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 4, Jul-Aug 2008 Previous Issue / Next Issue Genes AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)) (10p15.1). Hsueh Kung Lin. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 498-502. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/AKR1C3ID612ch10p15.html CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)) (11q22.3). Yatender Kumar, Vegesna Radha, Ghanshyam Swarup. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 503-518. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CASP1ID145ch11q22.html GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) (15q21.3). Prakash Radhakrishnan, Pi-Wan Cheng. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 519-524. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/GCNT3ID44105ch15q21.html HYAL2 (Hyaluronoglucosaminidase 2) (3p21.3). Lillian SN Chow, Kwok-Wai Lo. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 525-529. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/HYAL2ID40904ch3p21.html LMO2 (LIM domain only 2 (rhombotin-like 1)) (11p13) - updated. Pieter Van Vlierberghe, Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 530-535. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/RBTN2ID34.html PEBP1 (phosphatidylethanolamine binding protein 1) (12q24.23). Sandy Beach, Kam C Yeung. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 536-543. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PEBP1ID44021ch12q24.html RNF7 (RING finger protein-7) (3q22-24). Yi Sun. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 544-549. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/RNF7ID44108ch3q22.html STARD13 (StAR-related lipid transfer (START) domain containing 13) (13q13.3). Thomas Ho-Yin Leung, Judy Wai Ping Yam, Irene Oi-lin Ng. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 550-555. [Full Text] [PDF]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 I URL : http://atlasgeneticsoncology.org/Genes/STARD13ID44051ch13q13.html TTL (Twelve-thirteen Translocation Leukemia) (13q14.11). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 556-558. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TTLID529ch13q14.html ZFP36L1 (Zinc finger protein 36, C3H type-like 1) (14q24.1). Deborah J Stumpo, Perry J Blackshear. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 559-565. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ZFP36L1ID42866ch14q22.html ZNF384 (Zinc Finger protein 384) (12p13.31). Paolo Gorello, Roberta La Starza, Cristina Mecucci. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 566-571. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ZNF384ID42881ch12p13.html CD53 (CD53 molecule) (1p13.3). Pedro A Lazo. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 572-577. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CD53ID983ch1p13.html EVI1 (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)- EVI1) (3q26.2) - updated. Rotraud Wieser. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 578-587. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/EVI103q26ID19.html KIF14 (kinesin family member 14) (1q32.1). Brigitte L Thériault, Timothy W Corson. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 588-592. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/KIF14ID44138ch1q32.html NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) (9q21.33). Nadia Gabellini. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 593-600. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/NTRK2ID41589ch9q21.html PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)) (11q13.5). Dina Stepanova, Jonathan Chernoff. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 601-605. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PAK1ID41633ch11q13.html POU4F1 (POU class 4 homeobox 1) (13q31.1). Vishwanie Budhram-Mahadeo, David S Latchman. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 606-616. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/POU4F1ID44173ch13q31.html PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)) (17q12). Wael El-Rifai, Abbes Belkhiri. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 617-622. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PPP1R1BID44096ch17q12.html RMRP (RNA component of mitochondrial RNA processing endoribonuclease) (9p21-p12). Pia Hermanns, Kerstin Reicherter, Brendan Lee. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 623-632. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/RMRPID44001ch9p21.html TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) (20q13.3). Jiangping Wu, Bing Han. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 633-642. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TNFRSF6BID42628ch20q13.html TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) (3q26). Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 643-650. [Full Text] [PDF]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 II URL : http://atlasgeneticsoncology.org/Genes/TNFSF10ID42632ch3q26.html Leukaemias dic(1;15)(p11;p11). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 651-653. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/dic0115p11p11ID1159.html t(2;19)(p11;p13). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 654. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0219p11p13ID1288.html t(3;18)(q26;q11). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 655. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0318q26q11ID1283.html t(3;4)(p21;q34). Adriana Zamecnikova. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 656-658. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0304p21q34ID1433.html t(4;21)(q31;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 659-660. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0421q31q22ID1448.html Solid Tumours Cancer Prone Diseases Deep Insights Case Reports Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage. Marta Gallego, Mariela Coccé, Andrea Bernasconi, Maria Felice, Cristina Alonso, Myriam Guitter. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 661-663. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0812GallegoID100029.html A case of Chronic Lymphocytic Leukemia (CLL) with a rare chromosome abnormality: t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32). Alka Dwivedi, Thomas Casey, Siddharth G Adhvaryu. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 664-667. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0614AdhvaryuID100033.html Educational Items
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Atlas Genet Cytogenet Oncol Haematol 2008; 4 III Atlas of Genetics and Cytogenetics in Oncology and Haematology
AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II))
Identity Other names DD3 HA1753 HAKRB HAKRe HSD17B5 KIAA0119 hluPGFS HGNC AKR1C3 Location 10p15.1 DNA/RNA Transcription 1170 bp mRNA; transcript has been detected in brain, lung, liver, small intestine, mammary gland, uterus, prostate, testis. Protein Description 323 amino acids, molecular weight 37 kDa. Expression Activated macrophage, malignant prostate epithelium, normal mammary epithelium, mature blood vessel. Localisation Mainly in cytoplasm. Function AKR1C3 metabolizes various androgen metabolites including 5a-dihydrotestosterone to 5a-androstane-3a,17b-diol, Delta4-androstene-3,17-dione to testosterone, androstanedione to 5a-dihydrotestosterone, androsterone to 5a-androstane-3a,17b- diol. AKR1C3 is also involved in estrogen metabolism converting estrone to 17b-estradiol as well as progesterone metabolism converting prostaglandin D2 to 9a,11b-prostaglandin F2a. AKR1C3 has the capability of regulating the trans-activation of various nuclear receptors including androgen receptor, estrogen receptor, and peroxisome proliferator activated receptor (PPARG) by regulating the ligand availability for the nuclear receptors. Homology A member of the of AKR1C family proteins; AKR1C1, AKR1C2, AKR1C3, AKR1C4 in human, and AKR1C9 in rat. Mutations Note Mutation of AKR1C3 has not been identified. Implicated in Entity Various cancers Note Elevated levels of AKR1C3 expression are implicated in leukemia cell differentiation, prostate cancer (in both androgen-dependent and androgen-independent prostate cancer), and endometrial cancer. Expression of AKR1C3 was detected in a patient with myelodysplastic syndrome (MDS, refractory anemia) with progression to acute myelogenous leukemia. Overexpression of AKR1C3 in a human promyelocytic leukemia cell line, HL-60, rendered cells more resistant to all-trans retinoic acid (ATRA) and 1a,25-dihydroxyvitamin D3 induced cell differentiation. Entity Prostate cancer Disease Immunohistochemical staining of human prostate tissues detected negative or low levels of AKR1C3 expression in normal prostate epithelial cells. Strong positive AKR1C3 immunoreactivity was demonstrated in primary and androgen-independent prostate cancers. Variable increases in AKR1C3 expression were also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy, and urothelial cell metaplasia. Entity Endometrial cancer
Atlas Genet Cytogenet Oncol Haematol 2008; 4 498 Disease Quantitative transcriptosome analysis using real-time polymerase chain reaction, AKR1C3 mRNA expression was shown to be elevated in endometrial cancer versus adjacent normal endometrium. Entity Breast tumor Disease Expression of AKR1C3 mRNA was reduced in breast tumor as compared to adjacent normal breast tissue. Immunohistochemstry revealed that the ductal epithelial cells and stromal cells of the breast express AKR1C3. In myoepithelial cells of the breast, immunoreactive AKR1C3 was absent in normal tissues, whereas strong AKR1C3 staining was apparent in cells surrounding the neoplastic epithelium of ductal carcinoma in situ. External links Nomenclature HGNC AKR1C3 386 AKR1C3 8644 aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid Entrez_Gene dehydrogenase, type II) Cards Atlas AKR1C3ID612ch10p15 GeneCards AKR1C3 Ensembl AKR1C3 [Search_View] ENSG00000196139 [Gene_View] Genatlas AKR1C3 GeneLynx AKