [HAPMAP] COSMIC FOXP1 [Somatic mutation (COSMIC-CGP-Sanger)] TICdb FOXP1 [Translocation breakpoints In Cancer] HGMD FOXP1 General knowledge Family Browser FOXP1 [UCSC Family Browser] SOURCE NM_001012505 SOURCE NM_032682 SMD Hs.431498 SAGE Hs.431498 GO nucleic acid binding [Amigo] nucleic acid binding GO transcription factor activity [Amigo] transcription factor activity GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO zinc ion binding [Amigo] zinc ion binding
Atlas Genet Cytogenet Oncol Haematol 2008; 2 221 GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding GO metal ion binding [Amigo] metal ion binding PubGene FOXP1 Other databases Probes Probe FOXP1 Related clones (RZPD - Berlin) PubMed PubMed 22 Pubmed reference(s) in LocusLink Bibliography DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain. Li C, Tucker PW. Proc Natl Acad Sci U S A 1993; 90: 11583-11587. PMID 8265594
The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Banham AH, Beasley N, Campo E, Fernandez PL, Fidler C, Gatter K, Jones M, Mason DY, Prime JE, Trougouboff P, Wood K, Cordell JL. Cancer Res 2001; 61: 8820-8829. PMID 11751404
Forkhead transcription factors: key players in development and metabolism. Carlsson P, Mahlapuu M. Dev Biol 2002; 250: 1-23. (REVIEW) PMID 12297093
Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors. Wang B, Lin D, Li C, Tucker P. J Biol Chem 2003; 278: 24259-24268. PMID 12692134
Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS. Blood 2004; 104: 2933-2935. PMID 15238418
Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas. Fox SB, Brown P, Han C, Ashe S, Leek RD, Harris AL, Banham AH. Clin Cancer Res 2004; 10(10): 3521-3527. PMID 15161711
Human FOX gene family (Review). Katoh M, Katoh M. Int J Oncol 2004; 25: 1495-1500. (REVIEW) PMID 15492844
Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1. Shi C, Zhang X, Chen Z, Sulaiman K, Feinberg MW, Ballantyne CM, Jain MK, Simon DI. J Clin Invest 2004; 114: 408-418. PMID 15286807
Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Wang B, Weidenfeld J, Lu MM, Maika S, Kuziel WA, Morrisey EE, Tucker PW.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 222 Development 2004; 131: 4477-4487. PMID 15342473
Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Banham AH, Connors JM, Brown PJ, Cordell JL, Ott G, Sreenivasan G, Farinha P, Horsman DE, Gascoyne RD. Clin Cancer Res 2005; 11(3): 1065-1072. PMID 15709173
The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin's lymphoma. Brown P, Marafioti T, Kusec R, Banham AH. J Mol Histol 2005; 36: 249-256. PMID 16200457
T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. Leukemia 2005; 19: 652-658. PMID 15703784
FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Wlodarska I, Veyt E, De Paepe P, Vandenberghe P, Nooijen P, Theate I, Michaux L, Sagaert X, Marynen P, Hagemeijer A, De Wolf-Peeters C. Leukemia 2005; 19: 1299-1305. PMID 15944719 t(3;14)(p14;q32) results in aberrant expression of FOXP1 in a case of diffuse large B-cell lymphoma. Fenton JA, Schuuring E, Barrans SL, Banham AH, Rollinson SJ, Morgan GJ, Jack AS, van Krieken JH, Kluin PM. Genes Chromosomes Cancer 2006; 45(2): 164-168. PMID 16252263
Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1alpha expression. Giatromanolaki A, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, Banham AH. Mod Pathol 2006; 19: 9-16. PMID 16258506
Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. Haralambieva E, Adam P, Ventura R, Katzenberger T, Kalla J, Höller S, Hartmann M, Rosenwald A, Greiner A, Muller-Hermelink HK, Banham AH, Ott G. Leukemia 2006; 20: 1300-1303. PMID 16673020
Foxp1 is an essential transcriptional regulator of B cell development. Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, Tucker PW, Rao A. Nat Immunol 2006; 7: 819-826. PMID 16819554
Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma. Sagaert X, de Paepe P, Libbrecht L, Vanhentenrijk V, Verhoef G, Thomas J, Wlodarska I, De Wolf- Peeters C. J Clin Oncol 2006; 24(16): 2490-2497.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 223 PMID 16636337
Reduced expressions of Foxp1 and Rassf1a genes in lung adenocarcinomas induced by N- nitrosobis(2-hydroxypropyl)amine in rats. Shimizu K, Kato A, Hinotsume D, Shigemura M, Hanaoka M, Shimoichi Y, Honoki K, Tsujiuchi T. Cancer Lett 2006; 236: 186-190. PMID 16023287
Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia. Banham AH, Boddy J, Launchbury R, Han C, Turley H, Malone PR, Harris AL, Fox SB. Prostate 2007; 1: 1091-1098. PMID 17477366
FOXP1: a potential therapeutic target in cancer. Koon HB, Ippolito GC, Banham AH, Tucker PW. Expert Opin Ther Targets 2007; 11: 955-965.(REVIEW) PMID 17614763
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR. Nature 2007; 446: 758-764. PMID 17344859
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Contributor(s) Written 08-2007 Iwona Wlodarska Department of Human Genetics, Catholic University Leuven, Leuven, Belgium Citation This paper should be referenced as such : Wlodarska I . FOXP1 (Forkhead box P1). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/FOXP1ID40632ch3p14.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 224 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7)
Identity Other names ALK-SMase (Alkaline sphingomyelinase) E-NPP7 MGC50179 NPP-7 Hugo ENPP7 Location 17q25.3 Local_order Upstream to a hypothetical protein LOC146743 and downstream to CBX2. DNA/RNA
Structure of ENPP7 gene: intron-exon organization. Description The ENPP7 gene is 11.139 bp in length and is composed of 6 exons in the size of 1841 bp. The first 20 bp in exon 1, the last 17 bp in exon 5 and the exon 6 are not translated. Transcription Besides the wild type transcript shown above, different transcripts have been identified. The first is the one with exon 4 deletion, which has been found in HepG2 liver cancer cells and some human colon and liver cancer tissues. The second one also deletes exon 4 but inserts 7 foreign amino acids due to the shift of the splice site. This transcript was identified in human HT29 colon cancer cells. The third one has a larger exon 1 than the wild type, which includes upstream another starting codon (219 bp upstream), and was identified in one liver tumor. Some factors such as ursodeoxycholic acid and psyllium have been found to stimulate the expression of ENPP7 whereas high fat diet decreases ENPP7 expression. Pseudogene LOC401847 Protein
The structure of ENPP7 protein. The regions with green, red, gray, blue and white colors indicate the amino acids coded by different exons. The five N-glycosylation sites are shown above the bar and two metal binding sits formed by 6 amino acids are shown under the bar. Two hydrophobic domains (from T5 to A22, and P441 to V457) and the predicted catalytic site (T73-H79) are indicated. Description The wild type ENPP7 contains 458 amino acids, which shares 30-36% identity to other members of the NPP family. The protein has a signal peptide at the N-terminal, which is cleaved in the mature enzyme, and a transmembrane domain at the C-terminal, which anchors the enzyme on the plasma membrane. The rest part of the enzyme is located outside the cells. The enzyme has 5 N-glycosylation sites and glycosylation is important for both transport of the enzyme to the plasma membrane and for enzyme activity. Similar to other NPP members, ENPP7 has two metal binding sites formed by 6 amino acids. These sites are predicted to serve as substrate binding site. Expression The enzyme has so far been found to express in the intestinal mucosal cells of many species and additionally human liver cells. The expression in liver may be restricted to human, because no activity or mRNA of ENPP7 could be found in the bile or liver of many other species. The expression is associated with differentiation of both intestinal
Atlas Genet Cytogenet Oncol Haematol 2008; 2 225 and hepatic cells. ENPP7 is developed early in the fetus and high activity has been found in the meconium of human fetus at the age of 23 week gestation. Localisation The enzyme is localized at the apical part but not basolateral part of intestinal epithelial cells. The enzyme can be dissociated from the membrane by bile salt and by pancreatic trypsin and released into the lumen in fully active form. Along the intestinal tract, the activity is low in the duodenum, high in the jejunum, and rapidly decreasing in the distal part of ileum and colon. The enzyme is also found in human bile, which is expressed in the liver and released to the bile. Function ENPP7 is a member of the ecto-nucleotide pyrophosphatase/ phosphodiesterase (NPP) family with specific activity against lipids with positively charged phosphocholine headgroup including sphingomyelin, lysophosphatidylcholine and platelet activating factor (PAF). It hydrolyzes sphingomyelin to generate ceramide, a potent antiproliferative and proapoptotic molecule. It hydrolyzes lysophosphatidylcholine to monoglyceride and therefore competes with lysophospholipase D to reduce the formation of lysophosphatidic acid, a potent factor for inflammation and angiogenesis. It hydrolyses PAF to 1-0-alkyl-2-acetyl-sn-glycerol and inhibits PAF-induced inflammatory responses. ENPP7 has been proposed as a tumor suppressor protein. In addition, ENPP7 may influence cholesterol absorption by hydrolyzing sphingomyelin in the intestinal lumen and on the apical surface of microvilli, as the levels of sphingomyelin in the intestinal tract affect cholesterol absorption. Homology ENPP7 shares 30-35% homology with other members of ENPP family. Regard to ENPP7, human ENPP7 shares 85% identity with rat form (NP_001012484), 82% with the mouse form (NP_001025462.1), and 82% with fowl form (XP 423912.1). The N- glycosylation sites, the amino acids forming the metal coordinate sites and active core are all conserved in the forms mentioned above. Mutations
The figure shows the aberrant transcript forms of ENPP7 identified in colon and liver cancers. The first is the one with deleted exon 4, which was found in HepG2 liver cancer cells and human liver cancer and colon cancer tissues. The second is similar as the first one but with an insertion of 7 foreign amino acids due to the shift of the splice site. The third one has a larger exon 1 than the wild type, which includes another starting codon, and was identified in one liver tumor (not shown in the figure). Formation of these aberrant forms are not caused by genomic mutation, but alternative splicing. Implicated in Entity Colon cancer, inflammatory bowel diseases, and liver cancer Disease ENPP7 may have implications in colon cancer, inflammatory bowel diseases such as ulcerative colitis, necrotizing enterocolitis, and liver cancer. Significant reduction of ENPP7 activity has been found in human longstanding ulcerative colitis, sporadic colon cancer and familial adenomatous polyposis The reduction may be caused by formation of the aberrant transcripts, which cause the inactivation of ENPP7, and have been found in human HT29 colon cancer cells, HepG2 liver cancer cells and also in human colon and liver cancer tissues. The frequency of such mutations is unknown. ENPP7 may also affect the pathogenesis of atherosclerosis as it influences the sphingomyelin levels in the gut and thus affect cholesterol absorption. Prognosis The enzyme activity is easy to be determined in the feces. Fecal activity reflects the total enzyme levels in the intestinal tract and has been shown to be decreased in colonic inflammation and cancer. External links Nomenclature
Atlas Genet Cytogenet Oncol Haematol 2008; 2 226 Hugo ENPP7 GDB ENPP7 Entrez_Gene ENPP7 339221 ectonucleotide pyrophosphatase/phosphodiesterase 7 Cards Atlas ENPP7ID44055ch17q25 GeneCards ENPP7 Ensembl ENPP7 [Search_View] ENSG00000182156 [Gene_View] Genatlas ENPP7 GeneLynx ENPP7 eGenome ENPP7 euGene 339221 Genomic and cartography GoldenPath ENPP7 - 17q25.3 chr17:75319477-75330615 + 17q25.3 (hg18-Mar_2006) Ensembl ENPP7 - 17q25.3 [CytoView] NCBI Mapview HomoloGene ENPP7 Gene and transcription Genbank AK126250 [ ENTREZ ] Genbank AK128662 [ ENTREZ ] Genbank AY230663 [ ENTREZ ] Genbank AY358622 [ ENTREZ ] Genbank BC041453 [ ENTREZ ] RefSeq NM_178543 [ SRS ] NM_178543 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_024871 [ SRS ] NT_024871 [ ENTREZ ] RefSeq NW_926918 [ SRS ] NW_926918 [ ENTREZ ] AceView ENPP7 AceView - NCBI Unigene Hs.114084 [ SRS ] Hs.114084 [ NCBI ] HS114084 [ spliceNest ] Fast-db 15385 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q6UWV6 [ SRS] Q6UWV6 [ EXPASY ] Q6UWV6 [ INTERPRO ] Interpro IPR001952 Alk_phosphtse [ SRS ] IPR001952 Alk_phosphtse [ EBI ] IPR002591 Phosphodiest/P_Trfase [ SRS ] IPR002591 Phosphodiest/P_Trfase Interpro [ EBI ] CluSTr Q6UWV6 PF01663 Phosphodiest [ SRS ] PF01663 Phosphodiest [ Sanger ] pfam01663 Pfam [ NCBI-CDD ] Blocks Q6UWV6 Protein Interaction databases DIP Q6UWV6 IntAct Q6UWV6 Polymorphism : SNP, mutations, diseases SNP ENPP7 [dbSNP-NCBI] SNP NM_178543 [SNP-NCI] SNP ENPP7 [GeneSNPs - Utah] ENPP7] [HGBASE - SRS] HAPMAP ENPP7 [HAPMAP] HGMD ENPP7 General knowledge Family ENPP7 [UCSC Family Browser] Browser SOURCE NM_178543 SMD Hs.114084 SAGE Hs.114084
Atlas Genet Cytogenet Oncol Haematol 2008; 2 227 3.1.4.12 [ Enzyme-SRS ] 3.1.4.12 [ Brenda-SRS ] 3.1.4.12 [ KEGG ] 3.1.4.12 Enzyme [ WIT ] sphingomyelin phosphodiesterase activity [Amigo] sphingomyelin phosphodiesterase GO activity GO Golgi apparatus [Amigo] Golgi apparatus GO microvillus [Amigo] microvillus GO sphingomyelin metabolic process [Amigo] sphingomyelin metabolic process GO metabolic process [Amigo] metabolic process GO negative regulation of DNA replication [Amigo] negative regulation of DNA replication GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO hydrolase activity [Amigo] hydrolase activity KEGG Sphingolipid metabolism PubGene ENPP7 Other databases Probes Probe ENPP7 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography The presence of sphingomyelin- and ceramide- cleaving enzymes in the small intestinal tract. Nilsson A. Biochim Biophys Acta 1969; 176: 339-345. PMID 5775951
Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. Duan RD, Nyberg L, Nilsson A. Biochim Biophys Acta 1995; 1259: 49-55. PMID 7492615
Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences. Duan RD, Hertervig E, Nyberg L, Hauge T, Sternby B, Lillienau J, Farooqi A, Nilsson A. Dig Dis Sci 1996; 41: 1801-1806. PMID 8794797
Identification of an alkaline sphingomyelinase activity in human bile. Nyberg L, Duan RD, Axelson J, Nilsson A. Biochim Biophys Acta 1996; 1300: 42-48. PMID 8608160
Purification of a newly identified alkaline sphingomyelinase in human bile and effects of bile salts and phosphatidylcholine on enzyme activity. Duan RD, Nilsson A. Hepatology 1997; 26: 823-830. PMID 9328299
Alkaline sphingomyelinase is decreased in human colorectal carcinoma. Hertervig E, Nilsson A, Nyberg L, Duan RD. Cancer 1997; 79: 448-453. PMID 9028353
Sphingomyelin hydrolysis in the gut and clinical implications in colorectal tumorigenesis and other gastrointestinal diseases. Duan RD. Scand J Gastroenterol 1998; 33: 673-683 (Review). PMID 9712229
Atlas Genet Cytogenet Oncol Haematol 2008; 2 228
Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: an potential implication in tumorigenesis. Duan RD, Cheng Y, Tauschel HD, Nilsson A. Dig Dis Sci 1998; 43: 26-32. PMID 9508530
Ursodeoxycholic acid increases the activities of alkaline sphingomyelinase and caspase 3 in the rat colon. Cheng Y, Tauschel HD, Nilsson A, Duan RD. Scand J Gastroenterol 1999; 34: 915-920. PMID 10522612
Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation? Hertervig E, Nilsson A, Bjork J, Hultkrantz R, Duan RD. Br J Cancer 1999; 81: 232-236. PMID 10496347
Alkaline sphingomyelinase and ceramidase of the gastrointestinal tract. Nilsson A, Duan RD. Chem Phys Lipids 1999; 102: 97-105. (Review) PMID 11001564
Effects of phospholipids on sphingomyelin hydrolysis induced by intestinal alkaline sphingomyelinase: an in vitro study. Liu JJ, Nilsson A, Duan RD. J Nutr Biochem 2000;11:192-197. PMID 10827341
A mutual inhibitory effect on absorption of sphingomyelin and cholesterol. Nyberg L, Duan RD, Nilsson A. J Nutr Biochem 2000; 11: 244-249. PMID 10876096
Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase. Cheng Y, Nilsson A, Tomquist E, Duan RD. J Lipid Res 2002; 43: 316-324. PMID 11861674
In vitro effects of fat, FA and cholesterol on sphingomyelin hydrolysis induced by rat intestinal alkaline sphingomyelinase. Liu JJ, Nilsson A, Duan RD. Lipids 2002; 37: 469-574. PMID 12056588
Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity. Sjoqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Lofberg R. Inflamm Bowel Dis 2002;8:258-263. PMID 12131609
Identification of human intestinal alkaline sphingomyelinase as a novel ectoenzyme related to the nucleotide phosphodiesterase family. Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J, Nelander S, Palmberg C, Nilsson A. J Biol Chem 2003; 278: 38528-38536. PMID 12885774
Purification, localization, and expression of human intestinal alkaline sphingomyelinase. Duan RD, Cheng Y, Hansen G, Hertervig E, Liu JJ, Syk I, Sjostrom H, Nilsson A. J Lipid Res 2003; 44: 1241-1250.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 229 PMID 12671034
Purified intestinal alkaline sphingomyelinase inhibits proliferation without inducing apoptosis in HT29 colon carcinoma cells. Hertervig C, Nilsson A, Duan RD. J Cancer Res Clin Oncol 2003; 129: 577-582. PMID 12920578
Development of intestinal alkaline sphingomyelinase in rat fetus and newborn rat. Lillienau J, Cheng Y, Nilsson A, Duan RD. Lipids 2003; 38: 545-549. PMID 12880111
Psyllium and fat in diets differentially affect the activities and expression of colonic sphingomyelinases and caspases in mice. Cheng Y, Ohlsson L, Duan RD. Br J Nutr 2004; 91: 715-723. PMID 15137923
Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT29 cells and a differentiation -related expression of the wild-type enzyme in Caco-2 cells. Wu j, Cheng Y, Nilsson A, Duan RD. Carcinogenesis 2004; 25: 1327-1333. PMID 15016655
Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity. Wu J, Liu F, Nilsson A, Duan RD. Am J Physiol 2004; 287: G967-973. PMID 15205117
Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer. Di Marzio, L.Di Leo, A, Cinque, B, Fanini D, Agnifili A, Berloco P, Linsalata M, Lorusso D, Barone M, De Simone C, Cifone MG. Cancer Epidemiol Biomarkers Prev 2005; 14: 856-862. PMID 15824156
Anticancer compounds and sphingolipid metabolism in the colon. Duan RD. In Vivo 2005;19:293-300. (Review) PMID 15796189
Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank. Wu J, Cheng Y, Palmberg C, Bergman T, Nilsson A, Duan RD. Biochim Biophys Acta 2005; 1687: 94-102. PMID 15708357
Functional studies of human intestinal alkaline sphingomyelinase by deglycosylation and mutagenesis. Wu J, Hansen GH, Nilsson A, Duan RD. Biochem J 2005; 386: 153-160. PMID 15458386
Alkaline sphingomyelinase: an old enzyme with novel implications. Duan RD. Biochim Biophys Acta 2006; 1761: 281-191 (Review). PMID 16631405
Atlas Genet Cytogenet Oncol Haematol 2008; 2 230 Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Cac0-2 cells. Liu F, Cheng Y, Wu J, Tauschel HD, Duan RD. Cancer Lett 2006; 235: 141-146. PMID 1629092
Absorption and lipoprotein transport of sphingomyelin. Nilsson A, Duan RD. J Lipid Res 2006; 47: 154-171. (Review) PMID 16251722
Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. Wu J, Nilsson A, Jonsson BA, Stenstad H, Agace W, Cheng Y, Duan RD. Biochem J 2006; 394: 299-308. PMID 16255717
Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites. Duan RD, Cheng Y, Jonsson BA, Ohlsson L, Herbst A, Hellstrom-Westas L, Nilsson A. Pediatr Res 2007; 61: 61-66. PMID 17211142
Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase. Duan RD, Verkade HJ, Cheng Y, Havinga R, Nilsson A. Biochim Biophys Acta 2007; 1771: 196-201. PMID 17204455
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Contributor(s) Written 08-2007 Rui-Dong Duan Biomedical B11, Institution of Clinical Sciences, Lund University, Lund, Sweden Citation This paper should be referenced as such : Duan RD . ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ENPP7ID44055ch17q25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 231 Atlas of Genetics and Cytogenetics in Oncology and Haematology
DMBT1 (Deleted in malignant brain tumors 1)
Identity Other names gp-340 (glycoprotein-340; human) SAG (salivary agglutinin; human) apactin (mouse) CRP-ductin (mouse) gp300 (glycoprotein 300; mouse) muclin (mouse) vomeroglandin (mouse) ebnerin (rat) hensin (rabbit) BGM (bovine gallbladder mucin, cattle) H3 (rhesus monkey) Hugo DMBT1 Location 10q26.13 Local_order between D10S1421 and D10S1273E DNA/RNA
Genomic organization of DMBT1. Top line: scale in kb. Second line: exon-intron structure of DMBT1 drawn to scale. Exons have the color code of the domains they are coding for. Exon 55 marked in black represents an exon with homology to the mouse and rat homologues, in which it codes for a transmembrane domain. Exon 55 has not yet been identified in a human transcript. Arrows depict regions, in which exon and intron sequences share high homologies. Bottom line: domain organization of the DMBT1 protein predicted from assembly of the first 54 exons. Entries to color codes and abbreviations are depicted in the section describing the protein. Description The gene consists of 55 exons distributed over about 80 kb. Scavenger receptor cysteine-rich (SRCR) domains are coded by single exons. Two small exons coding for serine-threonine-proline-rich stretches of 20-24 amino acids in length follow each SRCR exon. To these stretches it has been referred to as SRCR-interspersed domains (SIDs). The only exception is that there is only one of the two SID exons between SRCR4 and SRCR5. Transcription Longest transcript identified so far: 7656 bp including 5'-utr, exons 1-16 and exons 18-54. Various alternative transcripts with variable numbers of SRCR and SID exons exist. Exon 55 has not yet been verified to be present in human transcripts. Pseudogene No pseudogene known so far. Protein
Domain organization of DMBT1. Prototype: protein assembled from the first 54 exons (corresponding transcripts not yet identified). DMBT1/8kb.2: secreted DMBT1 variant encoded by the largest known transcript. DMBT1/6kb.1: secreted DMBT1 variant encoded by the smallest known transcript. Pink triangle: signal peptide putatively required for secretion; blue box repetitive motif of unknown function; red circles: scavenger receptor cysteine-rich (SRCR) domains; orange circles: SRCR-interspersed domains (SIDs); orange circles with TTT and STP: threonine- and serine-threonine-proline-rich domains with limited similarity to SIDs; CUB: C1r/C1s-Uegf-Bmp1 domains; ZP: zona pellucida domain. Description The largest known protein variant (DMBT1/8kb.2) comprises 2413 amino acids and has a calculated molecular weight of 265 kDa. Probably due to glycosylation the molecular weight of the purified protein is approximately 340 kDa. The smallest known variant
Atlas Genet Cytogenet Oncol Haematol 2008; 2 232 (DMBT1/6kb.1), which lacks several SRCR domains and SIDs, comprises 1785 amino acids with a calculated molecular weight of 196 kDa. Various other protein variants lacking one or more SRCR domains may exist. The protein variants may arise due to genetic polymorphisms and/or alternative splicing. The SRCR domains are involved in ligand interactions. An 11 amino acid motif (GRVEVLYRGSW) present in each of the repeated SRCR domains has been shown to be responsible for the binding of a broad spectrum of Gram-positive and Gram- negative bacteria. The N-terminal SRCR1/SD1 domain has been shown to interact with HIV gp120 and to suppress HIV infection. The functions of the CUB domains and of SRCR14, which shows only limited similarity to the other SRCR domains within DMBT1, have not yet been determined. In other proteins, ZP domains have been shown to function in oligomerization. DMBT1 is also secreted as high molecular weight oligomers. SRCR, CUB, and ZP domains exclusively occur in multicellular animal organisms. Expression Main sites of DMBT1 expression are surface epithelial cells and associated glands, in particular in the respiratory and gastrointestinal tract. In most tissues low to moderate DMBT1 levels are expressed under normal conditions. An upregulation has been observed in response to various pathophysiological conditions, such as bacterial infection, inflammation, tumor-flanking tissues, carcinogen exposure, etc. Expression has also been noted in other tissues such as the brain and in immune cells. Localisation Extracellular. DMBT1 is either secreted to the mucus and other body fluids or to the extracellular matrix. Function DMBT1 exerts at least two distinct functions. As extracellular matrix protein, DMBT1 triggers polarity and terminal differentiation of epithelial cells as well as differentiation of embryonic stem cells to monolayered epithelia, which has been demonstrated by in vitro studies with rodent orthologs of DMBT1. DMBT1 secreted to the luminal side of epithelial surfaces plays a role in defense against bacterial and viral pathogens. This mechanism includes pathogen recognition through a peptide motif present in the SRCR domains and mediation of pathogen aggregation. DMBT1 further has been shown to exert anti-inflammatory effects. In response to activation of the intracellular pattern recognition molecule NOD2 and consecutive NFkB-activation, upregulation of DMBT1 takes place, which in turn hinders bacterial invasion and LPS-induced TLR4-activation. Hindrance of bacterial invasion may abolish NOD2 activation. Thus DMBT1 may act anti-inflammatory via inhibiting both NOD2- and TLR4-mediated NF-kB-activation. As DMBT1 is NF-kB responsive, this presumably builds up an autoregulatory homeostatic loop, by which DMBT1 is able to regulate its own expression as extracellular sensory element. These data point to a function in anti-inflammatory immune exclusion similar to mucosal antibodies (sIgA). Homology Homologies exist to other SRCR proteins such as CD5 and CD6, which function in immune defense. However, to date there is no SRCR protein known that additionally contains CUB and ZP domains. At the level of the SRCR domains, DMBT1 further shares some homologies with the sponge aggregation receptor (AR), which initiates the first steps in regeneration of a complete sponge body after dissociation. Mutations Germinal Initial evidence has been gained that the SRCR- and SID-coding exons are subjected to copy number variations. Somatic Few point mutations have been identified in cancer so far. There is no hard evidence for an inactivation by biallelic mutation in cancer. Copy number variations of the SRCR- and SID-coding exons have been noted in different cancer types, including brain, lung, breast, gastrointestinal tumors and melanoma. It has not yet been determined to which extent these represent de novo rearrangements or germline mutations/polymorphisms. Underexpression has been observed for lung, colon, gastric, esophageal, breast, and skin cancer. By contrast overexpression was observed for pancreatic and prostate cancer. Implicated in Entity Cancer Disease Based on underexpression and on its role in triggering differentiation, a role in tumor suppression of different cancer types, mainly of epithelial origin, has been proposed. A genetic scan in mice identified DMBT1 as candidate genetic modifier, which may
Atlas Genet Cytogenet Oncol Haematol 2008; 2 233 determine the penetrance of breast cancer in the presence of p53 mutations. Lower DMBT1 protein levels have been observed in the normal mammary gland epithelium of women, which developed breast cancer versus tissues obtained from healthy donors. Entity Crohn's Disease Disease Activation of DMBT1 was found to be impaired in the intestinal epithelium of Crohn's disease with predisposing NOD2 mutations. Entity Infection Disease Based on its broad bacterial binding specificity and inhibitory effects on bacterial and viral (HIV, influenza A viruses) infection in vitro, a role in infectious diseases has been proposed. Entity Caries Disease DMBT1 alias SAG (salivary agglutinin) has been studied for about two decades as the major caries bacteria agglutinating non-immunoglobulin in the saliva/oral cavity. Based on its capacity to aggregate caries bacteria (e. g. Streptococcus mutans), it was proposed to exert functions in preventing caries. Based on its capacity to mediate bacterial adhesion to enamel-like surfaces, it was proposed to exert functions in promoting caries by other groups. External links Nomenclature Hugo DMBT1 GDB DMBT1 Entrez_Gene DMBT1 1755 deleted in malignant brain tumors 1 Cards Atlas DMBT1ID309ch10q26 GeneCards DMBT1 Ensembl DMBT1 [Search_View] ENSG00000187908 [Gene_View] Genatlas DMBT1 GeneLynx DMBT1 eGenome DMBT1 euGene 1755 Genomic and cartography DMBT1 - 10q26.13 chr10:124310171-124393242 + 10q25.3-q26.1 (hg18- GoldenPath Mar_2006) Ensembl DMBT1 - 10q25.3-q26.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene DMBT1 Gene and transcription Genbank AB209691 [ ENTREZ ] Genbank AF159456 [ ENTREZ ] Genbank AJ000342 [ ENTREZ ] Genbank AJ243212 [ ENTREZ ] Genbank AJ243224 [ ENTREZ ] RefSeq NM_004406 [ SRS ] NM_004406 [ ENTREZ ] RefSeq NM_007329 [ SRS ] NM_007329 [ ENTREZ ] RefSeq NM_017579 [ SRS ] NM_017579 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_030059 [ SRS ] NT_030059 [ ENTREZ ] RefSeq NW_924884 [ SRS ] NW_924884 [ ENTREZ ] AceView DMBT1 AceView - NCBI Unigene Hs.279611 [ SRS ] Hs.279611 [ NCBI ] HS279611 [ spliceNest ] Fast-db 16977 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9UGM3 [ SRS] Q9UGM3 [ EXPASY ] Q9UGM3 [ INTERPRO ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 234 Prosite PS01180 CUB [ SRS ] PS01180 CUB [ Expasy ] Prosite PS00420 SRCR_1 [ SRS ] PS00420 SRCR_1 [ Expasy ] Prosite PS50287 SRCR_2 [ SRS ] PS50287 SRCR_2 [ Expasy ] Prosite PS00682 ZP_1 [ SRS ] PS00682 ZP_1 [ Expasy ] Prosite PS51034 ZP_2 [ SRS ] PS51034 ZP_2 [ Expasy ] Interpro IPR000859 CUB [ SRS ] IPR000859 CUB [ EBI ] Interpro IPR001507 Endoglin/CD105 [ SRS ] IPR001507 Endoglin/CD105 [ EBI ] Interpro IPR001190 Srcr_rcpt [ SRS ] IPR001190 Srcr_rcpt [ EBI ] CluSTr Q9UGM3 Pfam PF00431 CUB [ SRS ] PF00431 CUB [ Sanger ] pfam00431 [ NCBI-CDD ] Pfam PF00530 SRCR [ SRS ] PF00530 SRCR [ Sanger ] pfam00530 [ NCBI-CDD ] PF00100 Zona_pellucida [ SRS ] PF00100 Zona_pellucida [ Sanger ] pfam00100 Pfam [ NCBI-CDD ] Smart SM00042 CUB [EMBL] Smart SM00202 SR [EMBL] Smart SM00241 ZP [EMBL] Blocks Q9UGM3 HPRD 03575 Protein Interaction databases DIP Q9UGM3 IntAct Q9UGM3 Polymorphism : SNP, mutations, diseases OMIM 137800;155255;601969 [ map ] GENECLINICS 137800;155255;601969 SNP DMBT1 [dbSNP-NCBI] SNP NM_004406 [SNP-NCI] SNP NM_007329 [SNP-NCI] SNP NM_017579 [SNP-NCI] SNP DMBT1 [GeneSNPs - Utah] DMBT1] [HGBASE - SRS] HAPMAP DMBT1 [HAPMAP] HGMD DMBT1 General knowledge Family Browser DMBT1 [UCSC Family Browser] SOURCE NM_004406 SOURCE NM_007329 SOURCE NM_017579 SMD Hs.279611 SAGE Hs.279611 GO scavenger receptor activity [Amigo] scavenger receptor activity GO scavenger receptor activity [Amigo] scavenger receptor activity GO scavenger receptor activity [Amigo] scavenger receptor activity GO extracellular region [Amigo] extracellular region GO extracellular region [Amigo] extracellular region GO cytoplasm [Amigo] cytoplasm GO cell cycle [Amigo] cell cycle GO pattern recognition receptor activity [Amigo] pattern recognition receptor activity GO membrane [Amigo] membrane GO phagocytic vesicle membrane [Amigo] phagocytic vesicle membrane GO epithelial cell differentiation [Amigo] epithelial cell differentiation GO epithelial cell differentiation [Amigo] epithelial cell differentiation GO induction of bacterial agglutination [Amigo] induction of bacterial agglutination GO innate immune response [Amigo] innate immune response GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle
Atlas Genet Cytogenet Oncol Haematol 2008; 2 235 GO calcium-dependent protein binding [Amigo] calcium-dependent protein binding PubGene DMBT1 Other databases Other database Largest DMBT1 variant (DMBT1/8kb.2) Other database Smallest DMBT1 variant (DMBT1/6kb.1) Probes Probe DMBT1 Related clones (RZPD - Berlin) PubMed PubMed 53 Pubmed reference(s) in LocusLink Bibliography Isolation and characterization of a new member of the scavenger receptor superfamily, glycoprotein-340 (gp-340), as a lung surfactant protein-D binding molecule. Holmskov U, Lawson P, Teisner B, Tornoe I, Willis AC, Morgan C, Koch C, Reid KB. J Biol Chem 1997; 272: 13743-13749. PMID 9153228
DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-q26.1 is deleted in malignant brain tumors. Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A. Nat Genet 1997; 17: 32-39. PMID 9288095
Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Lin H, Bondy ML, Langford LA, Hess KR, Delclos GL, Wu X, Chan W, Pershouse MA, Yung WK, Steck PA. Clin Cancer Res 1998; 4: 2447-2454. PMID 9796977
Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression. Somerville RP, Shoshan Y, Eng C, Barnett G, Miller D, Cowell JK. Oncogene 1998; 17: 1755-1757. PMID 9796706
Only multimeric hensin located in the extracellular matrix can induce apical endocytosis and reverse the polarity of intercalated cells. Hikita C, Takito J, Vijayakumar S, Al-Awqati Q. J Biol Chem 1999; 274: 17671-17676. PMID 10364206
Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D. Holmskov U, Mollenhauer J, Madsen J, Vitved L, Gronlund J, Tornoe I, Kliem A, Reid KB, Poustka A, Skjodt K. Proc Natl Acad Sci U S A 1999; 96: 10794-10799. PMID 10485905
The genomic structure of the DMBT1 gene: evidence for a region with susceptibility to genomic instability. Mollenhauer J, Holmskov U, Wiemann S, Krebs I, Herbertz S, Madsen J, Kioschis P, Coy JF, Poustka A. Oncogene 1999;18: 6233-6240. PMID 10597221
Lack of DMBT1 expression in oesophageal, gastric and colon cancers. Mori M, Shiraishi T, Tanaka S, Yamagata M, Mafune K, Tanaka Y, Ueo H, Barnard GF, Sugimachi K. Br J Cancer 1999; 79: 211-213. PMID 9888459
Atlas Genet Cytogenet Oncol Haematol 2008; 2 236
Expression of the DMBT1 gene is frequently suppressed in human lung cancer. Takeshita H, Sato M, Shiwaku HO, Semba S, Sakurada A, Hoshi M, Hayashi Y, Tagawa Y, Ayabe H, Horii A. Jpn J Cancer Res 1999; 90: 903-908. PMID 10551316
Hensin, the polarity reversal protein, is encoded by DMBT1, a gene frequently deleted in malignant gliomas. Takito J, Yan L, Ma J, Hikita C, Vijayakumar S, Warburton D, Al-Awqati Q. Am J Physiol 1999; 277: F277-289. PMID 10444583
Hensin remodels the apical cytoskeleton and induces columnarization of intercalated epithelial cells: processes that resemble terminal differentiation. Vijayakumar S, Takito J, Hikita C, Al-Awqati Q. J Cell Biol 1999;144: 1057-1067. PMID 10085301
Expression of DMBT1, a candidate tumor suppressor gene, is frequently lost in lung cancer. Wu W, Kemp BL, Proctor ML, Gazdar AF, Minna JD, Hong WK, Mao L. Cancer Res 1999; 59: 1846-1851. PMID 10213490
Processing of pro-Muclin and divergent trafficking of its products to zymogen granules and the apical plasma membrane of pancreatic acinar cells. De Lisle RC, Ziemer D. Eur J Cell Biol 2000; 79: 892-904. PMID 11152281
Induction of terminal differentiation in epithelial cells requires polymerization of hensin by galectin 3. Hikita C, Vijayakumar S, Takito J, Erdjument-Bromage H, Tempst P, Al-Awqati Q. J Cell Biol 2000; 151: 1235-1246. PMID 11121438
DMBT1 encodes a protein involved in the immune defense and in epithelial differentiation and is highly unstable in cancer. Mollenhauer J, Herbertz S, Holmskov U, Tolnay M, Krebs I, Merlo A, Schroder HD, Maier D, Breitling F, Wiemann S, Grone HJ, Poustka A. Cancer Res 2000; 60: 1704-1710. PMID 10749143
Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340. Prakobphol A, Xu F, Hoang VM, Larsson T, Bergstrom J, Johansson I, Frangsmyr L, Holmskov U, Leffler H, Nilsson C, Boren T, Wright JR, Stromberg N, Fisher SJ. J Biol Chem 2000; 275: 39860-39866. PMID 11007786
Human salivary agglutinin binds to lung surfactant protein-D and is identical with scavenger receptor protein gp-340. Ligtenberg TJ, Bikker FJ, Groenink J, Tornoe I, Leth-Larsen R, Veerman EC, Nieuw Amerongen AV, Holmskov U. Biochem J 2001; 359: 243-248. PMID 11563989
Deleted in Malignant Brain Tumors 1 is a versatile mucin-like molecule likely to play a differential role in digestive tract cancer. Mollenhauer J, Herbertz S, Helmke B, Kollender G, Krebs I, Madsen J, Holmskov U, Sorger K, Schmitt
Atlas Genet Cytogenet Oncol Haematol 2008; 2 237 L, Wiemann S, Otto HF, Grone HJ, Poustka A. Cancer Res 2001; 61: 8880-8886. PMID 11751412
Identification of the bacteria-binding peptide domain on salivary agglutinin (gp-340/DMBT1), a member of the scavenger receptor cysteine-rich superfamily. Bikker FJ, Ligtenberg AJ, Nazmi K, Veerman EC, van't Hof W, Bolscher JG, Poustka A, Nieuw Amerongen AV, Mollenhauer J. J Biol Chem 2002; 277: 32109-32115. PMID 12050164
Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1. Bisgaard HC, Holmskov U, Santoni-Rugiu E, Nagy P, Nielsen O, Ott P, Hage E, Dalhoff K, Rasmussen LJ, Tygstrup N. Am J Pathol 2002; 161: 1187-1198. PMID 12368192
Sequential changes of the DMBT1 expression and location in normal lung tissue and lung carcinomas. Mollenhauer J, Helmke B, Muller H, Kollender G, Lyer S, Diedrichs L, Holmskov U, Ligtenberg T, Herbertz S, Krebs I, Wiemann S, Madsen J, Bikker F, Schmitt L, Otto HF, Poustka A. Genes Chromosomes Cancer 2002; 35: 164-169. PMID 12203780
The SRCR/SID region of DMBT1 defines a complex multi-allele system representing the major basis for its variability in cancer. Mollenhauer J, Muller H, Kollender G, Lyer S, Diedrichs L, Helmke B, Holmskov U, Ligtenberg T, Herbertz S, Krebs I, Madsen J, Bikker F, Schmitt L, Wiemann S, Scheurlen W, Otto HF, von Deimling A, Poustka A. Genes Chromosomes Cancer 2002; 35: 242-255. PMID 12353266
Rare mutations of the DMBT1 gene in human astrocytic gliomas. Mueller W, Mollenhauer J, Stockhammer F, Poustka A, von Deimling A. Oncogene 2002; 21: 5956-5959. PMID 12185598
DMBT1 polymorphisms: relationship to malignant glioma tumorigenesis. Sasaki H, Betensky RA, Cairncross JG, Louis DN. Cancer Res 2002; 62: 1790-1796. PMID 11912156
Peptidomics-based approach reveals the secretion of the 29-residue COOH-terminal fragment of the putative tumor suppressor protein DMBT1 from pancreatic adenocarcinoma cell lines. Sasaki K, Sato K, Akiyama Y, Yanagihara K, Oka M, Yamaguchi K. Cancer Res 2002; 62: 4894-4898. PMID 12208737
Terminal differentiation of epithelia. Al-Awqati Q, Vijayakumar S, Takito J. Biol Chem 2003; 384: 1255-1258. REVIEW. PMID 14515985
Lung and salivary scavenger receptor glycoprotein-340 contribute to the host defense against influenza A viruses. Hartshorn KL, White MR, Mogues T, Ligtenberg T, Crouch E, Holmskov U. Am J Physiol Lung Cell Mol Physiol 2003; 285: L1066-L1076. PMID 12871854
Atlas Genet Cytogenet Oncol Haematol 2008; 2 238 DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration? Kang W, Reid KB. FEBS Lett 2003; 540: 21-25. REVIEW. PMID 12681477
CRP-ductin, the mouse homologue of gp-340/deleted in malignant brain tumors 1 (DMBT1), binds gram-positive and gram-negative bacteria and interacts with lung surfactant protein D. Madsen J, Tornoe I, Nielsen O, Lausen M, Krebs I, Mollenhauer J, Kollender G, Poustka A, Skjodt K, Holmskov U. Eur J Immunol 2003; 33: 2327-2336. PMID 12884308
Mutation analysis of DMBT1 in glioblastoma, medulloblastoma and oligodendroglial tumors. Pang JC, Dong Z, Zhang R, Liu Y, Zhou LF, Chan BW, Poon WS, Ng HK. Int J Cancer 2003;105: 76-81. PMID 12672033
Salivary agglutinin inhibits HIV type 1 infectivity through interaction with viral glycoprotein 120. Wu Z, Van Ryk D, Davis C, Abrams WR, Chaiken I, Magnani J, Malamud D. AIDS Res Hum Retroviruses 2003; 19: 201-209. PMID 12689412
Decrease of deleted in malignant brain tumour-1 (DMBT-1) expression is a crucial late event in intrahepatic cholangiocarcinoma. Sasaki M, Huang SF, Chen MF, Jan YY, Yeh TS, Ishikawa A, Mollenhauer J, Poustka A, Tsuneyama K, Nimura Y, Oda K, Nakanuma Y. Histopathology 2003; 43: 340-346. PMID 14511252
Bacteria binding by DMBT1/SAG/gp-340 is confined to the VEVLXXXXW motif in its scavenger receptor cysteine-rich domains. Bikker FJ, Ligtenberg AJ, End C, Renner M, Blaich S, Lyer S, Wittig R, van't Hof W, Veerman EC, Nazmi K, de Blieck-Hogervorst JM, Kioschis P, Nieuw Amerongen AV, Poustka A, Mollenhauer J. J Biol Chem 2004; 279: 47699-47703. PMID 15355985
Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression. Hustinx SR, Cao D, Maitra A, Sato N, Martin ST, Sudhir D, Iacobuzio-Donahue C, Cameron JL, Yeo CJ, Kern SE, Goggins M, Mollenhauer J, Pandey A, Hruban RH. Cancer Biol Ther 2004; 3: 1254-1261. PMID 15477757
Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis. Mollenhauer J, Helmke B, Medina D, Bergmann G, Gassler N, Muller H, Lyer S, Diedrichs L, Renner M, Wittig R, Blaich S, Hamann U, Madsen J, Holmskov U, Bikker F, Ligtenberg A, Carlen A, Olsson J, Otto HF, O'Malley B, Poustka A. Genes Chromosomes Cancer 2004; 39: 185-194. PMID 14732920
Inflammation of the cystic fibrosis mouse small intestine. Norkina O, Kaur S, Ziemer D, De Lisle RC. Am J Physiol Gastrointest Liver Physiol 2004; 286: G1032-G1041. PMID 14739145
The Scavenger Receptor Cysteine-Rich (SRCR) domain: an ancient and highly conserved protein module of the innate immune system. Sarrias MR, Gronlund J, Padilla O, Madsen J, Holmskov U, Lozano F. Crit Rev Immunol 2004; 24: 1-37. REVIEW.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 239 PMID 14995912
Conversion of ES cells to columnar epithelia by hensin and to squamous epithelia by laminin. Takito J, Al-Awqati Q. J Cell Biol 2004; 166: 1093-1102. PMID 15452149 gp340 (SAG) binds to the V3 sequence of gp120 important for chemokine receptor interaction. Wu Z, Golub E, Abrams WR, Malamud D. AIDS Res Hum Retroviruses 2004; 20: 600-607. PMID 15242536
Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer. Kang W, Nielsen O, Fenger C, Leslie G, Holmskov U, Reid KB. Carcinogenesis 2005; 26: 1129-1137. PMID 15760920
Respiratory innate immune proteins differentially modulate the neutrophil respiratory burst response to influenza A virus. White MR, Crouch E, Vesona J, Tacken PJ, Batenburg JJ, Leth-Larsen R, Holmskov U, Hartshorn KL. Am J Physiol Lung Cell Mol Physiol 2005; 289: L606-L616. PMID 15951332
Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene. Li Z, Szabolcs M, Terwilliger JD, Efstratiadis A. Carcinogenesis 2006; 27: 1054-1067. PMID 16401639
The N-terminal SRCR-SID domain of gp-340 interacts with HIV type 1 gp120 sequences and inhibits viral infection. Wu Z, Lee S, Abrams W, Weissman D, Malamud D. AIDS Res Hum Retroviruses 2006; 22: 508-515. PMID 16796526
Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk. Blackburn AC, Hill LZ, Roberts AL, Wang J, Aud D, Jung J, Nikolcheva T, Allard J, Peltz G, Otis CN, Cao QJ, Ricketts RS, Naber SP, Mollenhauer J, Poustka A, Malamud D, Jerry DJ. Am J Pathol 2007; 170: 2030-2041. PMID 17525270
Innate immunity glycoprotein gp-340 variants may modulate human susceptibility to dental caries. Jonasson A, Eriksson C, Jenkinson HF, Kallestal C, Johansson I, Stromberg N. BMC Infect Dis 2007; 7: 57. PMID 17562017
Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion. Rosenstiel P, Sina C, End C, Renner M, Lyer S, Till A, Hellmig S, Nikolaus S, Folsch UR, Helmke B, Autschbach F, Schirmacher P, Kioschis P, Hafner M, Poustka A, Mollenhauer J, Schreiber S. J Immunol 2007; 178: 8203-8311. PMID 17548659
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed
Atlas Genet Cytogenet Oncol Haematol 2008; 2 240 BiblioGene - INIST Search in all EBI NCBI
Contributor(s) Written 08-2007 Jan Mollenhauer, Annemarie Poustka Division of Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer, Feld 280, 69120 Heidelberg, Germany Citation This paper should be referenced as such : Mollenhauer J, Poustka A . DMBT1 (Deleted in malignant brain tumors 1). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/DMBT1ID309ch10q26.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 241 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CDKN2a, cyclin dependent kinase 2a / p16
Identity Other names CDKN2a p16 INK4 p16- INK4a TP16 CDK4I MTS1 Hugo CDKN2A Location 9p21.3 DNA/RNA Description The gene encompasses 6.6 kb of DNA; 3 exons. Transcription 471 nucleotides mRNA. The CDKN2 gene generates several transcript variants from different promoters. Each transcript differs in its first exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16-INK4 transcript. A putative DNA replication origin has been identified in close proximity of INK4/Arf locus that appears to transcriptionally repress p16 in a manner dependent on CDC6. Protein Description 156 amino acids; 16.5 kDa protein. Expression Moderately expressed in many organs as thymus, liver, pancreas, prostate, lung, or kidney. Function P16-INK4a interacts strongly with cyclin-dependent kinase 4 and cyclin-dependent kinase 6 and inhibits their ability to interact with cyclins D. P16-INK4a induces cell cycle arrest at G1 and G2/M checkpoints, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle. P16-INK4a could act as a negative regulator of normal cells proliferation. Homology Belongs to the cdkn2 cyclin-dependent kinase inhibitor family. Implicated in Entity Cutaneous malignant melanoma 2 (CMM2) Disease Malignant melanoma arises de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites. Oncogenesis Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait. CDKN2a has been identified as a major susceptibility gene for melanoma. However this gene accounts for a minority of familial melanoma. P16 is functionally inactivated by mutations or deletions, however, because many such mutations occur in exon 2, they can potentially also affect the alternative reading frame (ARF) protein. Entity Familial atypical multiple mole melanoma carcinoma syndrome (FAMMM) Disease Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer. Oncogenesis FAMMM syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Germline mutations in the p16-INK4a gene were found in approximately 40% of the FAMMM syndrome. Entity Sporadic cancer Disease Defects in CDKN2a are involved in tumor formation in a wide range of tissues. Prognosis Aberrant p16 expression is associated with more aggressive behavior. Oncogenesis LOH on 9p21 is one of the most frequent genetic alterations identified in human cancer.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 242 However, point mutations of p16 on the other chromosome are relatively rare. Promoter methylation appears as the commonest mechanism of p16 gene inactivation. Entity Aging Note Expression of p16 increases markedly with aging in many human tissues. This finding has led to the proposal that p16 expression could be used as a biomarker of physiologic, as opposed to chronologic, age. It was suggested that an age-induced increase in p16 expression contributes to the decline of replicative potential of certain self-renewing compartments with aging. External links Nomenclature Hugo CDKN2A GDB CDKN2A Entrez_Gene CDKN2A 1029 cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) Cards Atlas CDKN2aID146 GeneCards CDKN2A Ensembl CDKN2A [Search_View] ENSG00000147889 [Gene_View] Genatlas CDKN2A GeneLynx CDKN2A eGenome CDKN2A euGene 1029 Genomic and cartography GoldenPath CDKN2A - 9p21.3 chr9:21957752-21984490 - 9p21 (hg18-Mar_2006) Ensembl CDKN2A - 9p21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CDKN2A Gene and transcription Genbank AF115544 [ ENTREZ ] Genbank AI859822 [ ENTREZ ] Genbank AJ844636 [ ENTREZ ] Genbank AL582909 [ ENTREZ ] Genbank BC015960 [ ENTREZ ] RefSeq NM_000077 [ SRS ] NM_000077 [ ENTREZ ] RefSeq NM_058195 [ SRS ] NM_058195 [ ENTREZ ] RefSeq NM_058197 [ SRS ] NM_058197 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_008413 [ SRS ] NT_008413 [ ENTREZ ] RefSeq NW_924062 [ SRS ] NW_924062 [ ENTREZ ] AceView CDKN2A AceView - NCBI Unigene Hs.512599 [ SRS ] Hs.512599 [ NCBI ] HS512599 [ spliceNest ] Fast-db 3514 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q8N726 [ SRS] Q8N726 [ EXPASY ] Q8N726 [ INTERPRO ] Interpro IPR010868 P19Arf_N [ SRS ] IPR010868 P19Arf_N [ EBI ] CluSTr Q8N726 PF07392 P19Arf_N [ SRS ] PF07392 P19Arf_N [ Sanger ] pfam07392 [ NCBI-CDD Pfam ] Blocks Q8N726 HPRD 02542 Protein Interaction databases DIP Q8N726 IntAct Q8N726
Atlas Genet Cytogenet Oncol Haematol 2008; 2 243 Polymorphism : SNP, mutations, diseases OMIM 151623;155601;155755;600160;606719 [ map ] GENECLINICS 151623;155601;155755;600160;606719 SNP CDKN2A [dbSNP-NCBI] SNP NM_000077 [SNP-NCI] SNP NM_058195 [SNP-NCI] SNP NM_058197 [SNP-NCI] SNP CDKN2A [GeneSNPs - Utah] CDKN2A] [HGBASE - SRS] HAPMAP CDKN2A [HAPMAP] COSMIC CDKN2A [Somatic mutation (COSMIC-CGP-Sanger)] TICdb CDKN2A [Translocation breakpoints In Cancer] HGMD CDKN2A General knowledge Family Browser CDKN2A [UCSC Family Browser] SOURCE NM_000077 SOURCE NM_058195 SOURCE NM_058197 SMD Hs.512599 SAGE Hs.512599 GO cell cycle checkpoint [Amigo] cell cycle checkpoint GO G1/S transition of mitotic cell cycle [Amigo] G1/S transition of mitotic cell cycle negative regulation of cell-matrix adhesion [Amigo] negative regulation of cell-matrix GO adhesion GO DNA binding [Amigo] DNA binding cyclin-dependent protein kinase inhibitor activity [Amigo] cyclin-dependent protein GO kinase inhibitor activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO nucleoplasm [Amigo] nucleoplasm GO nucleolus [Amigo] nucleolus GO cytoplasm [Amigo] cytoplasm GO DNA fragmentation during apoptosis [Amigo] DNA fragmentation during apoptosis GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO rRNA processing [Amigo] rRNA processing negative regulation of protein kinase activity [Amigo] negative regulation of protein GO kinase activity GO apoptosis [Amigo] apoptosis GO induction of apoptosis [Amigo] induction of apoptosis GO induction of apoptosis [Amigo] induction of apoptosis GO caspase activation [Amigo] caspase activation GO cell cycle [Amigo] cell cycle GO cell cycle arrest [Amigo] cell cycle arrest GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO apoptotic mitochondrial changes [Amigo] apoptotic mitochondrial changes GO senescence [Amigo] senescence regulation of G2/M transition of mitotic cell cycle [Amigo] regulation of G2/M transition GO of mitotic cell cycle GO protein kinase binding [Amigo] protein kinase binding GO negative regulation of cell growth [Amigo] negative regulation of cell growth inhibition of NF-kappaB transcription factor [Amigo] inhibition of NF-kappaB GO transcription factor
Atlas Genet Cytogenet Oncol Haematol 2008; 2 244 GO negative regulation of phosphorylation [Amigo] negative regulation of phosphorylation negative regulation of cyclin-dependent protein kinase activity [Amigo] negative GO regulation of cyclin-dependent protein kinase activity GO NF-kappaB binding [Amigo] NF-kappaB binding BIOCARTA Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes] BIOCARTA Cyclins and Cell Cycle Regulation [Genes] BIOCARTA CTCF: First Multivalent Nuclear Factor [Genes] BIOCARTA Cell Cycle: G1/S Check Point [Genes] KEGG Cell cycle PubGene CDKN2A Other databases Probes Probe CDKN2A Related clones (RZPD - Berlin) PubMed PubMed 499 Pubmed reference(s) in LocusLink Bibliography Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. Cowan JM, Halaban R, Francke U. J Nat Cancer Inst 1988; 80: 1159-1164. PMID 3166071
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Serrano M, Hannon GJ, Beach D. Nature 1993; 366: 704-707. PMID 8259215
A cell cycle regulator potentially involved in genesis of many tumor types. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH. Science 1994; 264: 436-440. PMID 8153634
Germline p16 mutations in familial melanoma. Thiagalingam S, Lengauer C, Leach FS, Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WHJr, Tucker MA, Dracopoli NC. Nature Genet 1994; 8: 15-21. PMID 7987387
Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ. Genes Chromosomes Cancer 1995; 14: 189-195. PMID 8589035
Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W, Rutter JL, Buckler A, Gabrielson E, Tockman M, Cho KR, Hedrick L, Bova GS, Isaacs W, Koch W, Schwab D, Sidransky D. Nature Genet 1995; 11: 210-212. PMID 7550353
Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Koh J, Enders GH, Dynlacht BD, Harlow E. Nature 1995; 375: 506-510. PMID 7777061
Methylation and p16: suppressing the suppressor. Little M, Wainwright B. Nature Med 1995; 1: 633-634.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 245 PMID 7585141
5-prime CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. Nature Med 1995; 1: 686-692. PMID 7585152
Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Cell 1995; 83: 993-1000. PMID 8521522
Complex structure and regulation of the p16(MTS1) locus. Stone S, Jiang P, Dayananth P, Tavtigian SW, Katcher H, Parry D, Peter G, Kamb A. Cancer Res 1995; 55: 2988-2994. PMID 7606716
Role of the INK4a locus in tumor suppression and cell mortality. Serrano M, Lee HW, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Cell 1996; 85: 27-37. PMID 8620534
The CDKN2A (p16) gene and human cancer. Foulkes WD, Flanders TY, Pollock PM, Hayward NK. Mol Med 1997; 3: 5-20. PMID 9132280
Cloning and characterization of murine p16(INK4a) and p15(INK4b) genes. Quelle DE, Ashmun RA, Hannon GJ, Rehberger PA, Trono D, Richter KH, Walker C, Beach D, Sherr CJ, Serrano M. Proc Nat Acad Sci 1997; 94: 669-673. PMID 9012842
Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A. Nature 2001; 413: 83-85. PMID 11544530
Loss of p16(Ink4a) with retention of p19(Arf) predisposes mice to tumorigenesis. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA. Nature 2001; 413: 86-91. PMID 11544531
The INK4a/ARF locus and melanoma. Sharpless E, Chin L. Oncogene 2003; 22: 3092-3098. PMID 12789286
FAMMM syndrome: pathogenesis and management. Czajkowski R, Placek W, Drewa G, Czajkowska A, Uchanska G. Dermatol Surg 2004; 30: 291-296. PMID 14871223
Ink4a/Arf expression is a biomarker of aging. Krishnamurphy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regalev K, Su L, Sharpless NE. J Clin Invest 2004; 114: 1299-1307. PMID 15520862
Atlas Genet Cytogenet Oncol Haematol 2008; 2 246 Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M. Nature 2006; 440: 702-706. PMID 16572177 p16INK4a induces an age-dependent decline in islet regenerative potential. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. Nature 2006; 443: 453-457. PMID 16957737
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Contributor(s) Written 08-2004 Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire Laboratoire de Biochimie Biologie moleculaire, Hopital Paul Brousse 94800 Villejuif, France Updated 08-2007 Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire Laboratoire de Biochimie Biologie moleculaire, Hopital Paul Brousse 94800 Villejuif, France Citation This paper should be referenced as such : Saffroy R, Lemoine A, Debuire B . CDKN2a, cyclin dependent kinase 2a / p16. Atlas Genet Cytogenet Oncol Haematol. August 2004 . URL : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html Saffroy R, Lemoine A, Debuire B . CDKN2a, cyclin dependent kinase 2a / p16. Atlas Genet Cytogenet Oncol Haematol. August 2007. URL : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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BAG3 (Bcl-2 associated athanogene 3)
Identity Other names BAG-3 BIS CAIR-1 Hugo BAG3 Location 10q26.11 DNA/RNA Description The gene encompasses 26449 bases, 4 exons. Transcription 2608 nucleotides mRNA. Protein Description 575 amino acids. 74 kDa protein, belonging to the evolutionary conserved family of BAG domain- containing proteins. Expression BAG3 protein is constitutively expressed in muscle and a few other normal cell types, and in some tumors; its expression can be induced by stressors in a number of cell types. Localisation BAG3 is a cytoplasmatic protein, particularly concentrated in the rough endoplasmic reticulum; a slightly different molecular weight, a doublet form or a nuclear localisation can be observed in some cell types and/or following cell exposure to stressors. Function Through its BAG domain, BAG3 protein binds with high affinity to the ATPase domain of Hsc70 and regulates its chaperone activity in a Hip-modulated manner; through its PXXP region, BAG3 binds to the SH3 domain of PLC-gamma and forms an epidermal growth factor (EGF)-regulated ternary complex; the proline-rich repeat appears to be involved in regulating cell adhesion and migration, through an indirect effect on focal adhesion kinase (FAK) and its downstream partners; BAG3 knockout mice develop a fulminant myopathy; downmodulation of BAG3 protein levels enhance cell apoptotic response to several inducers, while hyperexpression protects cells from apoptosis. Homology Other members of BAG family. Mutations Note Unknown. Implicated in Entity B-chronic lymphocytic leukaemia Disease Expression of BAG3 gene in leukaemic cell samples from a study on 24 B-CLL-affected patients was detected by RT-PCR and immunofluorescence. Downmodulation of its levels by antisense ODNs resulted in enhancing cytochrome c release, caspase 3 activation and appearance of hypodiploid elements in response to fludarabine. Entity Childhood acute lymphoblastic leukemia Disease Expression of BAG3 gene in leukaemic cell samples from a study on 11 ALL- affected patients was detected by immunofluorescence. Downmodulation of its levels by antisense ODNs resulted in stimulating caspase 3 activity and enhancing by more that 100% the percentages of apoptotic elements in primary cultures, either untreated or incubated with cytosine arabinoside. Entity Thyroid Carcinomas Disease BAG3 was expressed in human thyroid carcinoma cell lines; small interfering RNA- mediated downmodulation of its levels significantly enhanced NPA cell apoptotic response to TRAIL. The protein was not detectable in 19 of 20 specimens of normal thyroid or goiters, whereas 54 of 56 analyzed carcinomas (15 follicular carcinomas, 28 papillary carcinomas, and 13 anaplastic carcinomas) were clearly positive for BAG3 expression. External links Nomenclature
Atlas Genet Cytogenet Oncol Haematol 2008; 2 248 Hugo BAG3 GDB BAG3 Entrez_Gene BAG3 9531 BCL2-associated athanogene 3 Cards Atlas BAG3ID43160ch10q26 GeneCards BAG3 Ensembl BAG3 [Search_View] ENSG00000151929 [Gene_View] Genatlas BAG3 GeneLynx BAG3 eGenome BAG3 euGene 9531 Genomic and cartography BAG3 - 10q26.11 chr10:121400872-121427317 + 10q25.2-q26.2 (hg18- GoldenPath Mar_2006) Ensembl BAG3 - 10q25.2-q26.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BAG3 Gene and transcription Genbank AF071218 [ ENTREZ ] Genbank AF095193 [ ENTREZ ] Genbank AF127139 [ ENTREZ ] Genbank AK222800 [ ENTREZ ] Genbank AK291333 [ ENTREZ ] RefSeq NM_004281 [ SRS ] NM_004281 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_030059 [ SRS ] NT_030059 [ ENTREZ ] RefSeq NW_924884 [ SRS ] NW_924884 [ ENTREZ ] AceView BAG3 AceView - NCBI Unigene Hs.702046 [ SRS ] Hs.702046 [ NCBI ] HS702046 [ spliceNest ] Fast-db 16902 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O95817 [ SRS] O95817 [ EXPASY ] O95817 [ INTERPRO ] Prosite PS51035 BAG [ SRS ] PS51035 BAG [ Expasy ] Prosite PS01159 WW_DOMAIN_1 [ SRS ] PS01159 WW_DOMAIN_1 [ Expasy ] Prosite PS50020 WW_DOMAIN_2 [ SRS ] PS50020 WW_DOMAIN_2 [ Expasy ] Interpro IPR003103 BAG [ SRS ] IPR003103 BAG [ EBI ] Interpro IPR001202 WW_Rsp5_WWP [ SRS ] IPR001202 WW_Rsp5_WWP [ EBI ] CluSTr O95817 Pfam PF02179 BAG [ SRS ] PF02179 BAG [ Sanger ] pfam02179 [ NCBI-CDD ] Pfam PF00397 WW [ SRS ] PF00397 WW [ Sanger ] pfam00397 [ NCBI-CDD ] Smart SM00264 BAG [EMBL] Smart SM00456 WW [EMBL] Blocks O95817 HPRD 04860 Protein Interaction databases DIP O95817 IntAct O95817 Polymorphism : SNP, mutations, diseases OMIM 603883 [ map ] GENECLINICS 603883 SNP BAG3 [dbSNP-NCBI]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 249 SNP NM_004281 [SNP-NCI] SNP BAG3 [GeneSNPs - Utah] BAG3] [HGBASE - SRS] HAPMAP BAG3 [HAPMAP] COSMIC BAG3 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD BAG3 General knowledge Family Browser BAG3 [UCSC Family Browser] SOURCE NM_004281 SMD Hs.702046 SAGE Hs.702046 GO protein binding [Amigo] protein binding GO cellular_component [Amigo] cellular_component GO cytosol [Amigo] cytosol GO protein folding [Amigo] protein folding GO apoptosis [Amigo] apoptosis GO anti-apoptosis [Amigo] anti-apoptosis GO Hsp70/Hsc70 protein regulator activity [Amigo] Hsp70/Hsc70 protein regulator activity PubGene BAG3 Other databases Probes Probe BAG3 Related clones (RZPD - Berlin) PubMed PubMed 26 Pubmed reference(s) in LocusLink Bibliography Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death. Lee JH, Takahashi T, Yasuhara N, Inazawa J, Kamada S, Tsujimoto Y. Oncogene 1999; 18: 6183-6190. PMID 10597216
CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70. Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA, Blanchette J, Rizzo K, Kohn E. Oncogene 2000; 19: 4385-4395. PMID 10980614
Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein. Antoku K, Maser RS, Scully WJ Jr, Delach SM, Johnson DE. Biochem Biophys Res Commun 2001; 286: 1003-1010. PMID 11527400
The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines. Liao Q, Ozawa F, Friess H, Zimmermann A, Takayama S, Reed JC, Kleeff J, Buchler MW. FEBS Lett 2001; 503: 151-157. PMID 11513873
Induction of Bis, a Bcl-2-binding protein, in reactive astrocytes of the rat hippocampus following kainic acid-induced seizure. Lee MY, Kim SY, Choi JS, Choi YS, Jeon MH, Lee JH, Kim IK, Lee JH. Exp Mol Med 2002; 34: 167-171. PMID 12085992
Reactive astrocytes express bis, a bcl-2-binding protein , after transient forebrain ischemia. Lee MY, Kim SY, Shin SL, Choi YS, Lee JH, Tsujimoto Y, Lee JH. Exp Neurol 2002; 175: 338-346. PMID 12061864
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CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. Doong H, Rizzo K, Fang S, Kulpa V, Weissman AM, Kohn EC. J Biol Chem 2003; 278: 28490-28500. PMID 10980614
Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity. Pagliuca MG, Lerose R, Cigliano S, Leone A. FEBS Lett 2003; 541: 11-15. PMID 12706811
BAG3 protein controls B-chronic lymphocytic leukaemia cell apoptosis. Romano MF, Festa M, Pagliuca G, Lerose R, Bisogni R, Chiurazzi F, Storti G, Volpe S, Venuta S, Turco MC, Leone A. Cell Death Differ 2003; 10: 383-385. PMID 12700638
BAG3 protein regulates cell survival in childhood acute lymphoblastic leukemia cells. Romano MF, Festa M, Putrella A, Rosati A, Pascale M, Bisogni R, Poggi L, Kohn EC, Venuta S, Turco MC, Leone A. Cancer Biol Ther 2003; 2: 508-510. PMID 14614315
BAG3 protein regulates stress-induced apoptosis in normal and neoplastic leukocytes. Bonelli P, Petrella A, Rosati A, Romano MF, Lerose R, Pagliuca MG, Amelio T, Festa M, Martire G, Venuta S, Turco MC, Leone A. Leukemia 2004; 18: 358-360. PMID 14628070
Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27. Seo YJ, Jeon MH, Lee JH, Lee YJ, Youn HJ, Ko JH, Lee JH. Exp Mol Med 2005; 6: 624-630. PMID 16391524
BAG3 deficiency results in fulminant myopathy and early lethality. Homma S, Iwasaki M, Shelton GD, Engval E, Reed JC, Takayama S. Am J Pathol 2006; 3: 761-773. PMID 16936253
CAIR-1/BAG-3 modulates cell adhesion and migration by downregulating activity of focal adhesion proteins. Kassis JN, Guancial EA, Doong H, Virador V, Kohn EC. Exp Cell Res 2006; 15: 26962-26971. PMID 16859681
The anti-apoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by Tumor necrosis Factor-Related Apoptosis-inducing Ligand (Trail). Chiappetta G, Ammirante M, Basile A, Rosati A, Festa M, Monaco M, Vuttariello E, Pasquinelli R, Arra C, Zerilli M, Todaro M, Stassi G, Pezzullo L, Gentilella A, Tosaco A, Pascale M, Marzullo L, Belisario MA, Turco MC, Leone A. J Clin Endocrinol Metab 2007; 3: 1159-1163. PMID 17164298
Evidence for BAG3 Modulation of HIV-1 Gene Transcription. Rosati A, Leone A, Del Valle L, Amini S, Turco MC, Khalili K. J Cell Physiol 2007; 3: 676-683. PMID 17187345
Atlas Genet Cytogenet Oncol Haematol 2008; 2 251 Apoptosis inhibition in cancer cells: A novel molecular pathway that involves BAG3 protein. Rosati A, Ammirante M, Gentilella A, Basile A, Festa M, Pascale M, Marzullo L, Belisario MA, Tosco A, Franceschelli S, Moltedo O, Pagliuca G, Lerose R, Turco MC. Int J Biochem Cell Biol 2007; 39(7-8): 1337-1342. PMID 17493862
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Contributor(s) Written Arturo Leone, Alessandra Rosati, Massimo Ammirante, Maria Caterina 08-2007 Turco Department of Pharmaceutical Sciences, University of Salerno, 84084, Fisciano (SA), Italy Citation This paper should be referenced as such : Leone A, Rosati A, Ammirante M, Turco MC . BAG3 (Bcl-2 associated athanogene 3). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BAG3ID43160ch10q26.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 252 Atlas of Genetics and Cytogenetics in Oncology and Haematology
SPA17 (sperm autoantigenic protein 17)
Identity Other names SP17 SP17-1 Hugo SPA17 Location 11q24.2 DNA/RNA Description The SPA17 gene contains 5 exons and 4 introns and was predicted to span over approximately 23 kb of the genomic DNA. The first exon is encodes solely the 5' untranslated sequence. The exon 2 encodes the first 51 amino acid residue. Exon 3 and 4 are only 71 and 87 bp length and contain coding region. Exon 5 contains stop codon and followed by 3' untranslated sequence. The size of introns 2, 3 and 4 were 5970, 10.235 and 2520 bp, respectively. Transcription Two transcript variants encoding the same protein have been identified for SP17-1 gene. This variant which was named SP17-1A and SP17-1B, both cDNA encodes identical protein sequence and only differed in 5' UTR part. One hundred percent homology can be detected from the poly A tail up to SP17-1 position -62 for variant A and -31 for variant B. Pseudogene There is one pseudogene, SP17-2 intronless gene has all the hallmark of retro-position giving rise to a pseudogene, located on chromosome 10. SP17-2 gene had 61 point mutations, 4 nucleotide insertions and 2 deletions leading to internal stop codons and frame shifts which do not result in ORF encoding a full-length SPA17 polypeptide. Protein Description The SPA17 consists of 151 amino acids corresponding to a molecular weight of 17.4 kDa. SPA17 protein indicated to have functional role in cell regulation by its calmodulin binding site located at its C-terminal end. The N-terminal end of SPA17, similar to human cyclic adenosine 3'-5'-monophosphate (cAMP)-dependent protein kinase type II regulatory subunits (RII), may facilitate dimmer formation. SPA17's central domain is necessary for heparin-binding and exhibits the greatest sequence divergence of all three domains. This region plays an important role in cell-cell and/or cell matrix recognition process and/or cell regulation, possibly via its interaction with extra cellular heparin sulfate. Expression The SPA17 expression was originally found to be expressed exclusively in the testis. Recently, this gene also found in other somatic tissues. Localisation SPA17 is present throughout the cytoplasm and is particularly concentrated around the nucleus. It's also present on the surface of B-lymphocytes and granulocytes; T- lymphocytes and monocytes; most malignant B and T lymphocytes cell lines. Function SPA17 is highly antigenic, testes specific antigen and known have function to bind sperm to the zona pellucida of the oocyte. In addition, SPA17 may also have an alternative role in highly proliferating and neoplastic cells, such as a mediator of signal transduction, protein synthesis and/or unregulated growth. Homology The homologues of SPA17 protein sequences were found from eutherian and marsupial mammals, including rat, mouse, macaque, baboon, human, marmoset, rabbit, Monodelphis and wallaby. Implicated in Entity Immune system Disease SPA17 is a highly immunogenic protein. More than 90% of male spontaneously developed B-cell immunity of SPA17 following vasectomy. SPA17 can be easily generated SPA17-specific cytotoxic T lymphocytes (CTLs) from peripheral blood of healthy donors and also from peripheral blood of cancer-bearing patients. SPA17 have been tested as tumor vaccines in a phase I study. In addition, SPA17 gene was described in human rheumatoid arthritis (RA).
Atlas Genet Cytogenet Oncol Haematol 2008; 2 253 Entity Malignancy Disease SPA17 reported to be over-expressed in female reproduction organ, multiple myeloma, esthesioneuroblastoma, nervous system tumors and esophageal cancer. Prognosis SPA17 expression closely related with poor prognosis in malignancy. Oncogenesis SPA17 was identified as a candidate gene related to chemoresistance of clear cell adenocarcinoma of the ovary, which has a poor prognosis due to its chemoresistancy and early metastasis to the lymph nodes. External links Nomenclature Hugo SPA17 GDB SPA17 Entrez_Gene SPA17 53340 sperm autoantigenic protein 17 Cards GeneCards SPA17 Ensembl SPA17 [Search_View] ENSG00000064199 [Gene_View] Genatlas SPA17 GeneLynx SPA17 eGenome SPA17 euGene 53340 Genomic and cartography GoldenPath SPA17 - 11q24.2 chr11:124048950-124069895 + 11q24.2 (hg18-Mar_2006) Ensembl SPA17 - 11q24.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene SPA17 Gene and transcription Genbank AF334735 [ ENTREZ ] Genbank BC019224 [ ENTREZ ] Genbank BC032457 [ ENTREZ ] Genbank CR602938 [ ENTREZ ] Genbank CR625142 [ ENTREZ ] RefSeq NM_017425 [ SRS ] NM_017425 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_033899 [ SRS ] NT_033899 [ ENTREZ ] RefSeq NW_925173 [ SRS ] NW_925173 [ ENTREZ ] AceView SPA17 AceView - NCBI Unigene Hs.286233 [ SRS ] Hs.286233 [ NCBI ] HS286233 [ spliceNest ] Fast-db 14784 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q15506 [ SRS] Q15506 [ EXPASY ] Q15506 [ INTERPRO ] Prosite PS50096 IQ [ SRS ] PS50096 IQ [ Expasy ] IPR003117 cAMP-dep_prot_kin_reg_I/II_a/b [ SRS ] IPR003117 cAMP- Interpro dep_prot_kin_reg_I/II_a/b [ EBI ] Interpro IPR000048 IQ_CaM_bd_region [ SRS ] IPR000048 IQ_CaM_bd_region [ EBI ] Interpro IPR012105 Sp17 [ SRS ] IPR012105 Sp17 [ EBI ] CluSTr Q15506 Pfam PF00612 IQ [ SRS ] PF00612 IQ [ Sanger ] pfam00612 [ NCBI-CDD ] Pfam PF02197 RIIa [ SRS ] PF02197 RIIa [ Sanger ] pfam02197 [ NCBI-CDD ] Smart SM00015 IQ [EMBL] Smart SM00394 RIIa [EMBL] Blocks Q15506 HPRD 12272 Protein Interaction databases
Atlas Genet Cytogenet Oncol Haematol 2008; 2 254 DIP Q15506 IntAct Q15506 Polymorphism : SNP, mutations, diseases OMIM 608621 [ map ] GENECLINICS 608621 SNP SPA17 [dbSNP-NCBI] SNP NM_017425 [SNP-NCI] SNP SPA17 [GeneSNPs - Utah] SPA17] [HGBASE - SRS] HAPMAP SPA17 [HAPMAP] HGMD SPA17 General knowledge Family Browser SPA17 [UCSC Family Browser] SOURCE NM_017425 SMD Hs.286233 SAGE Hs.286233 GO signal transduction [Amigo] signal transduction GO spermatogenesis [Amigo] spermatogenesis GO single fertilization [Amigo] single fertilization GO binding of sperm to zona pellucida [Amigo] binding of sperm to zona pellucida cAMP-dependent protein kinase regulator activity [Amigo] cAMP-dependent protein GO kinase regulator activity GO membrane [Amigo] membrane PubGene SPA17 Other databases Probes Probe SPA17 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography Characterization of the rabbit sperm membrane autoantigen, RSA, as a lectin-like zona binding protein. O'Rand MG, Widgren EE, Fisher SJ. Dev Biol 1988; 129: 231-240. PMID 3410159 cAMP dependent protein kinase: framework for a diverse family of regulatory enzymes. Taylor SS, Buechler JA, Yonemoto W. Annu Rev Biochem 1990; 59: 971-1005. PMID 2165385
Cloning and sequencing of cDNAs encoding the human sperm protein, Sp17. Lea IA, Richardson RT, Widgren EE, O'Rand MG. Biochim Biophys Acta 1996; 1307: 263-266. PMID 8688458
Autoimmunity of the human sperm protein Sp17 in vasectomized men and identification of linear B epitopes. Lea IA, Adoyo P, O'Rand MG. Fertil Steril 1997; 67: 355-361. PMID 9022615
Idiotypic protein-pulsed dendritic cell vaccination in multiple myeloma. Lim SH, Bailey-Wood R. Int J Cancer 1999; 83: 215-222. PMID 10471530
Processing of the sperm protein Sp17 during the acrosome reaction and characterization as a
Atlas Genet Cytogenet Oncol Haematol 2008; 2 255 calmodulin binding protein. Wen Y, Richardson RT, O'rand MG. Dev Biol 1999; 206: 113-122. PMID 9986726
Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk. Chiriva-Internati M, Wang Z, Xue Y, Bumm K, Hahn AB, Lim SH. Eur J Immunol 2001; 31: 2277-2283. PMID 11477539
Sperm protein 17 is expressed on normal and malignant lymphocyte and promotes heparin sulfate-mediated cell-cell adhesion. Lacy HM, Sanderson RD. Blood 2001; 98: 2160-2165. PMID 11568003
Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Blood 2001; 97: 1508-1510. PMID 11222401
Characterization of Sp17: a ubiquitous three domain protein that binds heparin. Wen Y, Richardson RT, Widgren EE, O'Rand MG. Biochem J 2001; 357: 25-31. PMID 11415432
Genomic organization of an intron-containing sperm protein 17 gene (Sp17-1) and an intronless pseudogene (Sp17-2) in humans: a new model. Buchli R, De Jong A, Robbins DL. Biochim Biophys Acta 2002; 1578: 29-42. PMID 12393185
Sperm protein (Sp17) is a suitable target for immunotherapy of multiple myeloma. Chiriva-Internati M, Wang Z, Salati E, Bumm K, Barlogie B, Lim SH. Blood 2002; 100: 961-995. PMID 12130509
Tumor vaccine for ovarian carcinoma targeting sperm protein 17. Chiriva-Internati M, Wang Z, Salati E, Timmins P, Lim SH. Cancer 2002; 94: 2447-2453. PMID 12015770
Successful generation of sperm protein 17 (Sp17)-specific cytotoxic T lymphocytes from normal donors: implication for tumour-specific adoptive immunotherapy following allogeneic stem cell transplantation for Sp17-positive multiple myeloma. Chiriva-Internati M, Wang Z, Salati E, Wroblewski D, Lim SH. Scan J Immunol 2002; 56: 429-433. PMID 12234264
Characterization sperm protein 17 in human somatic and neoplastic tissue. De Jong A, Buchli R, Robbins D. Cancer Lett 2002; 186: 201-209. PMID 12213290
Expression of sperm protein 17 (Sp17) in ovarian cancer. Straughn JM Jr, Shaw DR, Guerrero A, Bhoola SM, Racelis A, Wang Z, Chiriva-Internati M, Grizzle WE, Alvarez RD, Lim SH, Strong TV. Int J Cancer 2004; 108: 805-811.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 256 PMID 14712480
Sperm protein 17 expression defines 2 subsets of primary esthesioneuroblastoma. Bumm K, Grizzi F, Franceschini B, Koch M, Iro H, Wurm J, Ceva-Grimaldi G, Dimmler A, Cobos E, Dioguardi N, Sinha UK, Kast WM, Chiriva-Internati M. Hum Pathol 2005; 36: 1289-1293. PMID 16311122
Sperm protein 17 is expressed in human nervous system tumors. Grizzi F, Gaetani P, Franceschini B, Di Ieva A, Colombo P, Ceva-Grimaldi G, Bollati A, Frezza EE, Cobos E, Rodriguez y Baena R, Dioguardi N, Chiriva-Internati M. BMC Cancer 2006; 6: 23. PMID 16438728
Clinical significance of sperm protein 17 expression and immunogenicity in esophageal cancer. Gupta G, Sharma R, Chattopadhyay TK, Gupta SD, Ralhan R. Int J Cancer 2007; 120: 1739-1748. PMID 17230514
Sperm protein 17 influences the tissue-specific malignancy of clear cell adenocarcinoma in human epithelial ovarian cancer. Nakazato T, Kanuma T, Tamura T, Faried LS, Aoki H, Minegishi T. Int J Gynecol Cancer 2007; 17: 426-432. PMID 17309563
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Contributor(s) Written 09-2007 Leri S. Faried, Ahmad Faried Department of Gynecology and Reproductive Medicine, Graduate School of Medicine, Gunma University, Japan (FLS); Department of Surgery I, Gunma University, Japan (FA). Citation This paper should be referenced as such : Faried LS, Faried A . SPA17 (sperm autoantigenic protein 17). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/SPA17ID42360ch11q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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SOCS1 (Suppressor of cytokine signaling 1)
Identity Other names JAB (JAK binding protein) CIS1 (cytokine-inducible SH2 protein 1) SSI1 (STAT-induced STAT inhibitor) TIP3 (Tec-interacting protein 3) CISH1 SSI-1 Hugo SOCS1 Location 16p13.13 DNA/RNA
The sequence numbering shown under the central diagram are according to Genebank accession no. NC000016 for SOCS1 DNA. Description The SOCS1 gene is divided in 2 exons. The exon 1 contains the 5'untranslated region. The exon 2 contains part of 5'untranslated region, the translation initiation ATG, the stop codon, and the 3'untranslated region. Transcription The 1216 bases of human SOCS1 mRNA contains an open reading frame of 633 bases, resulting in a protein of 211 amino acid residues. Protein Description The SOCS1 is a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. The SSI family members are cytokine-inducible negative regulators of cytokine signaling. The SOCS1 possesses tumor suppressor function. Localisation Cytoplasmic. Function The SOCS1 functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. The SOCS1 is rapidly induced following stimulation by several type I and type II cytokines, and it attenuates their signaling by its ability to bind and inhibit all four of the Janus family of intracellular tyrosine kinases (JAKs). The SOCS1 functions as a negative regulator in TNF-induced inflammation and activation of c-jun N-terminal kinase by mediating ASK1 degradation in endothelial cells. The SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC and targets Jak1 to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Mutations Note Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma are frequent. Somatic 191-218del (V64S, out-of-frame), 349-359del (V117, out-of-frame), 393-417del (Q131H, delA132-H136), 431-512del (F144C, out-of-frame), 435-446del (D145E, delC146-E149), 448C>G (L150V) The sequence numberings are according to the Genebank accession number NM_003745 for SOCS1 mRNA. Implicated in
Atlas Genet Cytogenet Oncol Haematol 2008; 2 258 Entity Various cancers and diseases Note Aberrant methylation in the CpG island of SOCS1. Disease Hepatocellular carcinoma, hepatoblastoma, hepatitis C virus-associated chronic hepatitis and liver cirrhosis, brain tumor, head and neck squamous cell carcinoma, gastric carcinoma, pancreatic cancer, colorectal cancer, acute myeloid leukemia, multiple myeloma, myelodysplastic syndrome, chronic myeloid leukemia. Oncogenesis Loss-of-expression by aberrant DNA methylation. Entity Hodgkin lymphoma, NOTE Somatic origin. Oncogenesis Loss-of-function mutations. External links Nomenclature Hugo SOCS1 GDB SOCS1 Entrez_Gene SOCS1 8651 suppressor of cytokine signaling 1 Cards GeneCards SOCS1 Ensembl SOCS1 [Search_View] ENSG00000185338 [Gene_View] Genatlas SOCS1 GeneLynx SOCS1 eGenome SOCS1 euGene 8651 Genomic and cartography GoldenPath SOCS1 - 16p13.13 chr16:11255775-11257540 - 16p13.13 (hg18-Mar_2006) Ensembl SOCS1 - 16p13.13 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene SOCS1 Gene and transcription Genbank AB000676 [ ENTREZ ] Genbank AB000734 [ ENTREZ ] Genbank AB005043 [ ENTREZ ] Genbank AK127621 [ ENTREZ ] Genbank BC029307 [ ENTREZ ] RefSeq NM_003745 [ SRS ] NM_003745 [ ENTREZ ] RefSeq AC_000059 [ SRS ] AC_000059 [ ENTREZ ] RefSeq NC_000016 [ SRS ] NC_000016 [ ENTREZ ] RefSeq NT_010393 [ SRS ] NT_010393 [ ENTREZ ] RefSeq NW_926018 [ SRS ] NW_926018 [ ENTREZ ] AceView SOCS1 AceView - NCBI Unigene Hs.50640 [ SRS ] Hs.50640 [ NCBI ] HS50640 [ spliceNest ] Fast-db 3574 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O15524 [ SRS] O15524 [ EXPASY ] O15524 [ INTERPRO ] Prosite PS50001 SH2 [ SRS ] PS50001 SH2 [ Expasy ] Prosite PS50225 SOCS [ SRS ] PS50225 SOCS [ Expasy ] Interpro IPR000980 SH2 [ SRS ] IPR000980 SH2 [ EBI ] Interpro IPR001496 SOCS_C [ SRS ] IPR001496 SOCS_C [ EBI ] CluSTr O15524 Pfam PF00017 SH2 [ SRS ] PF00017 SH2 [ Sanger ] pfam00017 [ NCBI-CDD ] PF07525 SOCS_box [ SRS ] PF07525 SOCS_box [ Sanger ] pfam07525 [ NCBI- Pfam CDD ] Smart SM00252 SH2 [EMBL] Smart SM00253 SOCS [EMBL] Prodom PD000093 SH2[INRA-Toulouse]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 259 O15524 SOCS1_HUMAN [ Domain structure ] O15524 SOCS1_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks O15524 HPRD 04669 Protein Interaction databases DIP O15524 IntAct O15524 Polymorphism : SNP, mutations, diseases OMIM 603597 [ map ] GENECLINICS 603597 SNP SOCS1 [dbSNP-NCBI] SNP NM_003745 [SNP-NCI] SNP SOCS1 [GeneSNPs - Utah] SOCS1] [HGBASE - SRS] HAPMAP SOCS1 [HAPMAP] COSMIC SOCS1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD SOCS1 General knowledge Family Browser SOCS1 [UCSC Family Browser] SOURCE NM_003745 SMD Hs.50640 SAGE Hs.50640 GO regulation of cell growth [Amigo] regulation of cell growth regulation of protein amino acid phosphorylation [Amigo] regulation of protein amino GO acid phosphorylation GO protein kinase inhibitor activity [Amigo] protein kinase inhibitor activity insulin-like growth factor receptor binding [Amigo] insulin-like growth factor receptor GO binding GO protein binding [Amigo] protein binding GO cytoplasm [Amigo] cytoplasm GO ubiquitin cycle [Amigo] ubiquitin cycle GO intracellular signaling cascade [Amigo] intracellular signaling cascade GO JAK-STAT cascade [Amigo] JAK-STAT cascade cytokine and chemokine mediated signaling pathway [Amigo] cytokine and chemokine GO mediated signaling pathway GO protein kinase binding [Amigo] protein kinase binding negative regulation of tyrosine phosphorylation of Stat3 protein [Amigo] negative GO regulation of tyrosine phosphorylation of Stat3 protein GO fat cell differentiation [Amigo] fat cell differentiation negative regulation of JAK-STAT cascade [Amigo] negative regulation of JAK-STAT GO cascade negative regulation of JAK-STAT cascade [Amigo] negative regulation of JAK-STAT GO cascade negative regulation of insulin receptor signaling pathway [Amigo] negative regulation GO of insulin receptor signaling pathway KEGG Jak-STAT signaling pathway KEGG Insulin signaling pathway KEGG Type II diabetes mellitus PubGene SOCS1 Other databases HREF="http://www.biocarta.com/pathfiles/h_il2rbPathway.asp">BIOCARTA: IL-2 Other database Receptor Beta Chain in T cell Activation Probes Probe SOCS1 Related clones (RZPD - Berlin) PubMed
Atlas Genet Cytogenet Oncol Haematol 2008; 2 260 PubMed 91 Pubmed reference(s) in LocusLink Bibliography A novel cytokine-inducible gene CIS, encodes an SH2-containing protein that binds to tyrosine- phosphorylated interleukin 3 and erythropoietin receptors. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A. EMBO J 1995; 14: 2816-2826. PMID 7796808
A new protein containing an SH2 domain that inhibits JAK kinases. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. Nature 1997; 387: 921-924. PMID 9202126
SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase. Ohya K, Kajigaya S, Yamashita Y, Miyazato A, Hatake K, Miura Y, Ikeda U, Shimada K, Ozawa K, Mano H. J Biol Chem 1997; 272: 27178-27182. PMID 9341160
A family of cytokine-inducible inhibitors of signalling. Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ. Nature 1997; 387: 917-921. PMID 9202125
Twenty proteins containing a C-terminal SOCS box form five structural classes. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, Starr R, Nicholson SE, Metcalf D, Nicola NA. Proc Nat Acad Sci 1998; 95: 114-119. PMID 9419338
A matrix associated region localizes the human SOCS-1 gene to chromosome 16p13.13. Kramer JA, Adams MD, Singh GB, Doggett NA, Krawetz SA. Somat Cell Molec Genet 1998; 24: 131-133. PMID 9919312
Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS. Proc Nat Acad Sci 1998; 95: 14395-14399. PMID 9826711
SOCS1 is a critical inhibitor of interferon-gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TWH; Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ. Cell 1999; 98: 597-608. PMID 10490099
SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN. Cell 1999; 98: 609-616. PMID 10490100
Inactivation of SSI-1, a JAK/STAT inhibitor, in human hepatocellular carcinomas, as revealed by two-dimensional electrophoresis. Nagai H, Kim YS, Lee KT, Chu MY, Konishi N, Fujimoto J, Baba M, Matsubara K, Emi M. J Hepatol 2001; 34: 416-421.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 261 PMID 11322203
SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG. Nature Genet 2001; 28: 29-35. PMID 11326271
Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Metcalf D, Mifsud S, Di Rago L, Nicola NA, Hilton DJ, Alexander WS. Proc Nat Acad Sci 2002; 99: 943-948. PMID 11782537
TRIM8/GERP RING finger protein interacts with SOCS-1. Toniato E, Chen XP, Losman J, Flati V, Donahue L, Rothman P. J Biol Chem 2002; 277: 37315-37322. PMID 12163497
Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Zardo G, Tiirikainen MI, Hong C, Misra A, Feuerstein BG, Volik S, Collins CC, Lamborn KR, Bollen A, Pinkel D, Albertson DG, Costello JF. Nature Genet 2002; 32: 453-458. PMID 12355068
Persistence of lesions in suppressor of cytokine signaling-1-deficient mice infected with Leishmania major. Bullen DVR, Baldwin TM, Curtis JM, Alexander WS, Handman E. J Immun 2003; 170: 4267-4272. PMID 12682261
SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Chen CY, Tsay W, Tang JL, Shen HL, Lin SW, Huang SY, Yao M, Chen YC, Shen MC, Wang CH, Tien HF. Genes Chromosomes Cancer 2003; 37: 300-305. PMID 12759928
Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. Fukushima N, Sato N, Sahin F, Su GH, Hruban RH, Goggins M. Br J Cancer 2003; 89: 338-343. PMID 12865927
SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG. Blood 2003; 101: 2784-2788. PMID 12456503
Regulation of cytokine receptor signaling by SOCS1. Ilangumaran S, Rottapel R. Immunol Rev 2003; 192: 196-211. PMID 12670405
Epigenetic alteration of the SOCS1 gene in chronic myeloid leukaemia. Liu TC, Lin SF, Chang JG, Yang MY, Hung Sy, Chang CS. Br J Haematol 2003; 123: 654-661. PMID 14616969
Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in
Atlas Genet Cytogenet Oncol Haematol 2008; 2 262 human hepatoblastomas. Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, Kawanami O, Kishimoto T, Konishi N, Nakamura M, Kobayashi Y, Emi M. J Hum Genet 2003; 48: 65-69. PMID 12601549
Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Okochi O, Hibi K, Sakai M, Inoue S, Takeda S, Kaneko T, Nakao A. Clin Cancer Res 2003; 9: 5295-5298. PMID 14614012
The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus- induced cardiac injury. Yasukawa H, Yajima T, Duplain H, Iwatate M, Kido M, Hoshijima M, Weitzman MD, Nakamura T, Woodard S, Xiong D, Yoshimura A, Chien KR, Knowlton KU. J Clin Invest 2003; 111: 469-478. PMID 12588885
Aberrant methylation of SOCS-1 was observed in younger colorectal cancer patients. Fujitake S, Hibi K, Okochi O, Kodera Y, Ito K, Akiyama S, Nakao A. J Gastroenterol 2004; 39: 120-124. PMID 15074307
Hypermethylation-associated inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human pancreatic cancers. Komazaki T, Nagai H, Emi M, Terada Y, Yabe A, Jin E, Kawanami O, Konishi N, Moriyama Y, Naka T, Kishimoto T. Jpn J Clin Oncol 2004; 34: 191-194. PMID 15121754
Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma. Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi T, Makuuchi M, Kimura S, Koike K. J Gastroenterol 2004; 39: 563-569. PMID 15235874
Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Oshimo Y, Kuraoka K, Nakayama H, Kitadai Y, Yoshida K, Chayama K, Yasui W. Int J Cancer 2004; 112: 1003-1009. PMID 15386345
SOCS-1 localizes to the microtubule organizing complex-associated 20S proteasome. Vuong BQ, Arenzana TL, Showalter BM, Losman J, Chen XP, Mostecki J, Banks AS, Limnander A, Fernandez N, Rothman PB. Mol Cell Biol 2004; 24: 9092-9101. PMID 15456882
SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y, Sata M, Nagai H, Yoshimura A. J Exp Med 2004; 199: 1701-1707. PMID 15197228
Hypermethylation of the suppressor of cytokine signalling-1 (SOCS-1) in myelodysplastic syndrome. Brakensiek K, Langer F, Schlegelberger B, Kreipe H, Lehmann U. Br J Haematol 2005; 130: 209-217. PMID 16029449
Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in
Atlas Genet Cytogenet Oncol Haematol 2008; 2 263 myelodysplastic syndromes and acute myeloid leukaemia. Johan MF, Bowen DT, Frew ME, Goodeve AC, Reilly JT. Br J Haematol 2005; 129: 60-65. PMID 15801956
SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. Evel-Kabler K, Song XT, Aldrich M, Huang XF, Chen SY. J Clin Invest 2006; 116: 90-100. PMID 16357940
IFN-gamma-dependent, spontaneous development of colorectal carcinomas in SOCS1- deficient mice. Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A. J Exp Med 2006; 203: 1391-1397. PMID 16717119
SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation. He Y, Zhang W, Zhang R, Zhang H, Min W. J Biol Chem 2006; 281: 5559-5566. PMID 12407264
Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein. Melzner I, Weniger MA, Bucur AJ, Bruderlein S, Dorsch K, Hasel C, Leithauser F, Ritz O, Dyer MJ, Barth TF, Moller P. Int J Cancer 2006; 118: 1941-1944. PMID 16287070
Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, Mattfeldt T, Barth TF, Moller P. Oncogene 2006; 25: 2679-2684. PMID 16532038
Clinical implications of SOCS1 methylation in myelodysplastic syndrome. Wu SJ, Yao M, Chou WC, Tang JL, Chen CY, Ko BS, Huang SY, Tsay W, Chen YC, Shen MC, Wang CH, Yeh YC, Tien HF. Br J Haematol 2006; 135: 317-323. PMID 16978223
The SOCS-1 gene methylation in chronic myeloid leukemia patients. Hatirnaz O, Ure U, Ar C, Akyerli C, Soysal T, Ferhanoqlu B, Ozcelik T, Ozbek U. Am J Hematol 2007; 82: 729-730. PMID 17315216
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Contributor(s) Written 09-2007 Liang-In Lin, Hwei-Fang Tien Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taiwan (LIL); Department of Internal Medicine, National Taiwan University Hospital, No.7, Chung-Shan S. Road, Taipei, Taiwan (HFT)
Atlas Genet Cytogenet Oncol Haematol 2008; 2 264 Citation This paper should be referenced as such : Lin LI, Tien HF . SOCS1 (Suppressor of cytokine signaling 1). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/SOCS1ID42350ch16p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 265 Atlas of Genetics and Cytogenetics in Oncology and Haematology
SEPT2 (septin 2)
Identity Other names KIAA0158 hNedd5 Pnutl3 Hugo SEPT2 Location 2q37.3 DNA/RNA
Genomic structure of published SEPT2 alternatively spliced transcripts. Boxes indicate exons with coding regions in red. Exons are tentatively positioned in relative genomic order with overlapping exons indicating identical sequences. Description The SEPT2 gene has 14 exons. Transcription SEPT2 has four types of transcripts with 3.6 kb, 3.5 kb, 3.4 kb and 3.3 kb encoding the same protein, as a result of alternative splicing. Protein
The SEPT2 protein showing the localization of the three function-defining domains: a P loop-based GTP- binding domain flanked by a polybasic domain and the coiled-coil-region. Description SEPT2 belongs to an evolutionarily conserved family of genes that encode a P loop- based GTP-binding domain flanked by a polybasic domain and (usually) a coiled-coil region, and assemble into homo- and hetero-oligomers and filaments with key roles in cell division cytoskeletal dynamics and secretion. The SEPT2 gene codes for a protein with 361 amino acids and a molecular weight of 41.5 kDa. Expression SEPT2 was identified as a gene expressed in early embryonic mouse brain and down- regulated during development. It is ubiquitously expressed in cell lines and tissues with the highest protein levels found in brain tissue. Localisation The SEPT2 protein, like other septin family members, is thought to be cytoplasmic. SEPT2 co-localises with actin filaments in interphase cells, and in dividing cells concentrates at the cleavage furrow. Function SEPT2 is a multifunctional protein that was shown to be required for cytokinesis and to bind actin and associate with focal adhesions. Recent data support the idea that SEPT2 can have a role in chromosome congression and segregation. Additional functions have also been suggested; for instance, in rat brain lysates SEPT2 is part of a multi-septin complex that interacts with the exocyst complex, which plays a role in secretion and neurite outgrowth. SEPT2 has also been localised to senile plaques of brains in patients with Alzheimer's disease suggesting a role in neurodegeneration. Homology The SEPT2 protein belongs to an evolutionarily family of proteins with at least 14
Atlas Genet Cytogenet Oncol Haematol 2008; 2 266 members and shares a very high homology with septin 1, septin 4 and septin 5. Implicated in Entity Acute myeloid leukemia Disease Therapy-related AML-M2 and AML-M4 Prognosis To date, the prognosis of acute leukaemia patients with the MLL-SEPT2 fusion is not known. Cytogenetics t(2;11)(q37;q23)
Schematic representation of the known MLL-SEPT6 genomic breakpoints as a result of the t(2;11)(q37;q23) translocation. To date, two different fusions between MLL and SEPT2 have been reported: A: MLL intron 6 fused with SEPT2 intron 2, and B: MLL intron 7 fused with SEPT2 intron 2. Hybrid/Mutated MLL-SEPT2. MLL exon 6 or 7 fused with SEPT2 exon 3. Gene Abnormal The N-terminal region of the MLL protein, including the AT hook, SNL-1, SNL-2 and Protein DNA methyltransferase domains, is fused to almost the entire open-reading frame of SEPT2, containing all the three septin function-defining domains, except for the first three aminoacids. So far, no studies regarding the MLL-SEPT2 localization and function in the leukemic cell were performed.
Structure of the normal MLL and SEPT2 proteins and the resulting MLL-SEPT2 fusion protein. Oncogenesis Although the presently available data suggest that the involvement of septins in MLL- related leukemia is only related to their capacity to oligomerize, there is some evidence that altered expression of SEPT2 may underlie the development of aneuploidy. External links Nomenclature Hugo SEPT2 GDB SEPT2 Entrez_Gene SEPT2 4735 septin 2 Cards Atlas SEPT2ID44125ch2q37 GeneCards SEPT2 Ensembl SEPT2 [Search_View] ENSG00000168385 [Gene_View] Genatlas SEPT2 GeneLynx SEPT2 eGenome SEPT2 euGene 4735
Atlas Genet Cytogenet Oncol Haematol 2008; 2 267 Genomic and cartography GoldenPath SEPT2 - 2q37.3 chr2:241903954-241942112 + 2q37 (hg18-Mar_2006) Ensembl SEPT2 - 2q37 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene SEPT2 Gene and transcription Genbank AF038404 [ ENTREZ ] Genbank BC014455 [ ENTREZ ] Genbank BC033559 [ ENTREZ ] Genbank BC040676 [ ENTREZ ] Genbank BC043180 [ ENTREZ ] RefSeq NM_001008491 [ SRS ] NM_001008491 [ ENTREZ ] RefSeq NM_001008492 [ SRS ] NM_001008492 [ ENTREZ ] RefSeq NM_004404 [ SRS ] NM_004404 [ ENTREZ ] RefSeq NM_006155 [ SRS ] NM_006155 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_005416 [ SRS ] NT_005416 [ ENTREZ ] RefSeq NW_921618 [ SRS ] NW_921618 [ ENTREZ ] AceView SEPT2 AceView - NCBI Unigene Hs.335057 [ SRS ] Hs.335057 [ NCBI ] HS335057 [ spliceNest ] Fast-db 16229 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q15019 [ SRS] Q15019 [ EXPASY ] Q15019 [ INTERPRO ] Interpro IPR000038 Cell_Div_GTP_bd [ SRS ] IPR000038 Cell_Div_GTP_bd [ EBI ] Interpro IPR008113 Septin2 [ SRS ] IPR008113 Septin2 [ EBI ] CluSTr Q15019 Pfam PF00735 Septin [ SRS ] PF00735 Septin [ Sanger ] pfam00735 [ NCBI-CDD ] Prodom PD002565 GTP_Cell_Div[INRA-Toulouse] Q15019 SEPT2_HUMAN [ Domain structure ] Q15019 SEPT2_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q15019 PDB 2QA5 [ SRS ] 2QA5 [ PdbSum ], 2QA5 [ IMB ] 2QA5 [ RSDB ] PDB 2QAG [ SRS ] 2QAG [ PdbSum ], 2QAG [ IMB ] 2QAG [ RSDB ] PDB 2QNR [ SRS ] 2QNR [ PdbSum ], 2QNR [ IMB ] 2QNR [ RSDB ] HPRD 03297 Protein Interaction databases DIP Q15019 IntAct Q15019 Polymorphism : SNP, mutations, diseases OMIM 601506 [ map ] GENECLINICS 601506 SNP SEPT2 [dbSNP-NCBI] SNP NM_001008491 [SNP-NCI] SNP NM_001008492 [SNP-NCI] SNP NM_004404 [SNP-NCI] SNP NM_006155 [SNP-NCI] SNP SEPT2 [GeneSNPs - Utah] SEPT2] [HGBASE - SRS] HAPMAP SEPT2 [HAPMAP] TICdb SEPT2 [Translocation breakpoints In Cancer] HGMD SEPT2 General knowledge
Atlas Genet Cytogenet Oncol Haematol 2008; 2 268 Family Browser SEPT2 [UCSC Family Browser] SOURCE NM_001008491 SOURCE NM_001008492 SOURCE NM_004404 SOURCE NM_006155 SMD Hs.335057 SAGE Hs.335057 GO nucleotide binding [Amigo] nucleotide binding GO protein binding [Amigo] protein binding GO GTP binding [Amigo] GTP binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO cell cycle [Amigo] cell cycle GO cell division [Amigo] cell division PubGene SEPT2 Other databases Probes Probe SEPT2 Related clones (RZPD - Berlin) PubMed PubMed 30 Pubmed reference(s) in LocusLink Bibliography The septin protein Nedd5 associates with both the exocyst complex and microtubules and disruption of its GTPase activity promotes aberrant neurite sprouting in PC12 cells. Vega IE, Hsu SC. Am J Pathol 1998; 153: 1551-1560. PMID 12544826
The pathobiology of the septin gene family. Hall PA, Russell SE. J Pathol 2004; 204: 489-505. (REVIEW). PMID 15495264
Expression profiling the human septin gene family. Hall PA, Jung K, Hillan KJ, Russell SE. J Pathol 2005; 206: 269-278. PMID 15915442
Mammalian chromosome congression and segregation. Spiliotis ET, Kinoshita M, Nelson WJ. Science 2005; 307: 1781-1785. PMID 15774761
SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23). Cerveira N, Correia C, Bizarro S, Pinto C, Lisboa S, Mariz JM, Marques M, Teixeira MR. Oncogene 2006; 25: 6147-6152. PMID 16682951
A new subtype of MLL-SEPT2 fusion transcript in therapy-related acute myeloid leukemia with t(2;11)(q37;q23): a case report and literature review. van Binsbergen E, de Weerdt O, Buijs A. Cancer Genet Cytogenet 2007; 176: 72-75. PMID 17574968
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Atlas Genet Cytogenet Oncol Haematol 2008; 2 269 BiblioGene - INIST Search in all EBI NCBI
Contributor(s) Written 09-2007 Nuno Cerveira, Manuel R Teixeira Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal (MRT) Citation This paper should be referenced as such : Cerveira N, Teixeira MR . SEPT2 (septin 2). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/SEPT2ID44125ch2q37.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 270 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit)
Identity Other names AMPK AMPKb AMPK beta AMPKbeta1 HAMPKb MGC17785 NM_006253 Hugo PRKAB1 Location 12q24.1 Local_order Centromere-H11-BC040553-PRKAB1-CIT-RAB35-telomere. DNA/RNA
PRKAB1 gene structure. UTR: untranslated region. Description The PRKAB1 gene, with a total genomic size of 13639 bp, is composed of 7 coding exons of varying lengths. Transcription The human PRKAB1 transcript has approximately 2500-bp and contains an open reading frame of 813 bases, resulting in a predicted protein of 270 amino acid residues. PRKAB mRNA is detected in most tissues. Protein Description PRKAB1 has a molecular mass of 30382 Da; This protein constitutes a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is an heterotrimer of an alpha catalytic, a beta and a gamma non-catalytic regulatory subunits, each encoded by two or three distinct genes (AMPKalpha1- AMPKalpha2; AMPKbeta1-AMPKbeta2; AMPKgamma1-AMPKgamma2- AMPKgamma3) which have varying tissue and subcellular expression. Post-translational modifications of PRKAB1 include myristoylation and phosphorylation in vivo at Ser24/25, Ser108 and Ser182. Phosphorylation at Ser108 is required for the activation of the AMPK enzyme, whereas phosphorylation at Ser24/25 and Ser182 affects the localization of the complex. Expression AMPKbeta1 protein expression is highest in the liver, and testis and low in kidney and skeletal muscle. In contrast, expression of PRKAB2, encoded by a different gene, is higher in skeletal muscle. This indicates a tissue specific pattern of expression of these two regulatory beta subunits. Localisation AMPKbeta1 localises in the cytoplasm. However nuclear translocation is possible because mutations of Ser24/25 and Ser182 to alanine lead to the redistribution of PRKAB1 to the nucleus. Function AMPKbeta1, may act as a positive regulator of AMPK activity and it may serve as an adaptor molecule for the catalytic subunit. It has also been reported that AMPKbeta1 contains a glycogen-binding domain (GBD) that may target the heterotrimer to glycogen storage sites. The heterotrimeric protein AMPK senses low intracellular energy levels upon increased in the AMP/ATP ratio. Binding of AMP results in allosteric activation, inducing phosphorylation on Thr-172 of the AMPKa regulatory subunit (PRKAA) by LKB1 in complex with STE20-related adapter-alpha (STRAD alpha). AMPK activation leads to the modulation of the activity of multiple downstream targets to normalize ATP levels. Among these substrates is the tuberin protein, the product of the tuberous sclerosis
Atlas Genet Cytogenet Oncol Haematol 2008; 2 271 complex 2 gene (TSC2) that upon activation by AMPK represses the activity of the mammalian target of rapamycin, mTOR. It has been reported that PRKAB1 and PRKAB2 contain a glycogen binding domain that targets AMPK to glycogen. Moreover, it has been shown that expression of PRKAB1 and PRKAB2 genes, in human cells, may be mediated by p53. Homology There is a AMPKbeta1 isoform, designated AMPKbeta2, encoded by the PRKAB2 gene. The N-terminal region of beta2 differs significantly from that AMPKbeta1 isoform, suggesting that this region could play a role in isoform-specific AMPK activity. The AMPKbeta subunit is the mammalian homolog of the S. cerevisiae Sip1p/Sip2p/Gal83p family of proteins that interact with the AMPKa homolog, Snf1p, and are involved in glucose regulation of gene expression. Mutations Note No germ-line or somatic mutations have been reported in the PRKAB1 gene. To be noted Although PRKAB1 itself does not seem to be directly implicated in human disease, there is an indirect relationship between AMPKbeta and heart disease and cancer due to the implication of other subunits of the AMPK complex or to the implication of other related kinases: AMPK in heart disease: Mutations at the PRAAG2 (encoding the gamma2 subunit of AMP-activated protein kinase) causes glycogen overload, Wolff-Parkinson-White syndrome, arrhythmias, and heart failure. AMPK in cancer: LKB1 is a serine/threonin kinase that phosphorylates and activates AMPK. Germ-line mutations at LKB1 lead to the cancer-prone syndrome Peutz-Jeghers syndrome whereas somatic mutations are implicated in the development of non-small cell lung cancer. External links Nomenclature Hugo PRKAB1 GDB PRKAB1 Entrez_Gene PRKAB1 5564 protein kinase, AMP-activated, beta 1 non-catalytic subunit Cards Atlas PRKAB1ID44100ch12q24 GeneCards PRKAB1 Ensembl PRKAB1 [Search_View] ENSG00000111725 [Gene_View] Genatlas PRKAB1 GeneLynx PRKAB1 eGenome PRKAB1 euGene 5564 Genomic and cartography GoldenPath PRKAB1 - 12q24.1 chr12:118590144-118603811 + 12q24.1 (hg18-Mar_2006) Ensembl PRKAB1 - 12q24.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PRKAB1 Gene and transcription Genbank AF022116 [ ENTREZ ] Genbank AJ224515 [ ENTREZ ] Genbank AK127820 [ ENTREZ ] Genbank BC001007 [ ENTREZ ] Genbank BC001056 [ ENTREZ ] RefSeq NM_006253 [ SRS ] NM_006253 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 2 272 RefSeq NT_009775 [ SRS ] NT_009775 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView PRKAB1 AceView - NCBI Unigene Hs.6061 [ SRS ] Hs.6061 [ NCBI ] HS6061 [ spliceNest ] Fast-db 14010 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9Y478 [ SRS] Q9Y478 [ EXPASY ] Q9Y478 [ INTERPRO ] Interpro IPR006828 AMPKBI [ SRS ] IPR006828 AMPKBI [ EBI ] Interpro IPR004193 Glyco_hydro_13_N [ SRS ] IPR004193 Glyco_hydro_13_N [ EBI ] CluSTr Q9Y478 Pfam PF04739 AMPKBI [ SRS ] PF04739 AMPKBI [ Sanger ] pfam04739 [ NCBI-CDD ] PF02922 Isoamylase_N [ SRS ] PF02922 Isoamylase_N [ Sanger ] pfam02922 Pfam [ NCBI-CDD ] Blocks Q9Y478 HPRD 04116 Protein Interaction databases DIP Q9Y478 IntAct Q9Y478 Polymorphism : SNP, mutations, diseases OMIM 602740 [ map ] GENECLINICS 602740 SNP PRKAB1 [dbSNP-NCBI] SNP NM_006253 [SNP-NCI] SNP PRKAB1 [GeneSNPs - Utah] PRKAB1] [HGBASE - SRS] HAPMAP PRKAB1 [HAPMAP] COSMIC PRKAB1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PRKAB1 General knowledge Family Browser PRKAB1 [UCSC Family Browser] SOURCE NM_006253 SMD Hs.6061 SAGE Hs.6061 hydrolase activity, hydrolyzing O-glycosyl compounds [Amigo] hydrolase activity, GO hydrolyzing O-glycosyl compounds GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO carbohydrate metabolic process [Amigo] carbohydrate metabolic process GO fatty acid biosynthetic process [Amigo] fatty acid biosynthetic process GO signal transduction [Amigo] signal transduction KEGG Insulin signaling pathway KEGG Adipocytokine signaling pathway PubGene PRKAB1 Other databases Probes Probe PRKAB1 Related clones (RZPD - Berlin) PubMed PubMed 45 Pubmed reference(s) in LocusLink Bibliography Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-activated protein kinase. Gao G, Fernandez CS, Stapleton D, Auster AS, Widmer J, Dyck JR, Kemp BE, Witters LA. J Biol Chem 1996; 271: 8675-8681. PMID 8621499
Posttranslational Modifications of the 5 -AMP-activated Protein Kinase beta 1 Subunit.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 273 Mitchelhill KI, Michell BJ, House CM, Stapleton D, Dyck J, Gamble J, Ullrich C, Witters LA, Kemp BE. J Biol Chem 1997; 272: 24475-24479. PMID 9305909
AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location. Stapleton D, Woollatt E, Mitchelhill KI, Nicholl JK, Fernandez CS, Michell BJ, Witters LA, Power DA, Sutherland GR, Kemp BE. FEBS Lett 1997; 409: 452-456. PMID 9224708
Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle. Thornton C, Snowden MA, Carling D. J Biol Chem 1998; 273: 12443-12450. PMID 9575201
Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Warden SM, Richardson C, O'Donnell J Jr, Stapleton D, Kemp BE, Witters LA. Biochem J 2001; 354: 275-283. PMID 11171104
Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Hardie DG. Endocrinology 2003; 144: 5179-5183. PMID 12960015
Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. J Biol 2003; 2: 28. PMID 14511394
TSC2 mediates cellular energy response to control cell growth and survival. Inoki K, Zhu T, Guan KL. Cell 2003; 115: 577-590. PMID 14651849
AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression. Li J, Jiang P, Robinson M, Lawrence TS, Sun Y. Carcinogenesis 2003; 24: 827-834. PMID 12771025
AMPK beta subunit targets metabolic stress sensing to glycogen. Polekhina G, Gupta A, Michell BJ, van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW, Kemp BE, Stapleton D. Curr Biol 2003; 13: 867-871. PMID 12747837
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D. Curr Biol 2003; 13: 2004-2008. PMID 14614828
Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. Woods A, Vertommen D, Neumann D, Turk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 274 J Biol Chem 2003; 278: 28434-28442. PMID 12764152
The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ. Cancer Res 2007; 67: 3043-3053. PMID 17409411
A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Sanchez-Cespedes M. Oncogene 2007 Jun 18; [Epub ahead of print] PMID 17599048
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Contributor(s) Written 09-2007 Monserrat Sanchez-Cespedes Molecular Pathology Program, Spanish National Cancer Center (cnio), Melchor Fernandez Almagro, 3, 28029 Madrid, Spain Citation This paper should be referenced as such : Sanchez-Cespedes M . PRKAB1 (protein kinase, AMP-activated, beta 1 non-catalytic subunit). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PRKAB1ID44100ch12q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 275 Atlas of Genetics and Cytogenetics in Oncology and Haematology
GNB2L1 (guanine nucleotide binding protein (G protein), beta polypeptide 2- like 1)
Identity Other names Gnb2-rs1 H12.3 HLC-7 PIG21 (proliferation-inducing gene 21) RACK1 (Receptor for activated kinase C) lung cancer oncogene 7 protein homologous to chicken B complex protein, guanine nucleotide binding Hugo GNB2L1 Location 5q35.3 Note Aberrations on 5q35.3 are reported to be associated with asbestos-related lung cancer. 5q35.3 also displays high frequency of deletions in non small lung carcinoma. DNA/RNA Description The gene spans approximatively 6.9 Kb. Orientation minus strand. Number of exons: 10. Transcription The length of GNB2L1 transcript is 951bp. Protein Description GNB2L1 encodes a cytosolic protein with a molecular mass of approximatively 35 kDa (317 amino acids). The protein has seven internal Trp-Asp 40 (WD40 domain) repeats. The WD40 repeats of RACK1/GNB2L1 are predicted to form a seven-bladed propeller structure, where each blade is composed of a four-stranded anti-parallel beta-sheet. The highly conserved WD repeat sequence of RACK1/GNB2L1 is found in a number of eukaryotic proteins and is implicated in a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly. Expression GNB2L1 is ubiquitously expressed in the tissues of higher mammals and humans including brain, liver, and spleen. Localisation GNB2L1 is a cytosolic protein. Function GNB2L1 was originally identified as an anchoring protein for protein kinase C beta (PKCbeta), which it stabilises in the active state and anchors to membranes or functional sites. However, evidence has accumulated to support a central role of RACK1/GNB2L1 in critical biological responses. In addition to binding specifically to the active form of PKCbeta isoforms, GNB2L1 also interacts with several other important signaling proteins including the Src kinase family, integrin beta1, integrin beta2, integrin beta3 and integrin beta5, beta-spectrin and dynamin, RasGAP, the androgen receptor , insulin-like growth factor 1 receptor (IGF-1r), Epstein-Barr virus trans-activator protein BZLF1, p73 and pRB. This suggests that GNB2L1 may act as an anchor or adaptor protein, recruiting other proteins to various transmembrane receptors, providing a platform for protein-protein interactions and acting as the focus for several cell-signaling pathways. Accordingly, a number of cellular functions have been attributed to GNB2L1, e.g. in cell growth, adhesion, protrusion and chemotactic migration. GNB2L1 might also have an effect on brain function; a reduction in GNB2L1 levels by around 50% has been reported in the brains of aged rats compared with adult or middle aged rat brains. GNB2L1 is also reported to be involved in number of functions in the nervous system. These include neurite growth, dendritic transport, glutamatergic and dopaminergic neurotransmissions and functioning of GABAA receptors. In addition, up-regulation of GNB2L1 in lymphocytes results in suppression of apoptosis, indicating that it also plays an important role in the regulation of apoptosis. It is also reported that GNB2L1 inhibits the effects of adenovirus E1a on yeast, Saos
Atlas Genet Cytogenet Oncol Haematol 2008; 2 276 osteosarcoma and HeLa cells, including the induction of apoptosis. In addition, GNB2L1 over-expression was reported to protect PC-12 cell survival on withdrawal of Nerve Growth Factor. Homology GNB2L1 is homologous to the G protein beta subunit, having 42% identity with many conserved amino acid substitutions. Mutations Note Mutations in the GNB2L1 gene have not been found in 274 samples from somatic cancer. However, GNB2L1 is reported to be up-regulated in angiogenesis and in human carcinomas. Implicated in Entity Brain pathologies and ageing Disease Changes in GNB2L1 levels were found in a number of brain pathologies and during ageing. GNB2L1 levels were significantly decreased in the cortex of patients with Down Syndrome, all of who develop Alzheimer's disease as young adults. Association of GNB2L1 with PKC was put forward as a putative cause of the increase in PKC activity observed in the frontal cortex of subjects with bipolar disorder. Entity Angiogenesis and tumor growth Oncogenesis GNB2L1 might contribute to angiogenesis and tumor growth, since it was shown to be up-regulated during angiogenesis in vitro and in vivo, and was also expressed in tumor angiogenesis. GNB2L1 expression was higher in human non-small cell lung and colon carcinomas than in the corresponding normal tissues. External links Nomenclature Hugo GNB2L1 GDB GNB2L1 GNB2L1 10399 guanine nucleotide binding protein (G protein), beta polypeptide 2- Entrez_Gene like 1 Cards Atlas GNB2L1ID43285ch5q3 GeneCards GNB2L1 Ensembl GNB2L1 [Search_View] ENSG00000204628 [Gene_View] Genatlas GNB2L1 GeneLynx GNB2L1 eGenome GNB2L1 euGene 10399 Genomic and cartography GoldenPath GNB2L1 - 5q35.3 chr5:180596534-180603512 - 5q35.3 (hg18-Mar_2006) Ensembl GNB2L1 - 5q35.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene GNB2L1 Gene and transcription Genbank AK095666 [ ENTREZ ] Genbank AK222488 [ ENTREZ ] Genbank AM393661 [ ENTREZ ] Genbank AY336089 [ ENTREZ ] Genbank BC000214 [ ENTREZ ] RefSeq NM_006098 [ SRS ] NM_006098 [ ENTREZ ] RefSeq AC_000048 [ SRS ] AC_000048 [ ENTREZ ] RefSeq NC_000005 [ SRS ] NC_000005 [ ENTREZ ] RefSeq NT_023133 [ SRS ] NT_023133 [ ENTREZ ] RefSeq NW_922818 [ SRS ] NW_922818 [ ENTREZ ] AceView GNB2L1 AceView - NCBI Unigene Hs.5662 [ SRS ] Hs.5662 [ NCBI ] HS5662 [ spliceNest ] Protein : pattern, domain, 3D structure
Atlas Genet Cytogenet Oncol Haematol 2008; 2 277 SwissProt P63244 [ SRS] P63244 [ EXPASY ] P63244 [ INTERPRO ] Prosite PS00678 WD_REPEATS_1 [ SRS ] PS00678 WD_REPEATS_1 [ Expasy ] Prosite PS50082 WD_REPEATS_2 [ SRS ] PS50082 WD_REPEATS_2 [ Expasy ] PS50294 WD_REPEATS_REGION [ SRS ] PS50294 WD_REPEATS_REGION Prosite [ Expasy ] IPR015943 WD40/YVTN_repeat-like [ SRS ] IPR015943 WD40/YVTN_repeat-like Interpro [ EBI ] Interpro IPR001680 WD40_repeat [ SRS ] IPR001680 WD40_repeat [ EBI ] CluSTr P63244 Pfam PF00400 WD40 [ SRS ] PF00400 WD40 [ Sanger ] pfam00400 [ NCBI-CDD ] Smart SM00320 WD40 [EMBL] Prodom PD000018 WD40[INRA-Toulouse] P63244 GBLP_HUMAN [ Domain structure ] P63244 GBLP_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P63244 HPRD 01503 Protein Interaction databases DIP P63244 IntAct P63244 Polymorphism : SNP, mutations, diseases OMIM 176981 [ map ] GENECLINICS 176981 SNP GNB2L1 [dbSNP-NCBI] SNP NM_006098 [SNP-NCI] SNP GNB2L1 [GeneSNPs - Utah] GNB2L1] [HGBASE - SRS] HAPMAP GNB2L1 [HAPMAP] COSMIC GNB2L1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD GNB2L1 General knowledge Family Browser GNB2L1 [UCSC Family Browser] SOURCE NM_006098 SMD Hs.5662 SAGE Hs.5662 GO receptor binding [Amigo] receptor binding GO cytoplasm [Amigo] cytoplasm GO cytoplasm [Amigo] cytoplasm GO cell soma [Amigo] cell soma PubGene GNB2L1 Other databases Probes Probe GNB2L1 Related clones (RZPD - Berlin) PubMed PubMed 92 Pubmed reference(s) in LocusLink Bibliography Identification of intracellular receptor proteins for activated protein kinase C. Mochly-Rosen D, Khanner H, Lopez J. Proc Natl Acad Sci USA 1991; 88: 3997-4000. PMID 1831196
The WD-40 repeat. van der Voom L, Ploegh HL. FEBS Lett 1992; 307: 131-134. PMID 1644165
Cloning of an intracellular receptor for protein Kinase C: A homolog of the beta subunit of G
Atlas Genet Cytogenet Oncol Haematol 2008; 2 278 proteins. Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D. Proc Natl Acad Sci USA 1994; 91: 839-843. PMID 8302854
Interaction of protein kinase C with RACK1, a receptor for activated C-kinase: a role in beta protein kinase C mediated signal transduction. Mochly-Rosen D, Smith BL, Chen CH, Disatnik MH, Ron D. Biochem Soc Trans 1995; 23: 596-600. PMID 8566424
Functional impairment in protein kinase C by RACK1 (receptor for activated C kinase 1) deficiency in aged rat brain cortex. Pascale A, Fortino I, Govoni S, Trabucchi M, Wetsel WC, Battaini F. J Neurochem 1996; 67: 2471-2477. PMID 8931480
The role of anchoring protein RACK1 in PKC activation in the aging rat brain. Battaini F, Pascale A, Paoletti R, Govoni S. Trends Neurosci 1997; 20: 410-415. PMID 9292970
RACK1, a receptor for activated protein kinase C, interacts with integrin b subunit. Liliental J, Chang DD. J Biol Chem 1998; 273: 2379-2383. PMID 9442085
Anchoring proteins for protein kinase C: a means for isozyme selectivity. Mochly-Rosen D, Gordon AS. FASEB J 1998; 12: 35-42. PMID 9438408
The PKC targeting protein RACK1 interacts with the Epstein-Barr virus activator protein BZLF1. Baumann M, Gires O, Kolch W, Mischak H, Zeidler R, Pich D, Hammerschmidt W. Eur J Biochem 2000; 267: 3891-3901. PMID 10849009
RACK1 is up-regulated in angiogenesis and human carcinoma. Berns H, Humar R, Hengerer B, Kiefer FN, Battegay EJ. FASEB J 2000; 14: 2549-2558. PMID 11099474
Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma. Mendes-da-Silva M , Moreira A, Duro-da-Costa J, Matias D, Monteiro C. Mol Pathol 2000; 53: 184-187. PMID 11040940
The WD protein RACK1 mediates protein kinase C and integrin-dependent cell migration. Buensuceso SC, Woodside D, Huff JL, Plopper GE, O'Toole TE. J Cell Sci 2001; 114: 1691-1698. PMID 11309199
Increased association of brain protein kinase C with the receptor for activated C kinase-1 (RACK1) in bipolar affective disorder. Wang H, Friedman E. Biol Psychiatry 2001; 50: 364-370. PMID 11543740
A novel substrate for the Src protein kinase. Chang BY, Harte RA, Cartwright CA.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 279 Oncogene 2002; 21: 7619-7629. PMID 12400005
Aberrant expression of signaling-related proteins 14-3-3 gamma and RACK1 in fetal Down Syndrome brain (trisomy 21). Peyrl A, Weitzdoerfer R, Gulesserian T, Fountoulakis M, Lubec G. Electrophoresis 2002; 23: 152-157. PMID 11824616
Function of p73 not of p53 is inhibited by the physical interaction with RACK1 and its inhibitory effect is counteracted by pRB. Ozaki T, Watanabe K, Nakagawa T, Miyazaki K, Takahashi M, Nakagawara A. Oncogene 2003; 22: 3231-3242. PMID 12761493
The scaffolding protein RACK1 interacts with androgen receptor and promotes cross talk through a protein kinase C signaling pathway. Rigas AC, Ozanne DM, Neal DE, Robson CN. J Biol Chem 2003; 278: 46087-46093. PMID 12958311
Functional expression cloning reveals a central role for the receptor for activated protein kinase C 1 (RACK1) in T cell apoptosis. Mourtada-Maarabouni M, Kirkham L, Farzaneh F, Williams GT. J Leukoc Biol 2005; 78: 503-514. PMID 15870214
RACK1 has the nerve to act: Structure meets function in the nervous system. Sklan EH, Podoly E, Sorek H. Prog Neurobiol 2005; 78: 117-134. Review. PMID 16457939
Identification of specific gene copy number changes in asbestos-related lung cancer. Nymark P, Wikman H, Ruosaari S, Hollmen J, Vanhala E, Karjalainen A, Anttila S, Knuutila S. Cancer Res 2006; 66: 5737-5743. PMID 16740712
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Contributor(s) Written 09-2007 Mirna Mourtada-Maarabouni School of Life Sciences, Keele University, Keele, Staffs, ST5 5BG, United Kingdom Citation This paper should be referenced as such : Mourtada-Maarabouni M . GNB2L1 (guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/GNB2L1ID43285ch5q35.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 280 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ERVWE1 (Endogenous Retroviral family W, Env(C7), member 1)
Identity Other names env enverin Env-W HERV-W HERV-W-ENV HERV-W_7q21.2 provirus ancestral Env polyprotein precursor HERV-7q HERVW Syncytin Syncytin-1 Hugo ERVWE1 Location 7q21.2 Note Sequences of retroviral origin represent about 8% of the human genome. There are at least 31 families of human endogenous retroviruses (HERVs). Each family derived from an independent infection of the germ line by an exogenous virus during the evolution of the human lineage. The infectious retrovirus founding the contemporary HERV-W family entered the human ancestor genome after the divergence between Catarrhini and Platyrrhini, i.e., less than 40 million years ago. The spread of the HERV- W family into the genome essentially results from events of intracellular retrotransposition of transcriptionally active copies, a phenomenon mediated either by their own reverse transcriptase (RT) machinery or by RT from LINE elements. Generally, due to the absence of a selective pressure, HERV-W elements have accumulated inactivating substitutions (frame-shifts, nonsense mutations), leading to complex multicopy families whose transmission is exclusively Mendelian. Thus, the contemporary HERV-W family consists of collections of heterogeneous elements, ranging from full-length defective proviruses (gag, pol, and env genes flanked at both extremities by two long terminal repeats (LTRs)) to isolated LTRs derived from recombination events. The human endogenous retrovirus HERV-W multicopy family includes a unique proviral locus, termed ERVWE1, which contains gag and pol pseudogenes and has retained a full-length envelope open reading frame (ORF) also named Syncytin or Syncytin-1. ERVWE1 is a bona fide gene involved in hominoid placental physiology. DNA/RNA
Atlas Genet Cytogenet Oncol Haematol 2008; 2 281
Figure 1: ERVWE1 provirus genomic structure and 7q21.2 chromosomal environment: Flanking black boxes correspond to the 24th exon and the 5th exon of the PEX1 and ODAG genes, respectively, defining a LTR element-rich region of 30 kb in human 7q21.2. Isolated LTR elements are depicted as red boxes (MaLR LTR) and green boxes (HERV-P LTR). U3 (white) , R (hatched) and U5 (dark grey) regions of 5' and 3' LTRs of ERVWE1 provirus are indicated. U3, R and U5 regions of 5' and 3' LTRs of HERV-H provirus LTRs are labelled in purple. Short direct repeats (light grey and dark grey arrows) located at each boundary of ERVWE1 and HERV-H proviruses indicates that integration of each element was mediated by an HERV- family specific reverse transcriptase. Pseudogenes (labelled Δ) are shown as boxes. The Syncytin-1 open reading frame is depicted by a large orange arrow. A 2-kb intron (black line) is located just downstream of the 5' ERVWE1 LTR. A double arrow indicates the ERVWE1 transcriptional regulatory region (see figure 3). Figure 2: ERVWE1 evolution and selection in primates. Figure 3: ERVWE1/Syncytin-1 transcriptional regulatory element: ERVWE1/Syncytin-1 expression is regulated by a bipartite element consisting of a cyclic AMP-inducible LTR retroviral promoter (ERVWE1 5'LTR U3 region) adjacent to an upstream regulatory element (URE) of composite origin. This URE consists of a 208 bp non-retroviral, non-repeated/transposable cellular sequence (non-TE region) and a 228pb MaLR LTR containing a trophoblast specific enhancer (TSE) which confers a high level of expression and placental tropism. True (top black boxes) and putative (bottom grey boxes) transcription factor binding sites along ERVWE1 5'LTR and URE are indicated. The positive (+) or negative (+) involvement of regulatory domains in placental tissue is annotated below the schematic representation. The CAP transcription initiation site (arrow) is located at the 5' end of the R region. Figure 4: ERVWE1 splicing strategy in placenta: The CAP transcription initiation site (right arrow) is located
Atlas Genet Cytogenet Oncol Haematol 2008; 2 282 at the 5' end of the R region of the 5'LTR. The polyadenylation signal (left arrow) is located toward the 3' end of the R region belonging to the 3'LTR. ERVWE1 produces three major single-spliced transcripts in placental tissue, the subgenomic 7.4-kb and 3.1-kb mRNAs and the fully-spliced 1.3-kb mRNA. Only the 3.1-kb variant is responsible for Syncytin-1 translation. Splice donor (SD) and acceptor (SA) sites are indicated by right and left arrows, respectively. SD and SA were identified by screening a placental cDNA library. SD2 site was identified in a single clone. Description DNA STRUCTURE ERVWE1 is a 10.2-kb long full-length provirus integrated on chromosome 7q21.2. Like the proviral form of simple exogenous retroviruses, ERVWE1 is structurally composed of two long terminal repeats (LTRs), flanking the internal sequence containing gag, pol and env genes. Each LTR is composed of three regions, i.e. from 5' to 3'U3, R and U5. As in other proviruses, the U3 region of ERVWE1 5'LTR serves as proviral promoter and the R region of the 3'LTR acts as a polyadenylation signal. Both gag and pol genes, normally coding respectively for the matrix, capsid and nucleocapsid proteins, and for the viral enzymatic machinery, are disrupted by stop codons. Only the full- length env gene that codes for the envelope glycoprotein, Syncytin-1, is functionally preserved. In addition ERVWE1 contains a 2-kb intron, at the 5'LTR/gag junction, with no trivial homology or known function. CLASSIFICATION The current classification and nomenclature of ERVs is complex and varies between and within species. Retroviral classification is initially based on virion morphology during maturation and assembly of particles at the cell membrane. Accordingly, retroviruses are designated A-, B-, C- and D-type. ERVs are also classified on the basis of the similarity of their pol region to those of exogenous retroviruses. This point is illustrated in class I and II which group the pol MuLV-like (Murine Leukemia Virus) and the pol MMTV-like (Mouse Mammary Tumor Virus) ERVs, respectively. The International Committee on Taxonomy of Viruses (I.C.T.V., http://www.ncbi.nlm.nih.gov/ ICTVdb) has established seven genera of Retroviridae, Alpha-, Beta-, Gamma-, Delta-, Epsilon-retrovirus, Lentivirus and Spumavirus. The ERV nomenclature is heterogeneous and complex due to the difficulty to associate HERVs with physiopathological functions. It is mainly based on the Primer Binding Site (PBS) sequence, which is recognized by a specific tRNA whose one letter code then becomes the ERV suffix. As the PBS located 4 bp downstream from the U5 subdomain of the 5' ERVWE1 LTR showed extensive homology with the avian retroviruses PBS used by tRNATrp (single letter code: W) for minus-strand DNA synthesis, this family was tentatively named HERV-W. Phylogenetic trees within the pol region showed that the HERV-W family is related to ERV-9 and RTVL-H families and thus belongs to the class I endogenous retroviruses. The homologies within the pol and env genes with the murine type C and simian type D retroviruses, respectively, suggest a chimeric genome structure as described for baboon endogenous virus. Based on the size criteria, such a chimerism seemed to exist within the LTR: the 247-nt U3 and the 79- to 81-nt R elements were comparable to avian or type D retrovirus U3 and mammalian type C R elements, respectively, although the 410- to 455-nt U5 element remained unclassified as unusually long. According to the new classification, HERV-W elements belong to the genus of gammaretroviruses. No replication-competent elements could be found within the HERV-W family and no corresponding exogenous retrovirus have been characterized. EVOLUTION HERV-W family: ERV-W elements are detectable in the genome of all Catarrhini, i.e. Hominidae (the human, chimpanzees, gorillas, orangutans), Hylobatidae (gibbons) and Cercopithecidae (Old World monkeys), but not in Platyrrhini (New World monkeys) nor in other more distant primates. Thus, the HERV-W family entered and began to spread in the genome of primates after the divergence of the Catarrhini and Platyrrhini, i.e. less than 40 million years ago (MYA). It has been estimated, based on the divergence of sequences, that the main period of spreading of the HERV-W family within the genome lasted for about 5 M years, between 15.5 to 28.6 MYA, before the Catarrhini divergence in Hominoidae and Cercopithecidae. The HERV-W family thus remained transcriptionally active over a short period of primate evolution, in contrast to other HERV families. This spreading gave rise in the human haploid genome to at least 1401 integration events, that can be classified into 3
Atlas Genet Cytogenet Oncol Haematol 2008; 2 283 subfamily, the subfamily 1 being the oldest. Many of them have recombined into solitary LTRs (343 to 1100 solo LTRs), and a large portion have been generated by Line1 retrotranspositional machinery (176 pseudogenes). Today only 29 to 39 proviruses are still full length and none has remained competent for replication due to frameshifts and stop codons within the ORFs for gag, pol and/or env. Only 30 env HERV-W related regions can be found in the genome, as compared to 70 gag and 100 pro regions, indicating a preferential loss of the envelope. In addition, only 5 ORFs longer than 1000 bp have been preserved: one gag, one pro, one pol, one full-length env (Syncytin-1) and one truncated env. Among these ORFs, only two proteins seem to be produced: a Gag protein encoded on a HERV-W pseudogene, and Syncytin-1, encoded by ERWE1, the unique full-length envelope glycoprotein. ERVWE1 integration: ERVWE1 integration occurred in the germ line of a Catarrhini ancestor before Hominoidae and Cercopithecidae divergence more than 19-25 MYA, as indicated by the identification of a deleted ERVWE1 orthologous locus in Old World Monkeys. ERVWE1 integrated on chromosome 7q21.2, into an old MaLR-e1 solo LTR. The presence in several species of 4-6 bp direct repeats, although degenerated, at both ends of the provirus attestes that ERVWE1 was generated by a retrovirus-like integration event, i.e. by using a functional ERV-W reverse transcriptase. However, whether it resulted from a re-infection, cis- or trans-retrotranspostion event remains unknown. The presence of a 12bp deletion in the env gene of ERVWE1 provirus in Hominoids and Cercopithecs suggests that this deletion, crucial for the Env fusogenic activity (see below, Protein), occured originally in a primary Catarrhini ancestor possibly soon after integration, in the youth of the ERV-W family. As ERVWE1 is part of the subfamily 3 of HERV-W elements, which is probably the youngest, this support the hypothesis that the HERV-W family remained active during a short period during primates evolution. This 12-bp deletion constitutes a signature, specific to ERVWE1. As it was shown to be unique among all ERV- W copies in human and chimpanzee genomes, this suggests that ERVWE1 did not retrotransposed after its integration and furthermore was not expressed in the hominoid germ line, as opposed to many other HERV-W loci which retrotransposed as cDNA structures (pseudogenes) using Line-1 reverse transcriptase machinery. ERVWE1 conservation and selection in Hominoidae: - Conservation: After integration within the Catarrhini genome, ERVWE1 genomic structure followed two divergent evolutionary pathways, a genetic drift in Cercopithecus sp. versus a domestication, in Hominoidae sp. (Hominidae and Hylobatidae). More precisely in Cercopithecus sp. an about 9kb region was deleted comprising the 4.3kb LTR-gag-pol 5' fraction of the ERVWE1 provirus, and the env ORF became further inactivated by accumulation of stop codons and frameshift mutations. In Hominoidae (Hominidae and Hylobatidae), on the contrary, ERVWE1 structure has been preserved, as well as the surrounding genomic structure within a 30kb area. gag and pol regions contain numerous stop codons and frameshifts in all Hominoidae, while Syncytin-1 ORF has been conserved. - Selection: Diverse facts emphasize the selective pressure on ERVWE1 locus in the Hominoidae lineage and the recruitement of its envelope gene to become a bona fide gene involved in placental morphogenesis. Notably comparative analysis of the ERVWE1 locus for 24 individuals showed a variable pattern of sequence variation along the proviral locus , that is compatible with a positive pressure on the elements critical for env activity maintenance. - Enhancer The MALR-e1 LTR portion located upstream of the ERVWE1 provirus has been shown to act as a trophoblast specific enhancer (TSE) that co-opted with the ERVWE1 5'LTR promoter, conferring on Syncytin-1 a specific and high activity in the placenta. This sequence is particularly conserved in humans as no polymorphism was observed in 48 sequences analyzed and is also strictly identical in all Hominidae sp. analyzed. In contrast, the portion located
Atlas Genet Cytogenet Oncol Haematol 2008; 2 284 downstream of the provirus is different for each Hominidae species. The MaLR co-optation however seems to be Hominidae-specific, as in the gibbon (Hylobatidae), the MaLR is deficient in enhancer activity. In contrast the gibbon 5'LTR presents higher promoter activity. - Promoter The 5'LTR exhibits an unusually low polymorphism (one variable site in 18.0 kb) as compared to the variability described for noncoding sequences (one every 0.47 kb) and repeated sequences (one every 0.31 kb), suggesting that there has been a selective sweep of this region. Conversely, the variability of the 3'LTR (one in 0.5 kb) is typical of repeated sequences. On line with this, the functional analysis of all U3 elements revealed that the human and other apes ERVWE1 5' LTRs were always more active in BeWo cells than the ERVWE1 3' LTRs. - Transcriptional termination and postranscriptional signals In all Hominoidae including the gibbon, the poly-A signal within the 3'LTR and the post-transcriptional regulation elements (env ATG context, 5' and 3' UTRs and splice sites including those for the env mRNA processing) are strictly identical. - Envelope ERVWE1 env, Syncytin-1, was shown to be the most conserved env ORF of the 16 human proviruses (from 9 HERV families) still containing a env gene, even though it is the fourth oldest. The observed variability of the env ORF (one variable site every 2.2 kb) fell within the same range as the variability described for human coding sequences (one every 1.08-2.00 kb), highlighting that the behavior of this gene of retroviral origin is similar to any essential cellular gene, as opposed to infectious retroviruses or more generally RNA- based organism. The critical domains essential for classical retroviral envelope expression and function are highly conserved and clearly under functional constraint in the entire Hominoidae lineage. Most of the amino-acid changes in Syncytin-1 evolution are located in positions that are variable across env proteins (surface domain involved in receptor recognition and binding, intracytoplasmic tail involved in fusogenic activity regulation), which could represent gradual adjustment to its cellular function. Interestingly, based on sequences comparison and according to the most parsimonious scenario, one of the nonsense mutations found in Cercopithecus lineage, which eliminates the last 30 amino-acids of the env protein, occured in the Catarrhini ancestor but reverted in Hominoidae re-establishing the full-length env ORF. Furthermore, the ERVWE1 signature, which consists of four amino-acid (12-bp) deletions in the intracytoplasmic tail of the glycoprotein, were shown to be crucial for the envelope fusogenicity and all tested Hominoidae Syncytin-1 proteins present similar fusogenic activity in heterologous cell fusion assays. Convergent evolution of endogenous retroviral envelopes: Another fusogenic endogenous retroviral envelope, Syncytin-2, has been functionally preserved in the human genome. Like Syncytin-1, Syncytin-2 is highly expressed in the placenta and thought to be involved in placental morphogenesis. Although not fusogene, a third endogenous reroviral envelope is believed to be involved in placenta development: it is the envelope gene of ERV3 provirus, whose function is associated with cell differentiation/proliferation. ERVWE1/Syncytin-1 and ERVFRDE1/Syncytin-2 are specific to primates and thus do not exist in other placentae. However, this apparent endogenous retrovirus hijacking for placentation use is not restricted to the primates. Indeed two unique endogenous envelope genes of retroviral origin have been found in the mouse, i.e Syncytin-A and -B. They both display fusogenic activity and specific expression in the syncytiotrophoblast-containing labyrinth. They are found in all Muridae tested and show striking conservation of their env coding status. In addition, the envelope of a particular class of sheep ERV, endogenous Jaagsiekte sheep retroviruses (enJSRVs), regulates trophectoderm growth and differentiation in the periimplantation conceptus and when blocked leads to pregnancy loss. Altogether the data strongly argue for convergent evolution of endogenous retroviral envelopes to serve for
Atlas Genet Cytogenet Oncol Haematol 2008; 2 285 placentation in mammals. REGULATION Note: ERVWE1 transcriptional activity was shown to be regulated by several transcription factors (cAMP/PKA pathway, Oct-1, GCMa, AP-2, Sp-1), hormones (steroid hormones: oestrogen and progesterone), cytokines (TNF- alpha, INF-gamma, IFN-beta, IL-6, IL-1), environmental conditions (hypoxia), exogenous virus infections and epigenetic methylation processes. Promoter region description: The ERVWE1 promoter is a bipartite element consisting of a retroviral promoter (the 5'LTR) and a "cellular" regulatory region, called the URE, within the 436pb sequence of the directly upstream ERVWE1 integration site. - URE: The 436bp URE is composed of three sub-domains: a cellular positive regulatory region from -436 to -128, a negative regulatory region from -128 to -67, and a trophoblast specific enhancer (TSE) from -67 to -35, all contained in the MaLR-e1 LTR. In the distal positive URE (-436 to -128), computational analyses indicated putative binding sites for transcription factors previously found to be involved in placental promoter regulation (Ap-2, Sp-1, PPAR- gamma, GATA, c-Myb, and GCMA), as well as for NF- kappa B (-214/-204) and Ap-1 (-146/-136). The p65/p50 NF-kappaB heterodimer binds to the distal URE NF-kappaB site. This binding site and the Ap-1 binding site are crucial for the positive regulation of Syncytin-1 expression by TNF-alpha, IFN-gamma, IL- beta, IL-6 and PMA as well as for its negative regulation by IFN-beta in astrocytes. However, activation by the two interleukins (IL) does not require binding of the p65 /p50 heterodimer to the NF-kappaB site. The central URE negative regulatory region contains another Ap-1 binding site as well as binding sites for glucocorticoid and progesterone receptors. However, these sites remain putative. The distal positive URE (-436 to -128) and the central negative URE (-128 to -67) have compensatory effects in the BeWo placenta cell line. Putative binding sites for ubiquitous Ap-2, Sp-1 and placenta-specific GCMa are essential constituents of the TSE. Sp-1 and GCMa effectively bind to these Sp-1 and GCMa binding sites respectively. The binding of GCMa greatly enhances promoter activity specifically in placenta cells. The most proximal region to the 5'LTR (-35 to +1) contains putative binding sites for c-Myc and two sites for placenta specific GATA transcription factors. GATA 2 and 3, but not GATA 1 and 4, are able to bind in this region, and the integrity of both GATA sites seems to be needed for GATA 2 and GATA 3 binding and placenta-specific positive regulation of ERVWE1 transcription. - 5'LTR: The retroviral promoter is formed by the U3 region, like other simple retroviruses. A little inhibitor activity has been found in the U5 region. The U3 region is 247bp long and can be sub-divided into two regions: a region responsible for basal placental activity from +1 to +125, and a core promoter from +125 to +310. Indeed, progressive deletions into the first 125 bp of the 5' region induce a corresponding progressive decrease in the promoter activity of the LTR, in different cell types, but activity always remains higher in placenta cells. This region contains several putative binding sites for ubiquitous and placenta specific transcription factors (GATA, Pit-1a, two Sp-1, Ap-2, Oct-1, PPAR-RXR and another GATA). The Sp-1 and Ap-2 binding sites spanning the region +55 to +74 have been found to be essential for LTR activity, but remain putative. Interestingly both of them are localised in an oestrogen response element (nt +51 to +87). DNA binding assays showed that purified ERalpha bound specifically to this ERE. Oestrogen (E2, 2-OH-E2, 4-OH-E2) as well as progesterone induces Syncytin-1 transcription up to 20 fold (after three days of growth and treatment) and also induces the other ERVWE1 mRNA species. The distal part of the U3 region (+125 to +247) is defined as the minimal promoter region. Indeed, this core promoter is active in all cell types. It contains an Oct-1 binding site and conventional CAAT and TATA boxes located at 43 and 26 bp upstream of the R CAP site (+248), and separated from each other by one Ap-2 and two Sp-1 putative binding sites. Oct-1, but not Oct-2, Oct-4 or Oct-6, binds to the Oct-1 binding site, which is also essential to core promoter activation. The functional roles of CAAT and TATA boxes have been confirmed
Atlas Genet Cytogenet Oncol Haematol 2008; 2 286 by mutant analyses, and this region was found to be induced by the cAMP/Protein Kinase A pathways. Furthermore cAMP/PKA stimulates GCMa association with CBP, and GCMa acetylation by CBP. This leads to the stimulation of ERVWE1 promoter activity. Note that GCMa also binds on a very distal binding site (about 2535) and is also involved in the high placenta transcriptional activity of ERVWE1. Exogene stimuli: - Environment: Hypoxia reduces the Syncytin-1 transcription level as demonstrated in cytotrophoblast BeWo cells, primary trophoblasts cultures, ex vivo perfused placental cotyledons under hypoxic conditions and observed in placental diseases associated with hypoxia, and overexpression of SOD-1 (superoxide dismutase-1), a regulator of oxygen species, also reduced Syncytin-1 transcription. Gene repressive effects of oxygen deficiency can be compensated by induction of the cAMP/PKA pathway. in vitro serum deprivation gives rise to an increase in the transcription of HERV-W elements, including ERVWE1. - Virus transactivation: Herpes virus simplex type I (HSV-1) and Influenza virus A/WSN/33 infections can transactivate ERVWE1 5'LTR as observed in vitro in neuronal and brain endothelial cells and in tumoral cell types. HSV immediate early proteins IE1 and IE3 both trigger ERVWE1 5'LTR activity, and when co-expressed act synergically to stimulate the ERVWE1 5'LTR promoter. HSV-1 IEs seem to mediate enhanced binding of Oct-1 to its cognate binding site (nt 144-168). The mechanisms by which Influenza A/WSN/33 activates the ERVWE1 promoter are unknown. However ERVWE1 transactivation by both viruses correlated with a corresponding elevation in IFN-beta transcription in SK-N-MC neuroepithelioma cells. Conversely, the observation that IFN-beta decreases ERVWE1 URE-LTR promoter activity in U-87MG astrocytic glial cells suggests complex regulatory mechanisms. Epigenetic: Imprint hypothesis: it has been suggested that the Syncytin-1 locus, ERVWE1, could be regulated by an imprinting mechanism, and more particularly by a maternal imprint. The hypothesis is based on the biological function of Syncytin-1 in placental, and thus embryonic, development, and on the proximity of the locus to two other maternally imprinted genes that are temporally regulated in the same manner as Syncytin-1 during pregnancy, one of these two imprinting genes being another retroelement (PEG10). However, this hypothesis has not yet been confirmed. The influence of methylation on the ERVWE1 U3 retroviral promoter has been investigated and was shown to suppress its activity in HeLa and BeWo cells. Correlating with methylation control of ERVWE1 transcriptional capacity, the U3 region was found to be highly methylated in several cell types and lines (skin fibroblasts, PBMC, one breast carcinoma sample, HeLa) where Syncytin-1 is not expressed, or not systematically expressed in the case of breast cancers. It was found likewise to be highly hypomethylated in full-term placenta samples and completely unmethylated in placental BeWo cells. Note that a global hypomethylation of HERV-W LTRs elements was found in ovarian malignant tissues. Transcription RNA: SPLICING STRATEGY ERVWE1 full-length transcript, which would include the 2-kb intron, has never been detected. Though, ERVWE1 provirus produces 3 major monospliced transcripts. The first one is 7.4kb long. It corresponds to a splice of the 2kb intronic sequence (SD1/SA1), and thus contains the gag, pro/pol and env frames. The second one is 3.1kb long and results from the splice of the 2-kb intron, gag and pro/pol sequence (SD1/SA2). It thus contains only the env gene and is responsible for Syncytin-1 translation. The third produced transcript is a 1.3kb long fully spliced transcript (SD1/SA3). Other splice variants may theoretically exist, as at least another splice donor located at the env 5'UTR/ORF junction (SD2) was found to be used in association with the SA3 splice acceptor near the end of the ORF, eliminating the full env region in one placenta cDNA. Physiological transcription of the ERVWE1 locus has been detected in several tissues. Transcription levels however are mainly low as demonstrated by the need for sensitive detection techniques such as RT-PCR or EST analyses. Besides, placental and, to a lesser extent, testicular tissues have high
Atlas Genet Cytogenet Oncol Haematol 2008; 2 287 ERVWE1 transcriptional activity as indicated by Northern blotting detection. In addition, ERVWE1/Syncytin-1 mRNAs have been detected in multiple sclerosis and tumoral tissues as well as cancerous cell lines. Table 1 shows all tissues where ERVWE1 and/or HERV-W env type transcripts have been reported. The finding of ERVWE1- specific transcripts are indicated, however the list may be not exhaustive. Moreover, these results must be treated with caution as (i) the biological significance of low expression levels could be questioned, and (ii) the Syncytin-1 sequence is present within both the 7.4 kb transcript (e.g. in the testis and placenta), and the Syncytin-1 producing 3.1 kb mRNA (to date observed exclusively in the placenta). TRANSCRIPTION Placental Syncytin-1 3.1kb mRNA expression occurs specifically in trophoblast cells (extravillous cytotrophoblasts, villous cytotrophoblasts, and the syncytiotrophoblast layer), but not in placenta parenchymal cells such as fibroblasts. The variation in Syncytin-1 mRNA levels during pregnancy has been the focus of several studies but results are to some extent controversial. Thus during the first trimester ERVWE1/Syncytin-1 expression is relatively high but stable. Conflicting results were obtained concerning the latter trimesters: (i) the level of expression is reduced during the second trimester and increases again in the third trimester to reach its highest level; (ii) this level increases progressively from the second to the third trimester and falls suddenly at term, (iii) at term, the expression level remains higher than in the first trimester or becomes lower. These discrepancies may be due to the amplification method (region amplified gag-pol versus env, ERVWE1 specificity, mRNA species specificity i.e. 7.4-, 3- kb or both) or the physiological sample. Indeed the observed loss of transcription during the second trimester is considered by the authors to be potentially an artefact linked to the medical -unknown- reason that lead to interruption of pregnancy in the second trimester. Protein
Figure 5: Organization of Syncytin-1 envelope glycoprotein: The surface (SU gp50, 22-317) and transmembrane (TM gp24, 318-538) domains are indicated in blue and yellow, respectively. They derive from the proteolytic cleavage of the gPr73 envelope precursor on the consensus furin cleavage site RNKR. The black dots indicate N-glycosylation sites (positions 169, 208, 214, 234, 242, 281, and 409). Gray boxes indicate the following conserved motifs: L, leader peptide (1-21); FP, fusion peptide (318-340); IM, putative immunosuppressive domain (377-396); TM (hatched), membrane anchorage domain (444-470). CYT, intracytoplasmic tail (471-538). The 124 N-terminal amino-acids of the HERV-W mature SU protein are sufficient to interact with the hASCT2 and hASCT1 amino-acid transporters and thus represent the receptor binding domain (RBD, medium blue). The 18AA-long SDGGGX2DX2R motif conserved among retroviruses of the same interference group (recognizing the same receptors) is indicated. Amine- and carboxy- heptad repeats (NHR 352-392, CHR 407-440) within the TM domain are indicated. They constitute the homotrimeric fusion active core structure which brings the phospholipid bilayers in two cells into close proximity, resulting in membrane fusion. The ERVWE1-specific LQMV deletion (del LQMV), absent from paralogous HERV-W copies, is indicated. This deletion within the CYT region is crucial for the Syncytin-1 constitutive fusogenic activity. CWIC and CX6CC motifs involved in disulfide bonding of SU and TM domains are indicated. Description ERVWE1 encodes a 538 amino-acid, 73-kDa glycosylated (53 kDa unglycosylated) envelope protein, Syncytin-1. Structurally, Syncytin-1 protein consists of a 20AA leader peptide at the amino end, a surface subunit (SU) (AA21-317) and a transmembrane subunit (TM) (AA318-538) at the carboxy end. Syncytin-1 is synthesized as a glycosylated gPr73 precursor that associates as a homotrimeric structure. Each precursor undergoes cleavage into two mature proteins: a gp50 surface unit (SU), and a gp24 transmembrane unit (TM). The cleavage occurs at a furin cleavage site (RNKR) located at the SU/TM junction. SU and TM are further covalently linked through a disulphid bond between CWIC and CX6CC motifs of the SU and TM respectively and reach the cellular membrane. SU is responsible for recognizing and binding to specific receptors on the host cell. TM presents a hydrophobic fusion peptide (AA320-340), and a fusion core made of N- and C-terminal heptad repeats (AA352-392 and AA407-440 respectively). Heptad repeats are also involved in the homotrimerization of the above- mentioned precursors. In addition TM contains an immunosuppressive region inside the C-terminal heptad repeat (AA377-396), a carboxy-transmembrane domain (AA444-469) for protein anchoring in the membrane and ends in a cytoplasmic tail.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 288 Function Receptor-binding: The intercellular fusion driven by Syncytin-1 is activated on interaction of the SU subunit with a type D mammalian retrovirus receptor (RDR). Among RDR, HERV-W env efficiently uses two human sodium-dependant neutral amino-acid transporters as receptors, i.e. hASCT1/SATT/SCL1A4 and hASCT2/ATB/SCL1A5. The minimal receptor binding domain, at least for interaction with hASCT2, consists of the N-terminal 124 AA of the mature SU. In particular a region of 18 residues containing a SDGGG(X)2D(X)2R motif, conserved among retroviruses of the same interference group, has been proved to be essential for Syncytin-1-hASCT2 interaction. Fusion/differentiation: The intracytoplasmic tail of the TM subunit is essential for the fusion process. As mentioned above, TM presents a hydrophobic fusion peptide (AA320-340), and a fusion core made of C- and N-heptad repeats (AA352-392 and AA407-440 respectively) able to form a highly thermo-stable coiled trimer. All these regions are needed for the fusion process of enveloped viruses. Yet it exhibits an unusual processing mechanism when compared with that found in infectious retroviruses. Indeed, retroviral envelope-induced fusion is prevented by the inhibitory action of an R peptide located in the intracytoplasmic tail of the TM subunit. The R peptide is removed upon viral protease cleavage of the upstream cognate cleavage site, during or shortly after homotrimer retroviral envelopes reach the plasma cell membrane, allowing fusion to occur. ERVWE1 possesses a four amino-acid deletion (LQMV) after AA485 which eliminates the viral protease cleavage site. However far from disturbing fusion ability, this deletion has been shown to be crucial for Syncytin-1 fusogenicity. Thus no HERV-W retroviral protease any longer exists in the human genome, as all protease ORFs are disrupted, and hence the integrity of the protease cleavage site would not have helped remove the inhibitory R peptide. Furthermore, LQMV deletion also leads to loss of inhibition control by the R peptide, making Syncytin-1 constitutively fusion competent, probably by disturbing R helical structure. In addition, the study of C-terminal truncated Syncytin-1 variants indicates that cytoplasmic residues adjacent to the membrane domain, in particular residues 477-480, are required for optimal fusion induction probably by forming a helical structure, while residue 480 and those after 515 partly inhibit it. It is to be noted that the LQMV deletion, crucial for the fusogenic function of ERVWE1, is specific to ERVWE1 (as compared with paralogous HERV-W env copies). Proliferation: Recent data lead towards another as yet undescribed function of Syncytin-1. Indeed this envelope glycoprotein seems able to promote cell proliferation in the presence of TGF-beta3 and TGF-beta1 in cultured cells. When Syncytin-1 production is blocked by an siRNA tool, TGF-beta does not lead to proliferation, indicating that Syncytin-1 is needed for the proliferation process. Conversely, in the absence of TGF-beta, Syncytin-1 leads to fusion. As TGF-beta does not changes the Syncytin-1 level, this suggests a control at the post-translational level. Anti-apoptotic potential: Syncytin-1 may exert an anti-apoptotic function under certain conditions. It has indeed been demonstrated that stable transfection of Syncytin-1 into Syncytin-1-negative CHO cells efficiently prevents CHO cell apoptosis induced by staurosporine. This anti-apoptotic function might be mediated by anti- apoptotic Bcl-2, as Bcl-2 upregulation was induced by Syncytin-1 expression in CHO cells, independently of staurosporine treatment. However, this anti-apoptotic potential remains to be confirmed in vivo. Interestingly, a significant reduction of Syncytin-1 gene expression is observed in pathological placenta along with a significant increase in apoptosis rate as compared with controls, both in vitro and in vivo. Cytotoxicity: Syncytin-1 expression can induce the activation of pro-inflammatory cytokines (IL-beta) (like other HERVs sequences) and redox-reactant release (iNOS), at least in astrocytes. In addition, ectopic expression of Syncytin-1 in an astrocytoma cell-line was shown to be associated with a lower activity of mitochondrial dehydrogenases. Although the mechanisms mediating this effect remain unknown, this obervation supports possible negative influences of ectopically expressed Syncytin-1 in multiple sclerosis. Immuno-suppression: Although the TM extracellular domain of Syncytin-1 contains a 25AA so-called immunosuppressive peptide conserved and proposed to mediate immuno-suppression in many retroviral Env proteins, no direct evidence of an immunological function was demonstrated to date for the Syncytin-1. Nevertheless,
Atlas Genet Cytogenet Oncol Haematol 2008; 2 289 Syncytin-1 is expressed at the cellular membrane of extravillous trophoblasts, which invade the spiral arteries of the maternal decidua. Because of this invasion by foetal cells, the maternal decidua should be a site of high immunological conflict, though the maternal immune system accepts the allogeneic embryo without general immunosuppression. This particular immune tolerance have been proposed to be mediated through DC-SIGN(+) dendritic cells, which proliferate in the decidua specifically at time of early pregnancy. Thus, the observed interaction between Syncytin-1 extracellular domain and DC-SIGN in vitro, may reflect an immunological property of the envelope glycoprotein. Retroviral infection: - Protection against retroviral infection Syncytin-1 confers host cell resistance to infection by the spleen necrosis virus, an exogenous retrovirus whose envelope protein also uses RDR to enter cells. This phenomenon is due to a competitive binding mechanism to receptor sites called "receptor interference" and Syncytin-1 may confer host protection against infection by other exogenous retroviruses of the same interference group. - Ectopic retroviral infection Syncytin-1 can also pseudotype HIV-1 virions and confers on them a tropism for CD4 negative cells through interaction with the RDR receptors hASCT1 and hASCT2, that are widely expressed in diverse human cell types. However, the unusually long intracytoplasmic tail of Syncytin-1 as compared with other type D or C retroviruses makes it suboptimal for formation of infectious viral pseudotypes. Indeed it might interfere with efficient processing of the precursor and/or incorporation of the processed env glycoprotein into virions. Mutations Note The conservation of ERVWE1 provirus genomic localisation and envelope open reading frame have been screened in 155 individuals. They are conserved in all individuals tested so far. Moreover, sequencing of critical elements of ERVWE1, including the env ORF but also LTR elements involved in transcriptional regulation and the splice sites necessary to generate subgenomic env mRNA, showed striking conservation among the 24 individuals (48 alleles) analysed. All the polymorphic variants of Syncytin-1 are fusogenic. Envelope allelic variants: Five mutations have been found within Syncytin-1 ORF. One is a synonymous mutation, while the four others are non-synonymous. These non- synonymous mutations are dispersed among five Syncytin-1 protein variants: V129- R138-S307-S477 (67% of the sequenced population), VRnS (25%), VqnS (4%), aRSS (2%), VqSf (2%). Each of the 24 analyzed individuals had at least one of the two major genotypes, i.e. VRSS and VRnS. Altogether, amino-acid variants (frequencies) are: AA129 V(0.979), a(0.021); AA138 R(0.9375), q(0.0625); AA307 S(0.7083), n(0.2917). All variants are functional and display the same fusogenicity. Germinal None yet described Somatic None yet described Implicated in Entity Placental diseases Note Placental Morphogenesis: In physiological conditions, Syncytin-1 is exclusively expressed in placenta cells, i.e. in cytotrophoblasts and more markedly in the syncytiotrophoblast layer, but not in placenta mesenchyme. Syncytin-1 is directly involved in the fusion of placenta villous cytotrophoblasts into the syncytiotrophoblast, which constitutes the interface layer between the mother and the developing foetus. Fusion occurs following Syncytin-1 interaction with hASCT2/hATB/SCL1A5 receptors, whose expression is restricted to cytotrophoblast cells. Neither local nor temporal variations of RDR/ASCT2 expression in villous cytotrophoblast cells seems to regulate the fusion of placental trophoblast cells. Note that a modulation of cell surface expression of hASCT2 appears associated with syncytialization of BeWo cells. The level of Syncytin-1 protein in villous trophoblasts increases during early pregnancy (at least from the 6th to the 12th week of gestation) but is markedly reduced in late pregnancy. The syncytiotrophoblast is a polarized multinucleated layer, with its apical membrane facing the maternal blood circulation and the basal membrane facing the underlying cytotrophoblasts. Subcellular localization of synyctin-1 within the
Atlas Genet Cytogenet Oncol Haematol 2008; 2 290 syncytiotrophoblast has been investigated but observations are controversial. Thus Syncytin-1 distribution has been described as diffuse within the syncytial layer with enhancement at the apical membrane during all trimesters of pregnancy, while another analysis reports basal membrane localisation. In the latter report, the apical localisation occurred only in syncytiotrophoblasts from women with pre-eclampsia (9 samples), and among them both basal and apical staining appeared once. Blocking Syncytin-1 proteins (at the translational or post-translational level) greatly reduced the fusion of cytotrophoblasts and syncytiotrophoblast formation but did not completely inhibit it indicating that there must be other proteins able to partially rescue the fusion of trophoblasts in the absence of Syncytin-1. One candidate is Syncytin-2, the envelope gene of an endogenous proviral copy from the HERV-FRD family. Indeed, even if this provirus is older than ERVWE1, the fusogenic property of Syncytin-2 has been also preserved and its expression is also high in the placenta. Syncytin-1 is also expressed, but at a much lower level, in all extravillous trophoblast types, at least in first trimester placentae. These cell types are CT cells of the implanting column, invading interstitial extravillous trophoblastic cells, multinucleated giant cells and endovascular trophoblasts. The role of Syncytin-1 in extravillous trophoblasts invading the maternal endometrium is not known. Extravillous trophoblasts are also giant polyploid cells, but this ploidy is thought to be the result of endoreplication rather than of cell-cell fusion. Syncytin-1 may also play a role in villous or extravillous trophoblast proliferation in the presence of TGF-beta1 or TGFbeta3, in mediating immune-tolerance through different mechanisms or in delayed syncytiotrophoblast apoptosis. Disease Pre-eclampsia: Pre-eclampsia (PE) and HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome are multisystem disorders of pregnant women associated with placental abnormalities. Among these abnormalities are excessive proliferation of cytotrophoblasts, defects in syncytiotrophoblast formation, increased number of syncytial knots of apoptotic nuclei and suboptimal invasion of trophoblasts. Syncytin-1 gene expression and protein levels are significantly reduced in PE and HELLP syndrome. Furthermore Syncytin-1 seems to be re-distributed within the syncytiotrophoblast in pre- eclamptic placenta. PE and HELLP syndrome are also characterised by hypoxia. Interestingly, hypoxia has been shown to inhibit cytotrophoblast fusion and to reduce the Syncytin-1 transcriptional level. Impaired cytotrophoblast cell-cell fusion observed in PE and HELLP syndrome is associated with increased apoptosis. This may correlate with Syncytin-1 down-regulation, as Syncytin-1 have been suggested to have anti-apoptotic potential in vitro. Thus, Syncytin-1 down-regulation has been proposed to contribute to syncytiotrophoblast formation defects observed in these disorders and subsequent disturbed placental function. Placenta dysfunction associated with Down's syndrome/ Trisomy 21: In trisomy 21-affected placenta, a defect (or a delay) in the syncytiotrophoblast formation and a decrease of the production of pregnancy-specific hormones have been observed. This has been related to the over-expression of SOD-1(a key regulator of reactive oxygen species), located on chromosome 21. Surprisingly, in vitro, SOD-1 overexpression has been shown to also reduce the Syncytin-1 expression level.
Figure 6: Syncytin-1 and hASCT2 localization in first trimester placental villi: Using specific antibodies, Syncytin-1 expression was mainly found located at the apical syncytiotrophoblast membrane, whereas hASCT2 receptor was expressed at the membrane of cytotrophoblastic cells underlying the syncytiotrophoblast. Entity Multiple sclerosis Note MSRV, multiple sclerosis associated retrovirus, was found originally in retrovirus-like particles budding from leptomeningeal-cells from MS patients. MSRV is closely related to the HERV-W family and Syncytin-1. However, the sequencing of ERVWE1 envelopes
Atlas Genet Cytogenet Oncol Haematol 2008; 2 291 confirmed that the MSRV envelope (GenBank accession no. AF331500) was not encoded by the ERVWE1 locus. As ERVWE1 is the only W-locus bearing a full-length envelope, it was proposed that MSRV particles may result either from transcomplementation of dispersed HERV-W copies simultaneously activated or from an as yet uncharacterised exogenous retrovirus. MSRV envelope has been proposed to exert various immune properties such as inducing immune response, triggering a superantigen effect, mediating cytokine production and activating innate immunity. Disease Multiple sclerosis (MS) is a complex inflammatory, auto-immune and demyelinating disease. Syncytin-1 is expressed in specific types of cells in the brain regions affected by MS. These cell types are the astrocytes, glial cells and activated macrophages of MS lesions. Syncytin-1 expression in astrocytes mediates neuroimmune activation and death of oligodendrocytes by inducing the release of redox reactants, cytotoxic for oligodendrocytes. In astrocytes, Syncytin-1 induces the expression of OASIS (old astocytes specifically induced substance), an endoplasmic reticulum stress sensor, which in turn leads to increased expression of inducible NO synthase and concurrent suppression of hASCT1 in astrocytes, resulting in diminished myelin protein production. What mechanisms reactivate Syncytin-1 in the brain in MS is still not clear. It could be the result of viral infection of the brain, such as herpes simplex virus, which has previously been shown to transactivate Syncytin-1 expression, or cytokine deregulation. Indeed it has been shown in astrocyte cultures that MS detrimental cytokines, IFN-gamma and TNF-alpha are able to induce Syncytin-1 expression through NF-kappaB activation, while MS protective IFN-beta inhibits its expression. In addition Syncytin-1 induction by exogenous TNF-alpha into the corpus callosum, a region of the brain frequently exhibiting demyelination in MS, leads to neuroinflammation, diminished myelin proteins and neurobehavioural deficits in Syncytin-1-transgenic mice, as observed in MS. Moreover in turn, endogenous TNF-alpha and other inflammatory cytokines are induced. These observed inductions seem to occur specifically in astrocytes. Another study from the same group reported an increase in ERVWE1 DNA copy number, without evidence of new integration events or viral replication. Whether these sequences are episomal, result of endoreplication of part or the whole of chromosome 7 or belong to another retroviral sequence remains to be clarified. Expression of Syncytin-1, like of other members from the HERV-W and other HERV families, in the MS brain are not thought to be an aetiological factor but more a consequence of increased immune activity, but it now seems clear that Syncytin-1 may have an important role in the pathogenesis of MS. Prognosis The presence of Syncytin-1 in MS may indicate a poor prognosis, as Syncytin-1 mediates the induction of redox reactants and causes oligodendrocyte death and demyelination. Entity Other brain neuro-inflammatory diseases Note HERV upregulation and their probable implication has been suggested in several other neurological disorders. However it has been shown that HERV-W env/ERVWE1 env mRNAs were not differentially regulated in schizophrenia and bipolar disorders compared with controls. Entity Cancers Note HERV expression/activation, including that of the HERV-W family seems to be a common feature in cancers, a phenomenon that has been linked to deregulation of methylation. However, whether they are triggers or markers of carcinogenesis has still not been elucidated. HERV-W env sequences have been detected by EST or RT-PCR in several cancers such as brain cancer, kidney cancer, ovary cancer and skin cancer and in various cancer cell lines (Table 1). Conversely, ERVWE1/Syncytin-1 mRNA has been found in 38% of breast cancer specimens and in all benign and malignant endometria with the highest expression in endometrial carcinoma (EnCa). In these cases Syncytin-1 protein was concurrently expressed and there is evidence of fusion between cancerous cells expressing Syncytin-1 and endothelial cells. in vitro studies showed the involvement of Syncytin-1 in the fusion process between breast cancer cell lines and endothelial cells, and in the fusion or the proliferation of EnCa. This last point is linked with cAMP- stimulated cell-cell fusion or hormone-induced cell proliferation. Indeed steroid hormones induce both Syncytin-1 and TGF-beta1 and TGF-beta3, and the latters operate a switch in Syncytin-1 function from fusion to cell differentiation. Prognosis In breast cancers, the expression of Syncytin-1 may indicate a good prognosis, as
Atlas Genet Cytogenet Oncol Haematol 2008; 2 292 suggested by one study. Indeed fusion between cancer and normal cells can either lead to restoration of the apoptosis cascade, or to cell differentiation, leading to a reduced tumorigenicity. However cancerous cells fusion may also lead on the contrary to a more aggressive phenotype, and, if fusion occurs with vascular endothelial cells, to metastasis. Furthermore, the cell proliferation and suggested anti-apoptotic capacities of Syncytin-1 are more characteristics of oncogenes.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 293 Detection Normal Tissue method env species Ref adrenal Q-RT-PCR ERVWE1 De Parseval 2003 RT-PCR, Q-RT- bone marrow ERVWE1 De Parseval 2003 PCR EST, RT-PCR, Q- ERVWE1 and De Parseval 2003; Yi 2004; Frank 2005; brain RT-PCR, DNA- HERV-W Perron 2005; Antony 2006 mircoarray, IM
breast Q-RT-PCR ERVWE1 De Parseval 2003 cervix EST ERVWE1 Villesen 2004 colon EST, Q-RT-PCR ERVWE1 De Parseval 2003; Villesen 2004 heart RT-PCR HERV-W Yi 2004 RT-PCR, Q-RT- ERVWE1 and kidney De Parseval 2003; Yi, 2004; PCR HERV-W liver RT-PCR Others Yi 2004 ERVWE1 and lung RT-PCR Yi 2004 HERV-W ovary Q-RT-PCR ERVWE1 De Parseval 2003
Blond 1999; Mi 2000; Knerr 2002; Frendo NB, RT-PCR, Q- ERVWE1, 2003; Smallwood 2003; De Parseval 2003; placenta RT-PCR, EST, HERV-W, Okahara 2004; Yi 2004; Villesen 2004; WB, IM Syncytin-1 Stauffer 2004; Chen 2005; strick 2006
villous cytotrophoblast/ IM, mRNA in-situ ERVWE1, Blond 2000; Mi 2000; Frendo 2003; syncytiotrophoblast hybridization Syncytin-1 Mallassiné 2005; Muir 2006
extravillous ERVWE1, IM, RT-PCR Smallwood, 2003; Mallassiné 2005; Muir 2006 cytotrophoblasts Syncytin-1
RT-PCR, Q-RT- ERVWE1 and prostate De Parseval, 2003; Yi, 2004 PCR HERV-W ERVWE1 and skeletal muscle RT-PCR Yi, 2004 HERV-W skin Q-RT-PCR ERVWE1 De Parseval, 2003 RT-PCR, Q-RT- ERVWE1 and spleen De Parseval, 2003; Yi, 2004 PCR HERV-W spleen/liver EST ERVWE1 Villesen, 2004 ERVWE1 and fœtal spleen/liver EST Blond1999 HERV-W stomach RT-PCR HERV-W Yi 2004 NB, RT-PCR, Q- ERVWE1 and testicules Mi, 2000 ; De Parseval, 2003; Yi, 2004 RT-PCR, EST HERV-W RT-PCR, Q-RT- ERVWE1 and thymus De Parseval, 2003; Yi 2004 PCR HERV-W thyroid Q-RT-PCR ERVWE1 De Parseval, 2003 trachea Q-RT-PCR ERVWE1 De Parseval, 2003 ERVWE1 and uterus RT-PCR Yi, 2004 HERV-W endometrium Q-RT-PCR ERVWE1 Strick 2006 myometrium Q-RT-PCR ERVWE1 Strick 2006 Neurological and Detection env species Ref placental diseases method Multiple scleoris
cerveau Q-RT-PCR, WB ERWE1 Perron, 1997; Antony, 2004; Antony 2006
macrophages IM Syncytin-1 Antony 2004; Perron 2005 microglia IM Syncytin-1 Antony, 2004 astrocytes IM Syncytin-1 Antony, 2004 Placental
dysfunction pre-eclamptia EST, RT-PCR ERVWE1 Stauffer 2004; Chen 2005; langbein 2007 HELLP syndrome RT-PCR ERVWE1 Knerr 2002; Langbein 2007 Down syndrome RT-PCR ERVWE1 Frendo 2001
Atlas Genet Cytogenet Oncol Haematol 2008; 2 294 Table1: HERV-W, ERVWE1 and Syncytin-1 expression: Detection of HERV-W env mRNA transcripts by Northern blot (NB), RT-PCR, real-time RT-PCR (Q-RT-PCR), or by analysis of Expressed Sequence Tag (ESTs) databases. Depending on the method used (e.g. primers within the env ORF, primers overlapping splice junction , ...), either only ERVWE1 specific transcripts are detected (labelled ERVWE1) or env-containing HERV-W transcripts are detected (labelled HERV-W). Relative expression of ERVWE1 transcripts in normal tissue is indicated in red (1,000-10,000), orange (10-100) and yellow (1-10). Whether ERVWE1 mRNA expression correlates with protein expression detected by immunocytochemistry (IM) or western blotting (WB) is indicated (glycoprotein detection is labelled Syncytin-1). Note that HERV-W mRNA expression does not preclude neither the presence nor the absence of ERVWE1 expression (labelled ERVWE1 and HERV-W when both are identified). External links Nomenclature Hugo ERVWE1 GDB ERVWE1 Entrez_Gene ERVWE1 30816 endogenous retroviral family W, env(C7), member 1 (syncytin) Cards Atlas ERVWE1ID40497ch7q21 GeneCards ERVWE1 Ensembl ERVWE1 [Search_View] ENSG00000197604 [Gene_View] Genatlas ERVWE1 GeneLynx ERVWE1 eGenome ERVWE1 euGene 30816 Genomic and cartography GoldenPath ERVWE1 - 7q21.2 Ensembl ERVWE1 - [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene ERVWE1 Gene and transcription Genbank AF072503 [ ENTREZ ] Genbank AF072505 [ ENTREZ ] Genbank AF072506 [ ENTREZ ] Genbank AF072507 [ ENTREZ ] Genbank AF072508 [ ENTREZ ] RefSeq NM_014590 [ SRS ] NM_014590 [ ENTREZ ] RefSeq AC_000050 [ SRS ] AC_000050 [ ENTREZ ] RefSeq AC_000068 [ SRS ] AC_000068 [ ENTREZ ] RefSeq NC_000007 [ SRS ] NC_000007 [ ENTREZ ] RefSeq NG_004112 [ SRS ] NG_004112 [ ENTREZ ] RefSeq NT_007933 [ SRS ] NT_007933 [ ENTREZ ] RefSeq NT_079595 [ SRS ] NT_079595 [ ENTREZ ] RefSeq NW_923574 [ SRS ] NW_923574 [ ENTREZ ] AceView ERVWE1 AceView - NCBI Fast-db 8315 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q9UQF0 [ SRS] Q9UQF0 [ EXPASY ] Q9UQF0 [ INTERPRO ] Interpro IPR002050 Env_polyprotein [ SRS ] IPR002050 Env_polyprotein [ EBI ] CluSTr Q9UQF0 PF00429 TLV_coat [ SRS ] PF00429 TLV_coat [ Sanger ] pfam00429 [ NCBI-CDD Pfam ] Blocks Q9UQF0 HPRD 05231 Protein Interaction databases DIP Q9UQF0 IntAct Q9UQF0
Atlas Genet Cytogenet Oncol Haematol 2008; 2 295 Polymorphism : SNP, mutations, diseases OMIM 604659 [ map ] GENECLINICS 604659 SNP ERVWE1 [dbSNP-NCBI] SNP NM_014590 [SNP-NCI] SNP ERVWE1 [GeneSNPs - Utah] ERVWE1] [HGBASE - SRS] HAPMAP ERVWE1 [HAPMAP] HGMD ERVWE1 General knowledge Family Browser ERVWE1 [UCSC Family Browser] SOURCE NM_014590 GO structural molecule activity [Amigo] structural molecule activity GO transposition, DNA-mediated [Amigo] transposition, DNA-mediated GO syncytium formation [Amigo] syncytium formation GO anatomical structure morphogenesis [Amigo] anatomical structure morphogenesis GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO virion [Amigo] virion GO viral capsid [Amigo] viral capsid GO viral envelope [Amigo] viral envelope PubGene ERVWE1 Other databases Probes Probe ERVWE1 Related clones (RZPD - Berlin) PubMed PubMed 41 Pubmed reference(s) in LocusLink Bibliography Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Cianciolo GJ, Copeland TD, Oroszlan S, Snyderman R. Science 1985; 230(4724): 453-455. PMID 2996136
Partial nucleotide sequence of the avian erythroblastosis virus (AEV ES4). Thoraval P, Savatier P, Xiao JH, Mallet F, Samarut J, Verdier G, Nigon V. Nucleic Acids Res 1987; 15(22): 9612. PMID 2825143
Structure and classification of retroviruses. Coffin JM In The Retroviridae, 1992, vol1, (2):19-49 Ed Levy JA, Plenum Press
The human endogenous retrovirus ERV-3 is upregulated in differentiating placental trophoblast cells. Boyd MT, Bax CM, Bax BE, Bloxam DL, Weiss RA. Virology 1993; 196(2): 905-909. PMID 8372456
Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, Mallet F, Tuke PW, Voisset C, Blond JL, Lalande B, Seigneurin JM, Mandrand B. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A. 1997; 94(14): 7583-7588. PMID 9207135
Toward a phylogenetic classification of Primates based on DNA evidence complemented by
Atlas Genet Cytogenet Oncol Haematol 2008; 2 296 fossil evidence. Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP. Mol Phylogenet Evol 1998; 9(3): 585-598. PMID 9668008
Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. Blond JL, Beseme F, Duret L, Bouton O, Bedin F, Perron H, Mandrand B, Mallet F. J Virol 1999; 73(2): 1175-1185. PMID 9882319
Specificities of multiple sclerosis cerebrospinal fluid and serum antibodies against mimotopes. Jolivet-Reynaud C, Perron H, Ferrante P, Becquart L, Dalbon P, Mandrand B. Clin Immunol 1999; 93(3): 283-293. PMID 10600340
Isolation and phylogeny of endogenous retrovirus sequences belonging to the HERV-W family in primates. Kim HS, Takenaka O, Crow TJ. J Gen Virol 1999; 80 ( Pt 10): 2613-2619. PMID 10573154
Molecular cloning and characterization of MSRV-related sequences associated with retrovirus- like particles. Komurian-Pradel F, Paranhos-Baccala G, Bedin F, Ounanian-Paraz A, Sodoyer M, Ott C, Rajoharison A, Garcia E, Mallet F, Mandrand B, Perron H. Virology 1999; 260(1): 1-9. PMID 10405350
Expression of endogenous retrovirus ERV-3 induces differentiation in BeWo, a choriocarcinoma model of human placental trophoblast. Lin L, Xu B, Rote NS. Placenta 1999; 20(1): 109-118. PMID 9950152
Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates. Voisset C, Blancher A, Perron H, Mandrand B, Mallet F, Paranhos-Baccala G. AIDS Res Hum Retroviruses 1999; 15(17): 1529-1533. PMID 10580403
An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL. J Virol 2000; 74(7): 3321-3329. PMID 10708449
Failure of differentiation of the trophoblast in trisomy 21 Evain-Brion D, Frendo JL, Vidaud M, Muller F, Porquet D, Blot P. Bull Acad Natl Med 2000;184(5): 1033-1047. (FRENCH). PMID 11077723
Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JC Jr, McCoy JM. Nature 2000; 403(6771): 785-789. PMID 10693809
Chromosomal distribution and coding capacity of the human endogenous retrovirus HERV-W
Atlas Genet Cytogenet Oncol Haematol 2008; 2 297 family. Voisset C, Bouton O, Bedin F, Duret L, Mandrand B, Mallet F, Paranhos-Baccala G. AIDS Res Hum Retroviruses 2000; 16(8): 731-740. PMID 10826480
Envelope gene of the human endogenous retrovirus HERV-W encodes a functional retrovirus envelope. An DS, Xie Ym, Chen IS. J Virol 2001; 75(7): 3488-3489. PMID 11238877
Overexpression of copper zinc superoxide dismutase impairs human trophoblast cell fusion and differentiation. Frendo JL, Therond P, Bird T, Massin N, Muller F, Guibourdenche J, Luton D, Vidaud M, Anderson WB, Evain-Brion D. Endocrinology 2001; 142(8): 3638-3648. PMID 11459813
Initial sequencing and analysis of the human genome. I. H. G. S. C. Nature 2001; 409(6822): 860-921. PMID 11237011
Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C. Ann Neurol 2001; 50(4): 434-442. PMID 11601494
Human endogenous retrovirus HERV-W family: chromosomal localization, identification, and phylogeny. Kim HS, Lee WH. AIDS Res Hum Retroviruses 2001; 17(7): 643-648. PMID 11375061
Downregulation of placental Syncytin expression and abnormal protein localization in pre- eclampsia. Lee X, Keith JC Jr, Stumm N, Moutsatsos I, McCoy JM, Crum CP, Genest D, Chin D, Ehrenfels C, Pijnenborg R, van Assche FA, Mi S. Placenta 2001; 22(10): 808-812. PMID 11718567
Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. Perron H, Jouvin-Marche E, Michel M, Ounanian-Paraz A, Camelo S, Dumon A, Jolivet-Reynaud C, Marcel F, Souillet Y, Borel E, Gebuhrer L, Santoro L, Marcel S, Seigneurin JM, Marche PN, Lafon M. Virology 2001; 287(2): 321-332. PMID 11531410
Characterization of the intragenomic spread of the human endogenous retrovirus family HERV- W. Costas J. Mol Biol Evol 2002; 19(4): 526-533. PMID 11919294
Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome. Knerr I, Beinder E, Rascher W. Am J Obstet Gynecol 2002; 186(2): 210-213. PMID 11854637
Atlas Genet Cytogenet Oncol Haematol 2008; 2 298
Changes in expression and function of Syncytin and its receptor, amino acid transport system B(0) (ASCT2), in human placental choriocarcinoma BeWo cells during syncytialization. Kudo Y, Boyd CA. Placenta 2002; 23(7): 536-541. PMID 12175968
The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D. J Virol 2002; 76(13): 6442-6452. PMID 12050356
Processed pseudogenes of human endogenous retroviruses generated by LINEs: their integration, stability, and distribution. Pavlicek A, Paces J, Elleder D, Hejnar J. Genome Res 2002; 12(3): 391-399. PMID 11875026
GCMa regulates the Syncytin-mediated trophoblastic fusion. Yu C, Shen K, Lin M, Chen P, Lin C, Chang GD, Chen H. J Biol Chem 2002; 277(51): 50062-50068. PMID 12397062
Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies Syncytin 2, a gene conserved on primate evolution. Blaise S, de Parseval N, Benit L, Heidmann T. Proc Natl Acad Sci U S A 2003; 100(22): 13013-13018. PMID 14557543
Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins. de Parseval N, Lazar V, Casella JF, Benit L, Heidmann T. J Virol 2003; 77(19): 10414-10422. PMID 12970426
Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. Firouzi R, Rolland A, Michel M, Jouvin-Marche E, Hauw JJ, Malcus-Vocanson C, Lazarini F, Gebuhrer L, Seigneurin JM, Touraine JL, Sanhadji K, Marche PN, Perron H. J Neurovirol 2003; 9(1): 79-93. PMID 12587071
Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F. Mol Cell Biol 2003; 23(10): 3566-3574. PMID 12724415
Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Kammerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, van Kooyk Y, Kampgen E. Am J Pathol 2003; 162(3): 887-896. PMID 12598322
Transcriptional effects of hypoxia on fusiogenic Syncytin and its receptor ASCT2 in human cytotrophoblast BeWo cells and in ex vivo perfused placental cotyledons. Knerr I, Weigel C, Linnemann K, Dotsch J, Meissner U, Fusch C, Rascher W. Am J Obstet Gynecol 2003; 189(2): 583-588. PMID 14520239
Atlas Genet Cytogenet Oncol Haematol 2008; 2 299
Hypoxia alters expression and function of Syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: implications for impaired trophoblast syncytialisation in pre-eclampsia. Kudo Y, Boyd CA, Sargent IL, Redman CW. Biochim Biophys Acta 2003; 1638(1): 63-71. PMID 12757936
Activation of the human endogenous retrovirus W long terminal repeat by herpes simplex virus type 1 immediate early protein 1. Lee WJ, Kwun HJ, Kim HS, Jang KL. Mol Cells 2003; 15(1): 75-80. PMID 12661764
Analysis of transcriptional regulatory sequences in the human endogenous retrovirus W long terminal repeat. Lee WJ, Kwun HJ, Jang KL. J Gen Virol 2003; 84(Pt 8): 2229-2235. PMID 12867655
Retroviral repeat sequences. Mager DL, Medstrand P. Encyclopedia of the human genome. Nature Publishing Group 2003 (5): 57-63 (REVIEW)
The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus. Ponferrada VG, Mauck BS, Wooley DP. Arch Virol 2003; 148(4): 659-675. PMID 12664292
Temporal regulation of the expression of Syncytin (HERV-W), maternally imprinted PEG10, and SGCE in human placenta. Smallwood A, Papageorghiou A, Nicolaides K, Alley MK, Jim A, Nargund G, Ojha K, Campbell S, Banerjee S. Biol Reprod 2003; 69(1): 286-293. PMID 12620933
Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Antony JM, van Marle G, Opii W, Butterfield DA, Mallet F, Yong VW, Wallace JL, Deacon RM, Warren K, Power C. Nat Neurosci 2004; 7(10): 1088-1095. PMID 15452578
Evidence of selection on the domesticated ERVWE1 env retroviral element involved in placentation. Bonnaud B, Bouton O, Oriol G, Cheynet V, Duret L, Mallet F. Mol Biol Evol 2004; 21(10): 1895-1901. PMID 15254254
Isolation and characterization of the human Syncytin gene promoter. Cheng YH, Richardson BD, Hubert MA, Handwerger S. Biol Reprod 2004; 70(3): 694-701. PMID 14613893
The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B. Proc Natl Acad Sci U S A 2004; 101(6): 1731-1736. PMID 14757826
Atlas Genet Cytogenet Oncol Haematol 2008; 2 300
L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas. Menendez L, Benigno BB, McDonald JF. Mol Cancer 2004; 3: 12. PMID 15109395
Expression analyses of human endogenous retroviruses (HERVs): tissue-specific and developmental stage-dependent expression of HERVs. Okahara G, Matsubara S, Oda T, Sugimoto J, Jinno Y, Kanaya F. Genomics 2004; 84(6): 982-990. PMID 15533715
A retroviral promoter and a cellular enhancer define a bipartite element which controls env ERVWE1 placental expression. Prudhomme S, Oriol G, Mallet F. J Virol 2004; 78(22): 12157-12168. PMID 15507602
Antigen-presenting cells in human endometrium during the menstrual cycle compared to early pregnancy. Rieger L, Honig A, Sutterlin M, Kapp M, Dietl J, Ruck P, Kammerer U. J Soc Gynecol Investig 2004; 11(7): 488-493. PMID 15458747
The role of human endogenous retroviruses in trophoblast differentiation and placental development. Rote NS, Chakrabarti S, Stetzer BP. Placenta 2004; 25(8-9): 673-683. (REVIEW). PMID 15450384
Digital expression profiles of human endogenous retroviral families in normal and cancerous tissues. Stauffer Y, Theiler G, Sperisen P, Lebedev Y, Jongeneel CV. Cancer Immun 2004; 4: 2. PMID 14871062
Emerging issues in virus taxonomy. van Regenmortel MH, Mahy BW. Emerg Infect Dis 2004; 10(1): 8-13. (REVIEW). PMID 15078590
Identification of endogenous retroviral reading frames in the human genome. Villesen P, Aagaard L, Wiuf C, Pedersen FS. Retrovirology 2004; 1: 32. PMID 15476554
Expression of the human endogenous retrovirus HERV-W family in various human tissues and cancer cells. Yi JM, Kim HM, Kim HS. J Gen Virol 2004; 85(Pt 5): 1203-1210. PMID 15105536
Natural history of the ERVWE1 endogenous retroviral locus. Bonnaud B, Beliaeff J, Bouton O, Oriol G, Duret L, Mallet F. Retrovirology 2005; 2: 57. PMID 16176588
Stimulation of GCMa transcriptional activity by cyclic AMP/protein kinase A signaling is attributed to CBP-mediated acetylation of GCMa. Chang CW, Chuang HC, Yu C, Yao TP, Chen H.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 301 Mol Cell Biol 2005; 25(19): 8401-8414. PMID 16166624
A placenta-specific enhancer of the human Syncytin gene. Cheng YH, Handwerger S. Biol Reprod 2005; 73(3): 500-509. PMID 15888734
Synthesis, assembly, and processing of the Env ERVWE1/Syncytin human endogenous retroviral envelope. Cheynet V, Ruggieri A, Oriol G, Blond JL, Boson B, Vachot L, Verrier B, Cosset FL, Mallet F. J Virol 2005; 79(9): 5585-5593. PMID 15827173
Comprehensive search for intra- and inter-specific sequence polymorphisms among coding envelope genes of retroviral origin found in the human genome: genes and pseudogenes. de Parseval N, Diop G, Blaise S, Helle F, Vasilescu A, Matsuda F, Heidmann T. BMC Genomics 2005; 6: 117. PMID 16150157
MSRV/HERV-W/Syncytin and its linkage to multiple sclerosis: the usability and the hazard of a human endogenous retrovirus. Dolei A. J Neurovirol 2005; 11(2): 232-235. (REVIEW) PMID 16036802
Syncytin-A and Syncytin-B, two fusogenic placenta-specific murine envelope genes of retroviral origin conserved in Muridae. Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T. Proc Natl Acad Sci U S A 2005; 102(3): 725-730. PMID 15644441
Human endogenous retrovirus expression profiles in samples from brains of patients with schizophrenia and bipolar disorders. Frank O, Giehl M, Zheng C, Hehlmann R, Leib-Mosch C, Seifarth W. J Virol 2005; 79(17): 10890-10901. PMID 16103141
Structural characterization of the fusion core in Syncytin, envelope protein of human endogenous retrovirus family W. Gong R, Peng X, Kang S, Feng H, Huang J, Zhang W, Lin D, Tien P, Xiao G. Biochem Biophys Res Commun 2005; 331(4): 1193-1200. PMID 15883002
Stimulation of GCMa and Syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions. Knerr I, Schubert SW, Wich C, Amann K, Aigner T, Vogler T, Jung R, Dotsch J, Rascher W, Hashemolhosseini S. FEBS Lett 2005; 579(18): 3991-3998. PMID 16004993
Expression of HERV-W Env glycoprotein (Syncytin) in the extravillous trophoblast of first trimester human placenta. Malassine A, Handschuh K, Tsatsaris V, Gerbaud P, Cheynet V, Oriol G, Mallet F, Evain-Brion D. Placenta 2005; 26(7): 556-562. PMID 15993705
Correlation between disease severity and in vitro cytokine production mediated byMSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 302 Rolland A, Jouvin-Marche E, Saresella M, Ferrante P, Cavaretta R, Creange A, Marche P, Perron H. J Neuroimmunol 2005; 160(1-2): 195-203. PMID 15710473
Quantitative analysis of human endogenous retrovirus-W env in neuroinflammatory diseases. Antony JM, Izad M, Bar-Or A, Warren KG, Vodjgani M, Mallet F, Power C. AIDS Res Hum Retroviruses 2006; 22(12): 1253-1259. PMID 17209768
Syncytin is involved in breast cancer-endothelial cell fusions. Bjerregaard B, Holck S, Christensen IJ, Larsson LI. Cell Mol Life Sci 2006; 63(16): 1906-1911. PMID 16871371
The gene of retroviral origin Syncytin 1 is specific to hominoids and is inactive in Old World monkeys. Caceres M; NISC Comparative Sequencing Program, Thomas JW. J Hered 2006; 97(2): 100-106. PMID 16424151
Altered placental Syncytin and its receptor ASCT2 expression in placental development and pre-eclampsia. Chen CP, Wang KG, Chen CY, Yu C, Chuang HC, Chen H. BJOG 2006; 113(2): 152-158. PMID 16411991
Identification of the hASCT2-binding domain of the Env ERVWE1/Syncytin-1 fusogenic glycoprotein. Cheynet V, Oriol G, Mallet F. Retrovirology 2006; 3: 41. PMID 16820059
C-Terminal truncations of Syncytin-1 (ERVWE1 envelope) that increase its fusogenicity. Drewlo S, Leyting S, Kokozidou M, Mallet F, Potgens AJ. Biol Chem 2006; 387(8): 1113-1120. PMID 16895482
Endogenous retroviruses regulate periimplantation placental growth and differentiation. Dunlap KA, Palmarini M, Varela M, Burghardt RC, Hayashi K, Farmer JL, Spencer TE. Proc Natl Acad Sci U S A 2006; 103(39): 14390-14395. PMID 16980413
CpG methylation suppresses transcriptional activity of human Syncytin-1 in non-placental tissues. Matouskova M, Blazkova J, Pajer P, Pavlicek A, Hejnar J. Exp Cell Res 2006; 312(7): 1011-1020. PMID 16427621
Human endogenous retrovirus-W envelope (Syncytin) is expressed in both villous and extravillous trophoblast populations. Muir A, Lever AM, Moffett A. J Gen Virol 2006; 87(Pt 7): 2067-2071. PMID 16760410
Transactivation of elements in the human endogenous retrovirus W family by viral infection. Nellaker C, Yao Y, Jones-Brando L, Mallet F, Yolken RH, Karlsson H. Retrovirology 2006; 3: 44. PMID 16822326
The envelope protein of a human endogenous retrovirus-W family activates innate immunity
Atlas Genet Cytogenet Oncol Haematol 2008; 2 303 through CD14/TLR4 and promotes Th1-like responses. Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN. J Immunol 2006; 176(12): 7636-7644. PMID 16751411
Regulation of human endogenous retrovirus W protein expression by herpes simplex virus type 1: implications for multiple sclerosis. Ruprecht K, Obojes K, Wengel V, Gronen F, Kim KS, Perron H, Schneider-Schaulies J, Rieckmann P. J Neurovirol 2006; 12(1): 65-71. PMID 16595376
Methylation of endogenous human retroelements in health and disease. Schulz WA, Steinhoff C, Florl AR. Curr Top Microbiol Immunol 2006; 310: 211-250. (REVIEW). PMID 16909913
The human endogenous retrovirus envelope glycoprotein, Syncytin-1, regulates neuroinflammation and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes. Antony JM, Ellestad KK, Hammond R, Imaizumi K, Mallet F, Warren KG, Power C. J Immunol 2007; 179(2): 1210-1224. PMID 17617614
Distribution of human endogenous retrovirus type W receptor in normal human villous placenta. Hayward MD, Potgens AJ, Drewlo S, Kaufmann P, Rasko JE. Pathology 2007; 39(4): 406-412. PMID 17676482
Fusiogenic endogenous-retroviral Syncytin-1 exerts anti-apoptotic functions in staurosporine- challenged CHO cells. Knerr I, Schnare M, Hermann K, Kausler S, Lehner M, Vogler T, Rascher W, Meissner U. Apoptosis 2007; 12(1): 37-43. PMID 17080327
Impaired cytotrophoblast cell-cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Langbein M, Strick R, Strissel PL, Vogt N, Parsch H, Beckmann MW, Schild RL. Mol Reprod Dev 2007; [Epub ahead of print] PMID 17546632
Syncytin and cancer cell fusions. Larsson LI, Bjerregaard B, Wulf-Andersen L, Talts JF. ScientificWorldJournal 2007; 7: 1193-1197. PMID 17704852
Prognostic role of Syncytin expression in breast cancer. Larsson LI, Holck S, Christensen IJ. Hum Pathol 2007; 38(5): 726-731. PMID 17306327
Expression of the fusogenic HERV-FRD Env glycoprotein (Syncytin 2) in human placenta is restricted to villous cytotrophoblastic cells. Malassine A, Blaise S, Handschuh K, Lalucque H, Dupressoir A, Evain-Brion D, Heidmann T. Placenta 2007; 28(2-3): 185-191. PMID 16714059
Regulation of the Syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines. Mameli G, Astone V, Khalili K, Serra C, Sawaya BE, Dolei A.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 304 Virology 2007; 362(1): 120-130. PMID 17258784
Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta. Strick R, Ackermann S, Langbein M, Swiatek J, Schubert SW, Hashemolhosseini S, Koscheck T, Fasching PA, Schild RL, Beckmann MW, Strissel PL. J Mol Med 2007; 85(1): 23-38. PMID 17066266
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Contributor(s) Written 09-2007 Juliette Gimenez, François Mallet UMR 2714 CNRS-bioMèrieux, IFR128 BioSciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France Citation This paper should be referenced as such : Gimenez J, Mallet F . ERVWE1 (Endogenous Retroviral family W, Env(C7), member 1). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ERVWE1ID40497ch7q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 305 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CTSH (cathepsin H)
Identity Other names ACC-4 ACC-5 CPSB DKFZp686B24257 EC 3.4.22.16 MGC1519 aleurain minichain Hugo CTSH Location 15q25.1 DNA/RNA Description The gene for human cathepsin H is located on chromosome 15q24-q25 and contains 12 exons spanning over 23 kb of genomic sequences. The junctions between the exons and 11 introns conform to the GT-AG rule. The preproenzyme transcript length is 1005 bp. Transcription The cathepsin H gene has a TATA- and CAAT-less promoter and upstretream of exon 1 only one GC box was detected, suggesting the presence of one more exon. Two different forms of cathepsin H cDNA, the full-length form (CTSH) and a truncated form with deletion of 12 amino acids at the signal peptide region (CTSHdelta10-21), were identified in prostate tissues and cancer cell lines. Protein
Richardson diagram of cathepsin H structure: a-helixes are shown in red and ß -sheets in green. Catalytic residues are shown in ball-and-stick representation: Cys141 in yellow, His281 in purple and Asn301 in pink. Carbohydrates are shown as CPK spheres in yellow. The mini chain is shown in grey (MEROPS: the peptidase database - C01.040). Description Cathepsin H belongs to the superfamily of papain-like cysteine proteases. It is synthesized as a preproenzyme of 335 amino acid residues with a calculated Mr of 37 403. It is proteolytically processed to an active single chain, i.e. mature form within the endosomes/lysosomes. A unique feature of this enzyme is that it acts as both an aminopeptidase and an endopeptidase although the latter activity is much lower than the former activity. Sequencing data revealed that in addition to the heavy and light
Atlas Genet Cytogenet Oncol Haematol 2008; 2 306 chains, which are typically found in a number of mammalian papain-like cysteine proteases, cathepsin H contains also an octapeptide EPQNCSAT originating from the propeptide, termed the mini-chain. It was shown that the mini-chain is disulfide linked to Cys205 of the main body of the enzyme and involved in the aminopeptidase activity of the enzyme. It was concluded that the mini-chain plays a key role in substrate recognition, and that the carbohydrate residues attached to the body of the enzyme are involved in the positioning the mini-chain in the active-site cleft. Procathepsin H has three potential carbohydrate binding sites. Glycosilation has been confirmed on Asn230 and on the mini-chain Asn101 of the mature enzyme. The recombinant form of human cathepsin H lacking the mini-chain was shown to be an endopeptidase. Cathepsin H hidrolyzes endopeptidase substrates such as Bz-Arg+NHNap, Bz-Arg+NHMec, Bz- Phe-Val-Arg+NHMec, and acts on Pro-Gly+Phe and Pro-Arg+NHNap much like a dipeptidyl-peptidase. It was shown to cleave several proteins preferring hydrophobic residues at P2 and P3, however the endopeptidase activity of the enzyme is limited. Collagen and laminin, for instance, were not degraded by cathepsin H. Naturally occurring inhibitors of cathepsin H are the cystatins, a2-macroglobulin and antigens from mouse cytotoxic lymphocytes CTLA-2ß. Expression Cathepsin H expression is ubiquitous, with very high expression in the kidney. There is growing evidence that the expression of cathepsin H is increased in diseases including breast, colorectal and prostate carcinoma, melanoma and gliomas. In contrast, decreased cathepsin H expression has been reported in squamous cell carcinoma of the head and neck. Other studies have found a higher cathepsin H expression in well- differentiated pancreatic cancer cells compared with less well-differentiated cancer cells. Localisation Cathepsin H is located manly at the endosomal-lysosomal compartments. Only 10 % of the enzyme is secreted. It has been shown that substantial concentrations of cathepsin H circulate in the blood. Function Cathepsin H is one of the lysosomal cysteine proteinases, which are involved in intracellular protein degradation. It is one of the few noncomplement proteases that cleave native C5 to generate the potent chemotaxin C5a. Cathepsin H was detected in extracellular compartments of atherosclerotic plaques. Although the pathogenic potential of cathepsin H in the development of the late, unstable plaque is quite evident, there is the possibility that this protease may play a role in early atherogenesis. Furthermore, it was found that cathepsin H could contribute to the transformation of LDL in monocyte-derived foam cells. Recently the enzyme was shown to be essential in one of the processing steps of hydrophobic surfactant- associated protein C. Cathepsin H is overexpressed in different tumour cells. However, the role of cathepsin H in tumour progression is not well understood. A possible function of cathepsin H in tumour progression is its ability to degrade fibrinogen and fibronectin, suggesting that, along with other proteases, cathepsin H may be involved in the destruction of extracellular matrix components leading to cancer proliferation, migration, and metastasis. Homology Cathepsins H exhibit a high degree of sequence homology to cathepsin B and other cysteine proteinases of the C1 (papain) family. Mutations Germinal Not yet reported Somatic Not yet reported Implicated in Entity Colorectal cancer Prognosis Protein levels of cathepsin H were measured by ELISA in preoperative sera from 324 patients with colorectal cancer. The level of cathepsin H was significantly increased in patient sera, the median level was 8.4 ng/mL versus 2.1 ng/mL in 90 healthy blood donors (p < 0.0001). In survival analysis a significant difference was found between the group of patients with low cathepsin H (first tertile) who had a poor prognosis and the remaining patients (p = 0.03). The risk of patients was further stratified when cathepsin H levels were combined with carcinoembryonic antigen (CEA). Patients with high CEA and low cathepsin H had the highest risk of death with a hazard ratio of 2.72 (95% CI 1.73-4.28), p < 0.0001.The prognostic information of cathepsin H differs from that of the
Atlas Genet Cytogenet Oncol Haematol 2008; 2 307 related cathepsins B and L and suggest different roles during the progression of malignant disease. Entity Melanoma Prognosis The level of cathepsin H was determined in the sera of 43 patients with metastatic melanoma, in 54 patients with treated cutaneous melanoma with no evidence of metastatic disease, and in 30 healthy blood donors, using quantitative ELISA. The levels were significantly higher within the group of metastatic melanoma patients compared with the healthy controls with a median of 13.7 versus 4.9 ng/ml (P < 0.0001). Cathepsin H was also significantly increased within the group of melanoma patients with no metastasis, with a median of 9.6 ng/ml. The serum level was increased in patients showing no response to the chemoimmunotherapy as compared to the level in responders. Metastatic melanoma patients with high content of cathepsin H experienced significantly shorter overall survival rates than the patients with low levels of the enzyme (Cat H: P < 0.006 and relative risk, 2.4, using median as cut-off value). Entity Head and neck carcinoma Prognosis To estimate the prognostic value of cathepsins H in head and neck carcinoma, its concentration was measured in cytosols of primary tumours and adjacent normal tissue from 21 patients. Cathepsin H concentration was higher in normal tissue (p = 0.001) than in tumour tissue and in laryngeal than in non-laryngeal normal and tumour tissues. Disease-free survival was poor in patients with lower concentrations of cathepsin H in tumour tissue (p = 0.055). Entity Bladder cell transitional cell carcinoma Note Using spectrofluorometric assay, catalytic activity of cathepsin H was measured in human bladder cell lines (HCV29, normal; RT4, well differentiated; J82, poorly differentiated) and in noncancerous and cancerous tissue samples (n = 20) of transitional cell carcinoma. In comparison to the intracellular activity of cathepsin H in the poorly differentiated cell line J82, the intracellular activity in the normal cell line HCV29 was significantly greater (P <0.05), independent of stage or grade. In contrast, the portion of cathepsin H released from cell line J82 into the supernatant, revealed higher values than that from cell line HCV29. In cancerous bladder tissue, the level of cathepsin H was significantly greater than in the matched normal tissue (P <0.05). Entity Lung cancer Note A transgenic mouse model of lung cancer was utilized to identify markers of early lung tumours in humans. Immunohistochemical analyses identified cathepsin H as being consistently elevated in the murine lung tumours compared to non-tumour bearing transgenic lung tissue surrounding the tumour. Importantly, the elevation was observed in early stage, indicating its ability to detect early lung lesions that would be amenable to surgical resection. Entity Glioma Note Cathepsin H activity was determined in normal brain tissue and tumour tissue extracts. The activity of cathepsin H was twofold higher in low grade glioma, fourfold higher in anaplastic astrocytoma and eightfold higher in glioblastoma than in normal brain tissue. Cathepsin H antibody inhibited the invasion of glioblastoma cell lines through Matrigel®. These data suggest that the tumour-specific increase in antigen may be a useful independent marker of tumour progression in central nervous system neoplasms. Entity Cervical carcinoma Note The expression of cathepsin H in cervical carcinoma cell lines and tissue was found to be down-regulated compared to normal tissue, using cDNA arrays. Entity Joint diseases Note The level of cathepsin H was determined in synovial fluids and sera of patients with inflammatory and metabolic joint diseases, using quantitative ELISA. Cathepsin H was not found in normal sera (values below 3 micrograms/l), but was measurable in patients' synovial fluids. The highest values of cathepsin H were measured in synovial fluids of patients with undifferentiated arthritis. There is yet no clear correlation between the quantity of the enzyme released in synovia and the clinical diagnosis or the stage of disease. Entity Alzheimer's disease Note Cultured fibroblasts from patients affected by Alzheimer's disease (AD) exhibited
Atlas Genet Cytogenet Oncol Haematol 2008; 2 308 alterations of the enzyme transketolase. Abnormalities (dubbed alkaline band) consisted of enzyme forms having unusually high pl and were proposed as a marker of the disease in living patients. Human cathepsin H was shown to partially induce an Alzheimer-like transketolase pattern and cleave normal transketolase to a 35 kDa fragment as spontaneously occurring in Alzheimer's disease fibroblasts. The explanation of transketolase abnormalities could be an imbalance of proteolysis in Alzheimer's disease fibroblasts due to a relative increase/derangement of cysteine proteinases, including cathepsin H. External links Nomenclature Hugo CTSH GDB CTSH Entrez_Gene CTSH 1512 cathepsin H Cards Atlas CTSHID40206ch15q25 GeneCards CTSH Ensembl CTSH [Search_View] ENSG00000103811 [Gene_View] Genatlas CTSH GeneLynx CTSH eGenome CTSH euGene 1512 Genomic and cartography GoldenPath CTSH - 15q25.1 chr15:77001147-77024475 - 15q24-q25 (hg18-Mar_2006) Ensembl CTSH - 15q24-q25 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CTSH Gene and transcription Genbank AF426247 [ ENTREZ ] Genbank AF426248 [ ENTREZ ] Genbank AI057198 [ ENTREZ ] Genbank AK026152 [ ENTREZ ] Genbank AK130158 [ ENTREZ ] RefSeq NM_004390 [ SRS ] NM_004390 [ ENTREZ ] RefSeq NM_148979 [ SRS ] NM_148979 [ ENTREZ ] RefSeq AC_000058 [ SRS ] AC_000058 [ ENTREZ ] RefSeq NC_000015 [ SRS ] NC_000015 [ ENTREZ ] RefSeq NT_010194 [ SRS ] NT_010194 [ ENTREZ ] RefSeq NW_925907 [ SRS ] NW_925907 [ ENTREZ ] AceView CTSH AceView - NCBI Unigene Hs.148641 [ SRS ] Hs.148641 [ NCBI ] HS148641 [ spliceNest ] Fast-db 9022 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P09668 [ SRS] P09668 [ EXPASY ] P09668 [ INTERPRO ] PS00640 THIOL_PROTEASE_ASN [ SRS ] PS00640 THIOL_PROTEASE_ASN Prosite [ Expasy ] PS00139 THIOL_PROTEASE_CYS [ SRS ] PS00139 THIOL_PROTEASE_CYS Prosite [ Expasy ] PS00639 THIOL_PROTEASE_HIS [ SRS ] PS00639 THIOL_PROTEASE_HIS Prosite [ Expasy ] Interpro IPR000169 Pept_cys_AS [ SRS ] IPR000169 Pept_cys_AS [ EBI ] Interpro IPR013128 Peptidase_C1A [ SRS ] IPR013128 Peptidase_C1A [ EBI ] Interpro IPR000668 Peptidase_C1A_C [ SRS ] IPR000668 Peptidase_C1A_C [ EBI ] Interpro IPR013201 Prot_inhib_I29 [ SRS ] IPR013201 Prot_inhib_I29 [ EBI ] CluSTr P09668
Atlas Genet Cytogenet Oncol Haematol 2008; 2 309 PF08246 Inhibitor_I29 [ SRS ] PF08246 Inhibitor_I29 [ Sanger ] pfam08246 Pfam [ NCBI-CDD ] PF00112 Peptidase_C1 [ SRS ] PF00112 Peptidase_C1 [ Sanger ] pfam00112 Pfam [ NCBI-CDD ] Smart SM00645 Pept_C1 [EMBL] Prodom PD000158 Peptidase_C1[INRA-Toulouse] P09668 CATH_HUMAN [ Domain structure ] P09668 CATH_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P09668 PDB 1BZN [ SRS ] 1BZN [ PdbSum ], 1BZN [ IMB ] 1BZN [ RSDB ] HPRD 00288 Protein Interaction databases DIP P09668 IntAct P09668 Polymorphism : SNP, mutations, diseases OMIM 116820 [ map ] GENECLINICS 116820 SNP CTSH [dbSNP-NCBI] SNP NM_004390 [SNP-NCI] SNP NM_148979 [SNP-NCI] SNP CTSH [GeneSNPs - Utah] CTSH] [HGBASE - SRS] HAPMAP CTSH [HAPMAP] HGMD CTSH General knowledge Family Browser CTSH [UCSC Family Browser] SOURCE NM_004390 SOURCE NM_148979 SMD Hs.148641 SAGE Hs.148641 3.4.22.16 [ Enzyme-SRS ] 3.4.22.16 [ Brenda-SRS ] 3.4.22.16 [ KEGG ] 3.4.22.16 [ Enzyme WIT ] GO cysteine-type endopeptidase activity [Amigo] cysteine-type endopeptidase activity GO cathepsin H activity [Amigo] cathepsin H activity GO lysosome [Amigo] lysosome GO proteolysis [Amigo] proteolysis GO proteolysis [Amigo] proteolysis PubGene CTSH Other databases Probes Probe CTSH Related clones (RZPD - Berlin) PubMed PubMed 25 Pubmed reference(s) in LocusLink Bibliography Generation of biologically active, complement-(C5) derived peptides by cathepsin H. Perez HD, Ohtani O, Banda D, Ong R, Fukuyama K, Goldstein IM. J Immunol 1983; 131: 397-402. PMID 6408181
Distribution of cathepsins B and H in rat tissues and peripheral blood cells. Kominami E, Tsukahara T, Bando Y, Katunuma N. J Biochem 1985; 98(1): 87-93. PMID 3900059
The cystatins: a diverse superfamily of cysteine peptidase inhibitors. Barrett AJ.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 310 Biomed Biochim Acta 1986; 45(11-12): 1363-1374. PMID 3555466
Intracellular transport and processing of lysosomal cathepsin H. Nishimura Y, Kato K. Biochem Biophys Res Commun 1987; 148(1): 329-334. PMID 3675581
Chromosome assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to 15q24-q25. Wang X, Chan SJ, Eddy RL, Byers MG, Fukushima Y, Henry WM. Cytogenet Cell Genet 1987; 46: 710-711.
Molecular cloning and sequencing of a cDNA coding for mature human kidney cathepsin H. Fuchs R, Machleidt W, Gassen HG. Biol Chem Hoppe Seyler 1988; 369(6): 469-475. PMID 2849458
Amino acid sequences of the human kidney cathepsins H and L. Ritonja A, Popovic T, Kotnik M, Machleidt W, Turk V. FEBS Lett 1988; 228(2): 341-345. PMID 3342889
Gene structure of rat cathepsin H. Ishidoh K, Kominami E, Katunuma N, Suzuki K. FEBS Lett 1989; 253(1-2): 103-107. PMID 2759235
Interaction of lysosomal cysteine proteinases with alpha 2-macroglobulin: conclusive evidence for the endopeptidase activities of cathepsins B and H. Mason RW. Arch Biochem Biophys 1989; 273(2): 367-374. PMID 2476070
Determination of cathepsins B and H in sera and synovial fluids of patients with different joint diseases. Gabrijelcic D, Annan-Prah A, Rodic B, Rozman B, Cotic V, Turk V. J Clin Chem Clin Biochem 1990; 28(3): 149-153. PMID 2329322
S-S bridges of cathepsin B and H from bovine spleen: a basis for cathepsin B model building and possible functional implications for discrimination between exo- and endopeptidase activities among cathepsins B, H and L. Baudys M, Meloun B, Gan-Erdene T, Fusek M, Mares M, Kostka V, Pohl J, Blake CC. Biomed Biochim Acta 1991; 50(4-6): 569-577. PMID 1801725
Characterization of a cathepsin-H-like enzyme from a human melanoma cell line. Tsushima H, Ueki A, Matsuoka Y, Mihara H, Hopsu-Havu VK. Int J Cancer 1991; 48(5): 726-732. PMID 2071233
Studies on the aminopeptidase activity of rat cathepsin H. Rothe M, Dodt J. Eur J Biochem 1992; 210(3): 759-764. PMID 1483460
The specificity and elastinolytic activities of bovine cathepsins S and H. Arch Biochem Biophys. Xin XQ, Gunesekera B, Mason RW. Arch Biochem Biophys 1992; 299(2): 334-349.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 311 PMID 1444473
Inhibition of cathepsin L-like cysteine proteases by cytotoxic T-lymphocyte antigen-2 beta. Delaria K, Fiorentino L, Wallace L, Tamburini P, Brownell E, Muller D. J Biol Chem 1994; 269(40): 25172-25177. PMID 7929206
Cathepsin S and related lysosomal endopeptidases. Kirschke H, Wiederanders B. Methods Enzymol 1994; 244: 500-511. PMID 7845228
Proteinases 1: lysosomal cysteine proteinases. Kirschke H, Barrett AJ, Rawlings ND. Protein Profile 1995; 2(14): 1581-1643. PMID 8771190
Prognostic value of cathepsins B, H, L, D and their endogenous inhibitors stefins A and B in head and neck carcinoma. Budihna M, Strojan P, Smid L, Skrk J, Vrhovec I, Zupevc A, Rudolf Z, Zargi M, Krasovec M, Svetic B, Kopitar-Jerala N, Kos J. Biol Chem Hoppe Seyler 1996; 377(6): 385-390. PMID 8839984
Expression and the role of cathepsin H in human glioma progression and invasion. Sivaparvathi M, Sawaya R, Gokaslan ZL, Chintala SK, Rao JS. Cancer Lett 1996; 104(1): 121-126. PMID 8640738
Cathepsins B, H, and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. Kos J, Stabuc B, Schweiger A, Krasovec M, Cimerman N, Kopitar-Jerala N, Vrhovec I. Clin Cancer Res 1997; 3(10): 1815-1822. PMID 9815568
Cysteine proteinases are responsible for characteristic transketolase alterations in Alzheimer fibroblasts. Paoletti F, Mocali A, Tombaccini D. J Cell Physiol 1997; 172(1): 63-68. PMID 8070542
Enzyme-linked immunosorbent assay for the detection of total cathepsin H in human tissue cytosols and sera. Schweiger A, Stabuc B, Popovic T, Turk V, Kos J. J Immunol Methods 1997; 201: 165-172. PMID 9050938
Crystal structure of porcine cathepsin H determined at 2.1 A resolution: location of the mini- chain C-terminal carboxyl group defines cathepsin H aminopeptidase function. Guncar G, Podobnik M, Pungercar J, Strukelj B, Turk V, Turk D. Structure 1998; 6(1): 51-61. PMID 9493267
Cathepsins B, H, L and cysteine protease inhibitors in malignant prostate cell lines, primary cultured prostatic cells and prostatic tissue. Friedrich B, Jung K, Lein M, Turk I, Rudolph B, Hampel G, Schnorr D, Loening SA. Eur J Cancer 1999; 35(1): 138-144. PMID 10211102
Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 312 del Re EC, Shuja S, Cai J, Murnane MJ. Br J Cancer 2000; 82(7): 1317-1326. PMID 10755408
Lysosomal cysteine protease, cathepsin H, is targeted to lysosomes by the mannose 6- phosphate-independent system in rat hepatocytes. Tanaka Y, Tanaka R, Himeno M. Biol Pharm Bull 2000; 23(7): 805-9. PMID 10919356
Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array. Tung WS, Lee JK, Thompson RW. J Vasc Surg 2001; 34: 143-150. PMID 11436088
Involvement of cathepsin H in the processing of the hydrophobic surfactant-associated protein C in type II pneumocytes. Brasch F, Ten Brinke A, Johnen G, Ochs M, Kapp N, Muller KM, Beers MF, Fehrenbach H, Richter J, Batenburg JJ, Buhling F. Am J Respir Cell Mol Biol 2002; 26(6): 659-670. PMID 12034564
Analysis of a truncated form of cathepsin H in human prostate tumor cells. Waghray A, Keppler D, Sloane BF, Schuger L, Chen YQ. J Biol Chem 2002; 277(13): 11533-11538. PMID 11796715
Enzymatically modified LDL induces cathepsin H in human monocytes: potential relevance in early atherogenesis. Han SR, Momeni A, Strach K, Suriyaphol P, Fenske D, Paprotka K, Hashimoto SI, Torzewski M, Bhakdi S, Husmann M. Arterioscler Thromb Vasc Biol 2003; 23(4): 661-667. PMID 12615673
Recombinant human cathepsin H lacking the mini chain is an endopeptidase. Vasiljeva O, Dolinar M, Turk V, Turk B. Biochemistry 2003; 42(46): 13522-13528. PMID 14621998
Serum cathepsin H as a potential prognostic marker in patients with colorectal cancer. Schweiger A, Christensen IJ, Nielsen HJ, Sorensen S, Brunner N, Kos J. Int J Biol Markers 2004; 19(4): 289-294. PMID 15646835
Use of a transgenic mouse model to identify markers of human lung tumors. Linnerth NM, Sirbovan K, Moorehead RA. Int J Cancer 2005; 114(6): 977-982. PMID 15645424
Overexpression of cathepsin F, matrix metalloproteinases 11 and 12 in cervical cancer. Vazquez-Ortiz G, Pina-Sanchez P, Vazquez K, Duenas A, Taja L, Mendoza P, Garcia JA, Salcedo M. BMC Cancer 2005; 5(1): 68. PMID 15989693
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Atlas Genet Cytogenet Oncol Haematol 2008; 2 313 Contributor(s) Written 09-2007 Zala Jevnikar, Janko Kos Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia Citation This paper should be referenced as such : Jevnikar Z, Kos J . CTSH (cathepsin H). Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CTSHID40206ch15q25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 314 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;3)(p24;q26)
Clinics and Pathology Disease Myelodysplastic syndrome Epidemiology Only one case to date, a 5 year old girl Prognosis No data Cytogenetics Cytogenetics Other anomalies were: -7 and +21 Morphological Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include:GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell- type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Mitelman database Other database t(3;3)(p24;q26) (CGAP - NCBI) CancerChromosomes Other database t(3;3)(p24;q26) (NCBI) To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. Genes Chromosomes Cancer. 2006; 45: 349-356. PMID 16342172
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R. Gene. 2007 Jul 15;396(2):346-57. PMID 17507183
Contributor(s) Written 06-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(3;3)(p24;q26). Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0303p24q26ID1277.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 315 Atlas of Genetics and Cytogenetics in Oncology and Haematology inv(3)(q23q26)
Clinics and Pathology Disease Chronic myelogenous leukaemia with t(9;22)(q34;q11) Epidemiology Only one case to date, a 64 year old female patient Prognosis No data Cytogenetics Cytogenetics Molecular Anomaly accompanying the t(9;22)(q34;q11) Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include:GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell- type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Other database inv(3)(q23q26) Mitelman database (CGAP - NCBI) To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. Genes Chromosomes Cancer. 2006; 45: 349-356. PMID 16342172
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R. Gene. 2007 Jul 15;396(2):346-57. PMID 17507183
Contributor(s) Written 06-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . inv(3)(q23q26). Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/inv3q23q26ID1276.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 316 Atlas of Genetics and Cytogenetics in Oncology and Haematology inv(3)(p12q26)
Clinics and Pathology Disease Chronic myelogenous leukaemia with t(9;22)(q34;q11) Epidemiology Only one case to date, a 74 year old female patient Prognosis No data Cytogenetics Cytogenetics Anomaly accompanying the t(9;22)(q34;q11) Morphological Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include:GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell- type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Other database inv(3)(p12q26) Mitelman database (CGAP - NCBI) To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. Genes Chromosomes Cancer. 2006; 45: 349-356. PMID 16342172
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R. Gene. 2007 Jul 15;396(2):346-57. PMID 17507183
Contributor(s) Written 06-2007 Jean-Loup Huret Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . inv(3)(p12q26). Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/inv3p12q26ID1275.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 317 Atlas of Genetics and Cytogenetics in Oncology and Haematology inv(11)(q21;q23) in therapy related leukemias
Clinics and Pathology Disease Therapy-related acute leukemia and myelodysplastic syndromes (MDS). Phenotype / cell stem M2-ANLL, acute monocytic leukemia, MDS, T-ALL. origin Etiology Latency from twenty months to six years after chemotherapy. Pathology inv(11) positive cells were detectable six years prior to apparent leukemia in one case. MLL-MAML2 positive cells were detectable up to two years prior to apparent leukemia in another case. Whole genome expression profiles demonstrated differential expression of both typical MLL and NOTCH downstream genes. Cytogenetics
inv(11)(q21q23) G-banding.
Detection of MLL rearranged cell by fluorescence in situ hybridization (FISH) with an MLL split signal probe. Genes involved and Proteins Gene Name MAML2 Location 11q21 Dna / Rna Spans 365 kb; 5 exons a major transcript of 7.5 kb. Protein 1153 aa, 125 kDa; conserved N-terminal basic domain (aa 29-92) which binds to the ankyrin repeat domain of Notch receptors; two acidic domains (aa 263-360 and 1124-1153) and a C-terminal transcriptional activation domain. Gene Name MLL Location 11q23
Atlas Genet Cytogenet Oncol Haematol 2008; 2 318 Dna / Rna 21 exons, spanning over 100 kb; 13-15 kb mRNA. Protein 3969 amino acids; 431 KDa; contains two DNA binding motifs: a AT hook homologous to high mobility group proteins HMGI-(Y) and HMGI(C) that binds to the minor groove of DNA , and zinc fingers, a DNA methyl transferase motif, a bromodomain, and segments of homology with trithorax, in particular in the C-terminal SET domain. Result of the chromosomal anomaly
Hybrid gene
Description MLL-MAML2 Transcript MLL-MAML2; exon 1-7 of MLL fused to exons 2-5 of MAML2.
Fusion Protein
Description Hybrid transcript MLL/MAML2 contains the following domains: from MLL: AT-hook, DNA-Methyltransferase; from MAML2: Q rich domain, acidic domain. External links Other inv(11)(q21;q23) in therapy related leukemias Mitelman database (CGAP - NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Secondary monocytic leukemia with rearrangement of the MLL gene occurring during the course of adult T-cell leukemia. Obama K, Furukawa Y, Tara M, Niina K. Int J Hematol. 1998; 68:323-326. PMID 9846017
Inv(11)(q21q23) fuses MLL to the NOTCH co-activator mastermind-like 2 in secondary T cell acute lymphoblastic leukemia. Metzler M, Zuna J, Stagee MS, Harder L, Meyer C, Flohr T, Meerpohl J, Fronkova E, Langer T, Harbott J, Trka J, Siebert R, Marschalek R, Niemeyer CM, Rascher W. Blood (ASH Annual Meeting Abstracts) 2006; 108: Abstract 4284.
Therapy-related acute myeloid leukemia 6 years after clonal detection of inv(11)(q21q23) and MLL gene rearrangement. Takei N, Suzukawa K, Mukai HY, Itoh T, Okoshi Y, Yoda Y, Nagasawa T. Int J Hematol. 2006; 83(3):247-251. PMID 16720556
Atlas Genet Cytogenet Oncol Haematol 2008; 2 319 Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T. Genes Chromosomes Cancer. 2007; [Epub ahead of print]. PMID 17551948
Contributor(s) Written 06-2007 Kazumi Suzukawa Department of Clinical and Experimental Hematology, Major of Advanced Medical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan Citation This paper should be referenced as such : Suzukawa K . inv(11)(q21;q23) in therapy related leukemias. Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/inv11q21q23ID1471.html © Atlas of Genetics and Cytogenetics in Oncology and indexed on : Mon Mar 17 17:08:19 Haematology 2008
Atlas Genet Cytogenet Oncol Haematol 2008; 2 320 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Digestive organs: Carcinoma of the gallbladder and extrahepatic bile ducts
Identity Note Defined as a malignant epithelial tumor arising in the gall bladder and extrahepatic bile ducts including ampulla of Vater. Other names Biliary tract carcinoma, cholangiocarcinoma
Extrahepatic bile duct carcinoma from the middle portion (percutaneous transhepatic cholangiography). Classification Note Tumor staging is separated by TNM classification (International Classification of Diseases, ICD). TNM classifications for carcinomas of the gallbladder, extrahepatic bile ducts and the ampulla of Vater. The histopathological classification of biliary tract carcinoma follows WHO classification: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, adenoendocrine cell carcinoma, undifferentiated carcinoma, and carcinosarcoma. Clinics and Pathology Disease Carcinoma of the gallbladder and extrahepatic bile ducts is an aggressive malignancy with a poor prognosis. Etiology Carcinoma of the gallbladder and extrahepatic bile ducts is more common in Eastern
Atlas Genet Cytogenet Oncol Haematol 2008; 2 321 Europe and Latin American countries, and in the yellow races. It occurs frequently in older age groups (6th to 7th decades of life). Statistical data in Japan and USA indicate that gallbladder carcinomas occur predominantly in female, whereas carcinoma of the extrahepatic bile duct occurs more frequently in males. Carcinoma of the extrahepatic bile duct is associated with primary sclerosing cholangitis, ulcerative colitis, abnormal choledochopancreatic junction, and parasitic infection (trematode). In gallbladder carcinomas, gallstones and abnormal choledochopancreatic junction are considered risk factors. Association with smoking and drinking is not established. Epidemiology One of the common carcinomas worldwide Clinics The clinical symptoms are affected by the complications such as gallstones and cholangitis. The most frequent symptom is right upper quadrant pain in gallbladder carcinomas and obstructive jaundice in extrahepatic bile duct carcinomas. Chills and fever appear when cholangitis develops. For early diagnosis, ultrasonography is useful; detection of biliary dilatation and tumor masses. For staging, computed tomography, magnetic resonance imaging, and endoscopic ultrasonography are effective. Percutaneous transhepatic cholangiography and endoscopic retrograde cholangiography are poorly available for qualitative diagnosis but performed in case of biliary drainage. Cytology Cytology of bile duct brushings is an important diagnostic tool for tumors of biliary ductal system presenting as duct strictures from which it can be difficult to obtain a histology biopsy. Bile duct brushings have been recognized as a technique of moderate sensitivity and high specificity in identifying carcinoma. Reported diagnostic sensitivities for malignancy have ranged from 20 to 70% and specificity is almost 100%. Therefore, positive diagnoses of malignancy are of great clinical value but a negative result is relatively little clinical aid.
Positive bile cytology specimen (Papanicolau stain). Isolated cells with increased nucleocytoplasmic ratio, marked anisocaryosis, loss of polarity, and prominent nucleoli.
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Carcinoma of the gallbladder; well differentiated adenocarcinoma. Treatment Surgical resection, chemotherapy, radiotherapy, immunotherapy Evolution Recurrence should be given care to. Prognosis The prognosis of biliary carcinomas depends primarily on the extent of disease. In inoperable cases, one-year survival rates in gallbladder carcinomas and extrahepatic bile duct carcinomas are 10% or less and 20% or less, respectively. Cytogenetics Note Loss of heterozygosity at chromosomal loci 8p, 9p, and 18q are frequently detected. Genes involved and Proteins Gene Name K-RAS Location 12p12.1 Dna / Rna 4 exons Protein Proto-oncogene. GTP-GDP binding protein with GTPase activity. The K-ras proto- oncogene is thought to exert control over some of the mechanisms of cell growth and differentiation. This gene is converted to an active oncogene by point mutations significantly concentrated in codons 12, 13, or 61. The incidence of the mutations has variously been reported to be 17-59% of gallbladder carcinomas and 23-100% of bile duct carcinomas. K-ras mutations in biliary tract carcinomas with a background of pancreaticobiliary maljunction is significantly higher than in those without it, namely, 50-100% and 6-36%, respectively. Alteration of the K-ras oncogene may be very important in the early stages of carcinogenesis of biliary mucosa, especially in association with anomalous connections of the pancreatobiliary ducts. K-ras mutation is more frequently detected in carcinomatous and dysplastic lesions in gallbladder carcinoma cases with gall stones than in those without stones. There was a large difference in the incidence of K-ras mutations between distal (47-75%) and middle or proximal (0-8%) bile duct carcinoma. The distal portion may be to some extent influenced by pancreatic juice because of its anatomical location. K-ras mutations in biliary tract carcinomas are not statistically significantly correlated with tumor staging, histological type and age, sex, or survival of the patients. Gene Name p53 Location 17p13 Dna / Rna 11 exons Protein Tumor suppressor. Wild-type p53 plays an important role in the regulation of the cell cycle process, cell growth, and apoptosis in the event of DNA damage. The mutant proteins from the mutated genes disrupt critical growth-regulating mechanisms and may play a crucial role in the carcinogenesis. The reported incidence of p53 mutation is 31-92% in gallbladder carcinoma and 33-73% in bile duct carcinoma. In general, there is a tendency for higher grade carcinomas to express more p53 protein. p53 abnormalities may appear early during the transition from low-grade to higher-grade tumors and may play a role in the development of more malignant tumor phenotypes. A statistically significant difference is found for the incidence of p53 protein expression
Atlas Genet Cytogenet Oncol Haematol 2008; 2 323 between extrahepatic bile duct carcinomas from the distal portion and those from the lower mid-region. This tendency is the same as that for K-ras mutations and the pancreaticobiliary maljunction may override the effect of p53 gene mutations. Gene Name p16 INK4A Location 9p21 Dna / Rna 3 exons Protein Regulatory protein in the cell cycle and cyclin-dependent kinase (cdk4/cdk6) inhibitor. The tumor suppressor gene p16 is commonly inactivated in many neoplasms. Three distinct mechanisms of p16 inactivation have been reported in biliary neoplasms: deletion and point mutations of the p16 gene, and hypermethylation of 5¹ regulatory regions of p16. It has been reported that 60-80% of primary biliary tract carcinomas had point mutations in the p16 gene. Allelic loss at the p16 locus on chromosome 9p21 or p16 promoter hypermethylation occurred with sufficient frequency in extrahepatic bile duct carcinomas and in gallbladder carcinomas. Therefore, the p16 gene may possibly be crucial for biliary tract carcinogenesis and progression. Gene Name c-ERB-2 Location 17q21.1 Dna / Rna 7 exons Protein Proto-oncogene. Amplification and overexpression of c-erbB-2 are frequently shown in biliary tract carcinomas. It is suggested that c-erbB-2 expression may be associated with neoplastic progression in biliary tracts.
Bibliography Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Levi S, Urbano-Ispizua A, Gill R, Thomas DM, Gilbertson J, Foster C, Marshall CJ. Cancer Res 1991, 51: 3497-3502. PMID 1675933 p53 and c-erbB-2 protein expression in adenocarcinomas and epithelial dysplasias of the gall bladder. Kamel D, Paakko P, Nuorva K, Vahakangas K, Soini Y. J Pathol 1993; 170: 67-72. PMID 8100854
K-ras codon 12 mutations in biliary tract tumors detected by polymerase chain reaction denaturing gradient gel electrophoresis. Imai M, Hoshi T, Ogawa K. Cancer 1994; 73: 2727-2733. PMID 8194013
Mutation of the p53 gene in gallbladder cancer. Takagi S, Naito E, Yamanouchi H, Ohtsuka H, Kominami R, Yamamoto M. Tohoku J Exp Med 1994; 172: 283-289. PMID 8073440
An immunohistochemical study of p53 protein in gallbladder and extrahepatic bile duct/ampullary carcinomas. Teh M, Wee A, Raju GC. Cancer 1994; 74: 1542-1545. PMID 7520348
Point mutation of K-ras gene codon 12 in biliary tract tumors. Watanabe M, Asaka M, Tanaka J, Kurosawa M, Kasai M, Miyazaki T. Gastroenterology 1994; 107: 1147-1153. PMID 7926462
Clinical importance of p53 protein in gall bladder carcinoma and its precursor lesions. Wee A, Teh M, Raju GC.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 324 J Clin Pathol 1994; 47: 453-456. PMID 8027399 p53 protein immunoreactivity in extrahepatic bile duct and gallbladder cancer: correlation with tumor grade and survival. Diamantis I, Karamitopoulou E, Perentes E, Zimmermann A. Hepatology 1995; 22: 774-779. PMID 7657282
Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile. Wistuba II, Sugio K, Hung J, Kishimoto Y, Virmani AK, Roa I Albores-Saavedra J, Gazdar AF. Cancer Res 1995; 55: 2511-2515. PMID 7780959
Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. Yoshida S, Todoroki T, Ichikawa Y, Hanai S, Suzuki H, Hori M, Fukao K, Miwa M, Uchida K. Cancer Res 1995; 55: 2756-2760. PMID 7796400
K-ras gene mutation in gall bladder carcinomas and dysplasia. Ajiki T, Fujimori T, Onoyama H, Yamamoto M, Kitazawa S, Maeda S, Saitoh Y. Gut 1996; 38: 426-429. PMID 8675098
K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Hanada K, Itoh M, Fujii K, Tsuchida A, Ooishi H, Kajiyama G. Cancer 1996; 77: 452-458. PMID 8630951
K-ras point mutations in carncerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction. Matsubara T, Sakurai Y, Sasayama Y, Hori H, Ochiai M, Funabiki T, Matsumoto K, Horono I. Cancer 1996; 77: 1752-1757. PMID 8608574
Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Tada M, Yokosuka O, Omata M, Ohto M, Isono K. Gastroenterology 1996; 110: 227-231. PMID 8630951
Expression of p53 in adenocarcinoma of the gallbladder and bile ducts. Washington K, Gottfried MR. Liver 1996; 16: 99-104. PMID 8740842 p16INK4 gene mutations are relatively frequent in ampullary carcinomas. Imai Y, Tsurutani N, Oda H, Nakatsuru Y, Inoue T, Ishikawa T. Jpn J Cancer Res 1997; 88: 941-946. PMID 9414654
APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis. Itoi T, Watanabe H, Ajioka Y. Pathol Int 1997; 47:525-530. PMID 8809879
General roles for surgical and pathological studies on cancer of the biliary tract.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 325 Japanese Society of Biliary Surgery. In ³Classification of biliary tract carcinoma² Editor Japanese Society of Biliary Surgery (1997) Kanehara & Co.
Diagnostic and prognostic value of incidence of K-ras codon 12 mutations in resected distal bile duct carcinoma. Rijken AM, van Gulik TM, Polak MM, Sturm PD, Gouma DJ, Offerhaus GJ. J Surg Oncol 1998; 68: 187-192. PMID 9701213
Prognostic significance of Ki-67 and p53 antigen expression in carcinomas of bile duct and gallbladder. Shrestha ML, Miyake H, Kikutsuji T, Tashiro S. J Med Invest 1998; 45: 95-102. PMID 9864969
Assessment of the expression of p53, MIB-1 (Ki-67 antigen), and argyrophilic nucleolar organizer lesions in carcinoma of the extrahepatic bile duct. Suto T, Sugai T, Nakamura S, Funato O, Nitta H, Sasaki R, Kanno S, Saito K. Cancer 1998; 82: 86-95. PMID 9428483
Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Hanada K, Tsuchida M, Iwao T, Eguchi N, Sasaki T, Morinaka K, Matsubara K, Kawasaki Y, Yamamoto S, Kajiyama G. Am J Gastroenterol 1999; 94: 1638-1642. PMID 10364037 p53 expression as a prognostic determinant in resected distal bile duct carcinoma. Rijken AM, Offerhaus GJ, Polak MM, Gouma DJ, van Gulik TM. Eur J Surg Oncol 1999; 25: 297-301. PMID 10336811
Carcinoma of the gallbladder and extrahepatic bile ducts. Albores-Saavedra J, Menck HR, Scoazec JC, Soehendra N, Wittekind C, Sriram PVJ, Sripa B. in ³WHO classification tumors of the digestive system² Editors Hamilton, SR. and Aaltonen, LA (2000) The IARC Press. REVIEW
Relation between K-ras codon 12 mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction. Masuhara S, Kasuya K, Aoki T, Yoshimatsu A, Tsuchida A, Koyanagi A. J Hepatobiliary Pancreat Surg 2000; 7: 198-205. PMID 10982614
Inactivation of the INK4A/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines. Caca K, Feisthammel J, Klee K, Tannapfel A, Witzigmann H, Wittekind C, Mössner J, Berr F. Int J Cancer 2002; 97: 481-488. PMID 11802210
Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients. Chaube A, Tewari M, Garbyal RS, Singh U, Shukla HS. BMC Cancer 2006, 6: 126. PMID 8100854
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 06-2007 Munechika Enjoji, Toyoma Kaku
Atlas Genet Cytogenet Oncol Haematol 2008; 2 326 Department of Hepatology and Pancreatology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan Citation This paper should be referenced as such : Enjoji M, Kaku T . Digestive organs: Carcinoma of the gallbladder and extrahepatic bile ducts. Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Tumors/GallbladderID5275.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 2 327 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Currarino Syndrome
Identity Note Currarino syndrome is a multiple congenital anomalies syndrome characterized by partial agenesis of the sacrum in association with pelvic malformation. Anal atresia and the presence of a pre-sacral mass (teratoma and/or anterior meningocoele) make up the so called Currarino triad. Other malformations, such as renal (35%) and gynaecological (19%) are common. Hirschsprungs diseasehas also been recorded. Other rarer complications include pelvic abcess, malignant degeneration of a pre-sacral teratoma, E Coli ascending meningitis and spinal cord tethering. Recurrence of a benign teratoma has been recorded. Urinary incontinence, dysmenorrhoea, dyspareunia, poor sphincter control, sacral anaesthesia and headaches precipitated by coughing or straining have been reported. Other names Currarino triad ASP (Anal atresia, sacral anomalies, presacral mass) Sacral defect with Anterior Meningocoele Inheritance Autosomal Dominant. De novo mutations have been recorded and account for approximately 15% of cases. Clinics Note Currarino syndrome was described as a triad by Guido Currarino, an American radiologist in 1981. The triad consists of: Sickle shaped sacrum Pre-sacral mass (meningocoele and/or tumour (teratoma; hamartoma) Anal atresia The term Currarino syndrome is preferred as it is now known that there are other components to this genetic disorder. Bowel obstruction in infancy or chronic constipation in childhood are the commonest presenting symptoms. Gynaecological and renal malformation are commonly described. Hirschsprungs disease and meningitis (often E Coli ascending meningitis) have been recorded. Perianal sepsis, which is found in at least 10% of patients, can indicate the presence of an underlying presacral mass. Tumour development within the teratoma has been documented. A report describing Currarino syndrome with ventriculomegaly due to a Arnold-Chiari type II malformation must be interpreted with caution. The affected child was dysmorphic with hypertelorism, a short enlarged neck and camptodactyly. The mother and brother also had Currarino syndrome without these added features. It is quite possible that this child had two co-existing disorders, one the Currarino inherited from a mother with typical features and secondly a de novo Arnold-Chiari type II malformation. As with many dominant disorders the phenotype is very variable. It is estimated that approximately 50% of those who inherit the gene will present with the severe phenotype (requiring surgery), 25% will have symptoms albeit milder and 25% will be asymptomatic heterozygotes.
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Figure A: Pelvic x ray of adult female showing a scimitar sacrum with a right sided defect. In our cohort, 38% had a sickle shaped sacrum with a left sided defect and 37% had a similar sickle shaped sacrum with a right sided defect. Figure B: Pelvic x ray of male child showing a left sided sacral defect with associated faecal loading. Courtesy Sally Ann Lynch, reprinted from J Med Genet. 2000; 37:561-566 by permission of the publisher BMJ Publishing Group Ltd of the BMA. Figure A: CT scan of pelvis showing a large anterior meningocele filling with contrast (this is the same patient as shown in fig 1A). Figure B: CT of pelvis of adult female showing gross distortion of pelvic anatomy with an abnormal sacral bone and a presacral mass.Courtesy Sally Ann Lynch, reprinted from J Med Genet. 2000; 37:561-566 by permission of the publisher BMJ Publishing Group Ltd of the BMA. Table 1 summary of the malignant tumours reported in the literature.
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Neoplastic risk The presacral mass associated with the Currarino triad may be a teratoma, hamartoma, neuroenteric cyst, anterior meningocoele or a combination of these three. A teratoma is a neoplasm originating from primordial germ cells and is derived from all three embryonal germ layers. A hamartoma is a mass produced by disorganized local tissue growth and can contain all three germ layers. A teratoma carries a risk for germ cell malignancy, a hamartoma does not. It has been argued that the reason the risk for malignant degeneration in Currarino syndrome is low is because most of these pre-sacral masses which have previously been classified as teratomas are more likely to be hamartomas. In those rare instances where malignancy has been recorded it is possible that this could have resulted from a secondary carcinoma developing in a chronically inflamed hamartoma rather than a germ cell malignancy. Malignant change of the pre-sacral tumour has been described but is a rare occurance. The histological appearances are varied and often poorly described particularly in the older literature. A 32 year old women, who was known to have a pre-sacral teratoma, died from metastatic spread of the tumour. Histological findings were not included in the report (Ashcraft 1973; same patient also reported by Hunt, 1977). A 54 year old male from a known Currarino family was diagnosed with a presacral mass. This was shown to be a teratoma which had undergone malignant change. A relative of this man, aged 14 years, who had been treated for a rectal stricture, died from a brain tumour, no histology was available. (Yates et al 1983). A child who died from probable brain metastases was reported in a large Irish pedigree (O'Riordain et al 1991). Histology was not available and the child did not have a post mortem. This child had presented at birth with a pre-sacral mass and had surgery. The presacral teratoma recurred at aged 4 years and she died from a brain tumour shortly afterwards. A female infant who had complete excision of a benign pre-sacral teratoma aged 14
Atlas Genet Cytogenet Oncol Haematol 2008; 2 330 months had a recurrence of a pre-sacral mass at aged 2 ( Tander et al 1999). Histology confirmed recurrence of the teratoma with malignant transformation. The AFP level was extremely high. Treatment was by excision and chemotherapy (bleomycin, etopside and cis-platin) but unfortunately the tumour recurred after 12 months She responded to the same course of chemotherapy but an aggressive recurrence at age 4 years did not respond to treatment and she died from pulmonary metastases. A 22 year old male was reported who developed a malignant neuroectodermal tumour arising from a pre-sacral mass, (Urioste 2004). He had previously been asymptomatic. He presented with a painless abdominal swelling. A CT scan showed multiple cysts in the liver and it was thought he had isolated liver cystic disease. Lytic pelvic lesions were identified 1 year later on CT and a biopsy of one of these lesions confirmed a well differentiated neuroendocrine tumour. A presacral mass was identified in follow up scans suggestive of a presacral mass with malignant transformation. Biopsy of the mass and the liver confirmed the presence of a neuroendocrine tumour. Chemotherapy was ineffective and he subsequently died. Autopsy confirmed tumour invasion of the liver, pancreas, kidneys and mesenteric lympth nodes. The pre-sacral mass was comprised of neoplastic tissue, teratoma, muscle and fibroadipous tissue. A 4 year old girl was reported with Currarino syndrome who developed an ectopic nephroblastoma and pulmonary metastases from a presacral mass (Martucciello G 2004). She died despite chemo and radiotherapy. A 2 year old girl developed a malignant teratoma from a pre-existing presacral mass (Cretolle et al 2006). She was well following chemotherapy. A 3 year old girl was reported with a malignant tumour arising within a teratoma (Sen et al 2006). Histology revealed the presence of two components; residual mature teratoma and a necrotic malignant tumour resembling a primitive peripheral neuroectodermal tumour. A chemotherapy regimen according to the Euro Ewing 99 protocol was given in addition to radiotherapy. She remained well 8 months following her treatment. One report of leiomyosarcoma in a grandmother of an affected child with Currarino has been reported (Norum 1991). In addition, a further case of Leiomyomatosis peritonealis disseminate (LPD) in a 27 year old female with Currarino syndrome has been described in the literature (Nappi 2006). Malignant degeneration of LPD to a leiomyosarcoma has been reported but is rare. A sacrococcygeal teratoma has been described with a deletion of chromosome 7q, partial trisomy 2p. Malignant degeneration had not occurred and the child died from post-operative complications (Le Caignec 2003). This teratoma was a posterior teratoma and similar to the type often identified antenatally. It is thought to have a different genetic basis to the teratomas seen in the Currarino syndrome. No mutations in the HLXB9 gene have been found in such cases. It is therefore interesting that this child had deleted the HLXB9 gene suggesting some genetic relationship between both conditions. In classical Currarino syndrome the pre-sacral mass tends to be anterior to the sacrum. The sacrococcygeal teratomas have appeared to be a different group in that they present in the posterior coccygeal region, are often sporadic, occur more commonly in females and commonly become malignant. Mutational analysis of the HLXB9 gene has been negative in a number of cases. This recent case is interesting as it does suggest that HLXB9 is involved in some cases of posterior teratomas (the gene was shown to be deleted in this case) in some cases. Treatment Symptomatic: those children who present at birth with imperforate anus will require emergency surgery. Surgery for the pre-sacral mass is usually advised. The mass can cause an obstruction or other symptoms such as ascending meningitis if an enteric fistula is present. There is also the risk of malignant transformation. Treatment of the mass if it undergoes malignant transformation involves both a surgical and chemothereputic approach. Bleomycin, etoposide and carboplatin are now the gold standard chemotherapeutic treatments. Carboplatin has recently replaced cisplatin as it is less nephro and ototoxic. Some patients may develop symptoms as a result of their renal or gynaecological malformation and these need to be managed appropriately. Spinal cord tethering is recognized and may recur requiring long term surveillance. Many individuals suffer
Atlas Genet Cytogenet Oncol Haematol 2008; 2 331 from chronic constipation. Patients with a pre-sacral mass, particularly those with an anterior meningocoele, can develop headaches if pressure is increased within the abdominal cavity from coughing or sneezing or by lying on their abdomens. Evolution In those children where this condition is diagnosed at birth, a good clinical plus radiological assessment (including pelvic MRI) will identify most of the malformations. Surgery should be considered if a presacral mass is present. Many of the complications listed above can be avoided if appropriate action is taken in early childhood. Prognosis Generally very good. In some patients a colostomy bag is required for life. Some women can present symptoms from their gynaecological malformation and require assessment and occasionally treatment for this. Spinal cord tethering can be another debilitating problem that can recur despite treatment. If malignant transformation occurs chemotherapy can be effective but recurrences can occur which are resistant to treatment. There are no case reports recording a long remission but as the case reports are so few it is not possible to give definitive prognostic indicators. People have reported recurrence of a teratoma and therefore it is possible that malignancy could occur even if surgery has removed a presacral teratoma. However, the malignancy risk, which is already very small must be reduced even further by elective removal of any pre-sacral mass. Cytogenetics Note Cytogenetic analysis will be normal in most cases. However, some cases are associated with a 7q36 deletion or a translocation involving this region. It is worth considering FISH analysis of 7q36 in cases where Currarino syndrome is associated with developmental delay. Cytogenetics There is no information on the cytogenetic analysis of the pre-sacral tumours. of cancer Genes involved and Proteins
Gene Name HLXB9 Location 7q36 Note HLXB9 is a Homeobox gene. Proteins encoded by homeobox-containing genes are sequence-specific DNA binding proteins implicated in the control of gene expression in both developing and adult tissues. DNA/RNA Description The HLXB9 gene has 3 exons. The phenotype results from haploinsufficiency of this gene. Protein Description The three exons encode a 403 amino acid protein containing a homeodomain preceded by a very highly conserved 82 amino acid domain. The remainder of the protein is not well conserved. This second highly conserved 82 amino acid domain encoded by HLXB9 may have a regulatory role and/or be involved in protein-protein associations. Amino acid substitutions in this area could conceivably give rise to different clinical phenotypes. There is a polyalanine region consisting of 16 alanines. There are population differences in the polyalanine domain but little correlation between the presence of disease or the variable penetrance of disease and the number of GCC repeats in patients. Expression In humans, studies have shown expression in the basal plate of the spinal cord and hindbrain and in the pharynx, oesophagus, stomach and pancreas and lymphoid tissue. Significant spatial and temporal expression differences were evident when expression of the gene in human and mouse were compared which may explain the phenotypic disparities observed between the two species. Tailbud expression has been noted in Xenopus laevis. Studies on human embryos demonstrated expression in the sacral region during embryogenesis albeit predominantly in the anterior horn regions of the spinal cord. In adults the HLXB9 gene is predominantly expressed in the pancreas. A mouse model of the Currarino triad demonstrated that abnormal differentiation of the
Atlas Genet Cytogenet Oncol Haematol 2008; 2 332 tail bud mesenchyme led to defects of the tailgut and neural tube. Etretinate (the teratogenic agent used) disrupted secondary neurulation and resulted in malformations resembling the Currarino triad. The cloacal plate appeared to play a critical role in the development of the anorectum and deficiencies of this caused anorectal malformation. Function The HLXB9 gene functions as a transcription factor regulating gene expression in both developing and adult tissues. Little is known about target genes or protein partners. Homology The HLXB9 sequence shows up to 96%, 91% and 80% identity to orthologues in mouse, chick and Xenopus respectively. Sequence homology to Drosphilia homeobox genes and to the human homeobox gene PDX-1 suggest that some mutations within the HLXB9 homeodomain may alter the DNA binding specificity while other mutations may reduce nuclear translocation of the mutated protein. Mutations Note Nonsense, frameshift and missense mutations have been identified. Most mutations are located within exon 1 and the homeodomain. Most missense mutations are clustered in the homeodomain whereas nonsense and frameshift mutations are mostly on the NH2 terminus of the protein. There is poor genotype phenotype correlation. Reduced penetrance has also been recorded by several groups. It appears, from in vitro assays that the missense mutations disrupt the binding of the homeodomain to the target DNA motif TAAT. Whilst mutations have been identified in almost all the familial cases, it appears that mutations are only found in 30% of sporadic cases. Somatic mosaicism is most favoured explanation. It is also possible that mutations might be present outside of the coding region and genetic heterogeneity remains a possiblity. Germinal There have been no recorded cases of germ line mosaicism. Somatic There have been no recorded cases of somatic mosaicism.
Bibliography Hereditary presacral teratoma. Ashcraft KM, Holder T. J Pediatr Surg 1974; 9:691-697. PMID 4418917
Radiography of hereditary presacral teratoma. Hunt PT, Davidson KC, Ashcraft KW, Holder TM. Pediatr Radiol 1977; 122:187-191. PMID 830336
Triad of anorectal, sacral and presacral anomalies. Currarino G, Coln D, Vottler T. AJR 1981; 137:395-398. PMID 6789651
Anterior sacral defects: An autosomal dominantly inherited condition. Yates VD, Wilroy RS, Whitington GL, Simmons JCH. Journal of Pediatrics 1983; 102:239-242. PMID 6822928
Incomplete Currarino syndrome with a presacral leiomyosarcoma. Norum J, Wist E, Bostad L. Acta Oncol 1991; 30:987-988. PMID 1777251
Hereditary sacral agenesis with presacral mass and anorectal stenosis: the Currarino triad. O'Riordain DS, O'Connell PR, Kirwan WO. Br J Surg 1991; 78:536-538. PMID 2059799
A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 333 Ross AJ, Ruiz-Perez V, Wang Y, Hagan DM. Nat Genet. 1998; 20(4):358-361. PMID 9843207
A case of incomplete Currarino triad with malignant transformation. Tander B, Baskin D, Bulut M. Pediatr Surg Int 1999; 15(5-6):409-410. PMID 10415302
Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene. Hagan DM, Ross AJ, Strachan T, Lynch SA, Ruiz-Perez V, Wang YM, Scambler P, Custard E, Reardon W, Hassan S, Nixon P, Papapetrou C, Winter RM, Edwards Y, Morrison K, Barrow M, Cordier-Alex MP, Correia P, Galvin-Parton PA, Gaskill S, Gaskin KJ, Garcia-Minaur S, Gereige R, Hayward R, Homfray T. Am J Hum Genet. 2000; 66(5):1504-1515. PMID 10749657
Autosomal dominant sacral agenesis: Currarino syndrome. Lynch SA, Wang Y, Strachan T, Burn J, Lindsay S. J Med Genet 2000 37; 8:561-566. PMID 10922380
Spectrum of mutations and genotype-phenotype analysis in Currarino syndrome. Kochling J, Karbasiyan M, Reis A. Eur J Human Genetics 2001; 9: 599-605. PMID 11528505
Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p. Le Caignec C, Winer N, Boceno M, Delnatte C, Podevin G, Liet JM, Quere MP, Joubert M, Rival JM. Prenat Diagn 2003; 23(12): 981-984. PMID 14663834
Sharing of the same embryogenic pathway in anorectal malformations and anterior sacral myelomeningocoele formation. Liu Y, Sugiyama, Yagami K, Ohkawa H. Pediatr Surg Int 2003; 19:152-156. PMID 12682745
Teratomas in the Currarino triad: A misnomer. Weinberg AG. Pediatr Dev Pathology 2003; 110-112. PMID 10594140
Currarino syndrome:proposal of a diagnostic and therapeutic protocol. Martucciello G, Torre M, Belloni E Lerone M, Pini Prato A, Carna A, Jasonni V. J Ped Surg 2004; 39:1305-1311. PMID 15359381
Malignant degeneration of presacral teratoma in the Currarino anomaly. Urioste M, Garcia-Andrade Mdel C, Valle L, Robledo M, Gonzalez-Palacios F, Mendez R, Ferreiros J, Nuno J, Benitez J. Am J Med Genet 2004; 128A:299-304. PMID 15216552
New clinical and therapeutic perspectives in Currarino Syndrome (study of 29 cases). Cretolle C, Zerah M, Jaubert F, Sarnacki S, Revillon Y, Lyonnet S, Nihoul-Fekete C. J Ped Surg 2006; 41:126-131. PMID 16410121
Atlas Genet Cytogenet Oncol Haematol 2008; 2 334 Population differences in the polyalnine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome. Garcia-Barcelo M, So MT, Lau DK, Leon TY, Yuan ZW, Cai WS, Lui VC, Fu M, Herbrick JA, Gutter E, Proud V, Li L, Pierre-Louis J, Aleck K, van Heurn E, Belloni E, Scherer SW, Tam PK. Clinical Chemistry 2006; 52(1): 46-52. PMID 16254195
Leiomyomatosis peritonealis disseminate in association with Currarino syndrome? Nappi C, Di Spiezio Sardo A, Mandato VD, Bifulco G, Merello E, Savanelli A, Mignogna C, Capra V, Guida M. BMC Cancer 2006; 10(6): 127-133. PMID 16686944
Familial Currarino syndrome presenting with peripheral primitive neuroectodermal tumour arising with a sacral teratoma. Sen G, Sebire NJ, Olsen O, Kiely E, Levitt GA. Pediatr Blood cancer 2006; epub. PMID 16685735
Currarino syndrome shown by prenatal onset ventriculomegaly and spinal dysraphism. Cretolle C, Sarnacki S, Amile J, Genevieve D, Encha-Razavi F, Zrelli S, Zereh M, Nihoul Fekete C, Lyonnet S. Am J Med Genet 2007; 143A:871-874. PMID 17352395
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 06-2007 Sally Ann Lynch Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, NE1 4LP, UK Citation This paper should be referenced as such : Lynch SA . Currarino Syndrome. Atlas Genet Cytogenet Oncol Haematol. June 2007 . URL : http://AtlasGeneticsOncology.org/Kprones/CurrarinoID10082.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)
A t(4;12)(q11;p13) in a patient with coincident CLL at the same time of AML diagnosis
Paola Dal Cin, Daniel J DeAngelo, Richard M Stone Clinics Age and sex : 56 year(s) old male patient. Previous History : no preleukemia no previous malignant disease (, but coincident CLL at the same time of AML diagnosis. No prior therapy for CLL) no inborn condition of note Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes Blood WBC : 52.2 x 109/l; Hb : 10.2 g/dl; platelets : 158.0 x 109/l; blasts : 86% ((peripheral blood)) Cyto pathology classification Cytology : M0 Immunophenotype : A population of immature cells positive for CD45(dim), HLA-DR, CD7, CD34 (majority) and myeloid markers CD33 and CD13, with absence of staining for B cell, monocytic, and other T cell markers, consistent with myeloblast. A minor clonal kappa positive (moderate intensity) population of CD5 positive B cells which were negative for CD23 was also detected, suggesting a co- existing CD5 positive B cell lymphoproliferative disorder. A minor population of CD19 positive B cells co-expresses CD5 and exhibits monotypic surface immunoglobulin kappa light chain staining, consistent with involvement by the patient's known B cell lymphoproliferative disorder. Rearranged Ig Tcr : n/a Pathology : Cellular aspirate with prominent population of "blast-like" large cells with dispersed chromatin, distinct nucleoli and modest amounts of blue, agranular cytoplasm. Electron microscopy : n/a Precise diagnosis : Acute Myelogenous Leukemia and Chronic Lymphocytic Leukemia Survival Date of diagnosis: 01-2002 Treatment : Induction: ADE consisting of daunorubicin, cytarabine and etoposide plus PSC-833 (he was randomized to the treatment arm) on CALGB 19808. Consolidation with high-dose cytarabine and etoposide with stem cell harvest as per CALGB 19808.ÝAuto stem cell transplant: on April 24, 2002. Conditioning regimen consisted of busulfan and etoposide as per CALGB 19808. Complete remission was obtained Comments : on BM on Feb 8, 2002 Treatment related death : - Relapse : + June 17, 2003 Phenotype at relapse : AML M0 Status : Dead 06-2003 Survival : 21 month(s) Karyotype Sample : Bone Marrow ; culture time : 24 h ; banding : GTG Results : 46,XY,t(4;12)(q11-12;p13)[18]/46,XY[2] Karyotype at relapse : 46,XY,t(4;12)(q11-q2;p13),+16,-17[1]/46,XY[19] Other molecular studies technics : FISH with LSI (TEL/AML1 ES Dual Color Translocation Probe (Vysis, Inc.)) on metaphases results : ish der(4)(dimTEL+), der(12)(dimTEL+)
Atlas Genet Cytogenet Oncol Haematol 2008; 2 336 Partial GTG-banding karyotype showing t(4;12)(q11;p13) (a ). Partial FISH analysis showing the ETV6 hybridization signals on derivative chromosomes 4 and 12, and on the normal chromosome 12 (b)‚
Comments The findings are consistent with AML. Although histologic features of chronic lymphocytic leukemia (CLL) are not seen, flow cytometric analysis shows a small subset of monoclonal B cells, consistent with persistent involvement by the patient's known CLL. Internal links Atlas Card t(4;12)(q11-q21;p13) Case Report Case Report t(4;12)(q11;p13) in an acute myeloid leukemia without maturation with myelodysplasia Contributor(s) Written 05-2007 Paola Dal Cin, Daniel J DeAngelo, Richard M Stone Citation This paper should be referenced as such : Dal Cin P, DeAngelo DJ, Stone RM . A t(4;12)(q11;p13) in a patient with coincident CLL at the same time of AML diagnosis. Atlas Genet Cytogenet Oncol Haematol. May 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0412DalCinID100023.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) t(3;5)(q25;q35) as a sole anomaly in acute myeloid leukemia patient
Adriana Zamecnikova Clinics Age and sex : 36 year(s) old female patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement Blood WBC : 1.9 x 109/l; Hb : 10.0 g/dl; platelets : 41 x 109/l; blasts : 11% Cyto pathology classification Cytology : Acute Myeloid Leukemia. Immunophenotype : Not available. Rearranged Ig Tcr : - Pathology : - Electron microscopy : - Precise diagnosis : Acute Myeloid Leukemia, M2. Survival Date of diagnosis: (03-2007) Treatment : Left for treatment abroad. Complete remission was obtained Comments : /-. Not known as the patient left for treatment abroad. Treatment related death : - Relapse : - Phenotype at relapse : - Status : Lost (03-2007) Survival : 1 month(s) Karyotype Sample : BM ; culture time : 24 h ; banding : G-band Results : 46,XY,t(3;5)(q25;q35) Other molecular cytogenetics technics : Fluorescence in situ hybridisation (FISH), with LSI 5q EGR1 SO/D5S23 SG) and LSI BCL6 DC probes obtained from Vysis (Downers Grove IL, USA). Other molecular cytogenetics results : Analysis with LSI 5q EGR1 SO/D5S23 SG probe revealed one red and green signal on normal chromosome 5 and on der(5) chromosome. Analysis with LSI BCL6 DC probe revealed one fusion signal on normal chromosome 3 and a fusion signal on der(5) distal to EGR1 locus confirming the t(3;5).
Atlas Genet Cytogenet Oncol Haematol 2008; 2 338 Karyotype of the patient demonstrating the t(3;5)(q25;q35).
Atlas Genet Cytogenet Oncol Haematol 2008; 2 339 LSI BCL6 DC, Break Apart Rearrangement Probe exhibiting one red/green fusion on normal chromosome 3 and fusion signal on der(5) distal to EGR1. Hybridization with LSI 5q EGR1 SO/D5S23 SG probe on metaphase showing one red and green signal on normal and der(5) chromosome. Comments A 36-years old Kuwaiti female was referred to our hospital due to pancytopenia and hair loss. Initial investigation showed: WBC 1.9 x 109/l (neutr 35%, lymphocy 50%, mono 2%, eos 1%, myelo 1%), blasts 11%, NRBC 8/100. Based on laboratory findings the diagnosis of AML-M2 was made. The chromosomal translocation t(3;5)(q25;q35) was observed only in individual cases. From the 5 described cases, 3 cases (2 male 1 female) were diagnosed with MDS and 2 cases with AML-M6 (1 male 1 female) suggesting the rearrangement with possible involvement of NPM/MLF1 genes is associated with myeloid malignancies. Internal links Atlas Card t(3;5)(q25;q34)
Atlas Genet Cytogenet Oncol Haematol 2008; 2 340 Bibliography Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Olopade OI, Thangavelu M, Larson RA, Mick R, Kowal-Vern A, Scumacher HR, LeBeau MM, Vardiman JW, Rowley JD. Blood 1992; 80:2873-2882. PMID 1450412
Detection of NPM/MLF1 fusion in t(3;5)-positive acute myeloid leukemia and myelodysplasia. Arber DA, Chang KL, Lyda MH, Bedell V, Spielberger R, Slovak ML. Human Pathol 2003; 34:809-813. PMID 14506644
Loss of the NPM1 gene in myeloid disorders with chromosome 5 rearrangements. Berger R, Busson M, Baranger L, Hélias C, Lessard M, Dastugue N, Speleman F. Leukemia 2006; 20:319-321. PMID 16341035
Contributor(s) Written 05-2007 Adriana Zamecnikova Citation This paper should be referenced as such : Zamecnikova A . t(3;5)(q25;q35) as a sole anomaly in acute myeloid leukemia patient. Atlas Genet Cytogenet Oncol Haematol. May 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0305ZamecnikovaID100025.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient
Adriana Zamecnikova Clinics Age and sex : 32 year(s) old male patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : hepatomegaly ; splenomegaly ; enlarged lymph nodes ; no central nervous system involvement Blood WBC : 68.4 x 109/l; Hb : 11.7 g/dl; platelets : 120 x 109/l; blasts : 93% Cyto pathology classification Cytology : Acute Myeloid Leukemia Immunophenotype : Positive for CD 34, HLDR, CD33, CD34, CD68, myeloperoxidase. Rearranged Ig Tcr : - Pathology : - Electron microscopy : - Precise diagnosis : Acute Myeloid Leukemia, M1. Survival Date of diagnosis: 05-2006 Treatment : Allopurinol, Hydroxyurea, Tazocin, Amikacin (ADE 10, ADE 8). Complete remission : None Treatment related death : - Relapse : - Phenotype at relapse : - Status : Alive 05-2007 traveled to receive BMT, allogenic BMT on 29-08-06. Survival : 12 month(s) Karyotype Sample : BM ; culture time : 24 h ; banding : G-band Results : 46,XY,t(3;4)(p21;q34) Other molecular cytogenetics technics : Fluorescence in situ hybridisation (FISH), with WCP 3 and 4 probes to confirm the t(3;4). To confirm the translocation of 3p and to exclude the translocation t(3;5) (q25;q34-35) FISH studies with LSI BCL6 and EGR1 SO/D5S23 probes were performed (Vysis, Downers Grove IL, USA). Other molecular cytogenetics results : Using WCP 3 and 4 probes we confirmed the rearranged chromosomes 3 and 4. Analysis with LSI BCL6 probe revealed one red/green fusion signal on the 3q27 allele in the normal chromosome 3, and a fusion signal on the long arm of the der(3). Hybridization with LSI 5q SpectrumOrange/5p SpectrumGreen probe revealed 2 normal chromosomes 5, excluding the rearrangement of chromosome 5. Other findings results : LDH almost 3 folds upper normal limit.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 342 Partial karyotypes (G-banding) demonstrating rearrangened chromosomes 3 and 4.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 343 Whole chromosome paintings with rearrangened chromosomes 3 and 4 and hybridization with LSI BCL6 and LSI 5qSO/5pSG probes showing the fusion signal on normal chromosome 3 and on der(3) chromosome and two normal chromosomes 5. Comments A 31-year-old Kuwaiti male presented with 3-months history of fatigue, recurrent sore throat attacks and a 2-day history of recurrent vomiting and loose motions. Physical examinations revealed left cervical lymphadenopaty and hepatosplenomegaly. Laboratory investigations showed Hb 11.7g/dl, platelets 120x109/l and white blood cells 68.4x109/L. Bone marrow smears were markedly hypercellular with 93% large blast cells. Cytochemical studies showed myeloperoxydase positive (60%), Sudan Black B positive (74.6%), PAS and non-specific esterase negative blast cells. On the basis of these morphological findings, a diagnosis of acute myeloid leukemia (FAB-M1 type) was made. 3p21 is a recurrent breakpoint in MDS/AML and t-MDS/t-AML suggesting, 3p21 site is likely to contain a gene (genes) involved in the pathogenesis of t(3;4)(p21;q34). One previous case of t(3;4)(p21;q34) was found in a refractory anemia, making this anomaly recurrent. The similar cytogenetic appearance of a rare t(3;4)(p21;q34) and the more frequent t(3;5)(q25;q34) in suboptimal preparations reinforces the utility of FISH technique for assessing chromosomal abnormalities in AML. Internal links Atlas Card t(3;4)(p21;q34) Bibliography 3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia. Shi G, Weh HJ, Martensen S, Seeger D, Hossfeld DK. Cytogenet Cell Genet 1996; 74:295-299. PMID 8976389
Risk factor analysis in myelodysplastic syndrome patients with del(20q): prognosis revisited. Liu YC, Ito Y, Hsiao HH, Sashida G, Kodama A, Ohyashiki JH, Ohyashiki K.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 344 Cancer Genet Cytogenet 2006; 171:9-16. PMID 17074585
Contributor(s) Written 05-2007 Adriana Zamecnikova Citation This paper should be referenced as such : Zamecnikova A . t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient. Atlas Genet Cytogenet Oncol Haematol. May 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0304ZamecnikovaID100026.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) t(1;16)(q11-12;q11) presented as a der(16)t(1;16) in a patient with acute lymphoblastic leukemia.
Adriana Zamecnikova Clinics Age and sex : 56 year(s) old male patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement Blood WBC : 213 x 109/l; Hb : 9.6 g/dl; platelets : 23 x 109/l; blasts : 93% Cyto pathology classification Cytology : Acute Lymphoblastic Leukemia Immunophenotype : Positive for CD45, CD10, CD19, CD34, HLADR, TdT. Rearranged Ig Tcr : - Pathology : - Electron microscopy : - Precise diagnosis : Acute Lymphoblastic Leukemia, L1 (pre-B). Survival Date of diagnosis: 08-2006 Treatment : Methotrexate, Ara-C, Hyper-CVAD protocol. Complete remission was obtained Treatment related death : - Relapse : - Phenotype at relapse : - Status : Alive (04-2007) Survival : 9 month(s) Karyotype Sample : BM ; culture time : 24 h ; banding : G-band Results : 46,XY,der(16)t(1;16)(q11-12;q11) [20] Other molecular cytogenetics technics : Fluorescence in situ hybridisation (FISH), with LSI CBFB DC and WCP probes for chromosome 1 and 16 (WPC DNA Probe 1, SpectrumOrange; WPC DNA Probe 16, SpectrumGreen) obtained from Vysis (Downers Grove IL, USA). Other molecular cytogenetics results : The analysis with LSI CBFB DC probe revealed one normal signal on the CBFB allele in the normal chromosome 16, while on the der(16) no red/green signal was detected, confirming the rearrangement of 16q. Hybridization with WCP 1 SpectrumOrange and WCP 16 SpectrumGreen probes revealed 2 normal chromosomes 1, one normal chromosome 16 and confirmed the der(16)t(1;16). Other molecular studies technics : RT-PCR for BCR-ABL results : The BCR-ABL transcript was negative by the conventional method of molecular analysis.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 346 Partial karyotypes demonstrating 2 normal chromosomes 1, one normal chromosome 16 and the der(16)t(1;16). C-banded chromosomes on the right side.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 347 LSI CBFB DC, Break Apart Rearrangement Probe exhibiting one normal signal on the CBFB allele on normal chromosome 16.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 348 Whole chromosome painting showing 2 normal chromosomes 1 and the rearrangened chromosomes 1 and 16. Comments A 47-years old Filipino male was diagnosed with ALL in August 2006. Cytogenetic analysis of the bone marrow sample revealed a clearly abnormal chromosome 16 and the karyotype 46,XY,-16,+der(16)t(1;16)(q11-12;q11) was identified in all the 30 examined metaphases. Recurrent whole-arm translocation of 1q to the centromeric region of chromosome 16 has been detected in a number of malignancies, but only occasionally described in hematological malignancies. The previously described 3 MDS, 4 AML and 3 ALL cases with t(1;16)(q11-q12;q11-12) were always unbalanced, suggesting either trisomy of 1q or monosomy of 16q may potentially contribute to leukemogenesis. Internal links Atlas Card t(1;16)(q11;q11) Bibliography Translocation (1;16) identified by chromosome painting, and PRimed IN Situ-labeling (PRINS). Report of two cases and review of the cytogenetic literature.
Atlas Genet Cytogenet Oncol Haematol 2008; 2 349 Hindkjaer J, Hammoudah SAFM, Bendix Hansen K, Jensen PD, Koch J, Pedersen B. Cancer Genet Cytogenet 1995; 79:15-20. PMID 7850745
Der(16)t(1;16)(q11;q11) in myelodysplastic syndromes: a new non-random abnormality characterized by cytogenetic and fluorescence in situ hybridization studies. Mugneret F, Dastugue N, Favre B, Sidaner I, Salles B, Huguet-Rigal F, Solary E. Br J Haematol 1995; 90:119-124. PMID 7786773
Contributor(s) Written 05-2007 Adriana Zamecnikova Citation This paper should be referenced as such : Zamecnikova A . t(1;16)(q11-12;q11) presented as a der(16)t(1;16) in a patient with acute lymphoblastic leukemia.. Atlas Genet Cytogenet Oncol Haematol. May 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0116ZamecnikovaID100024.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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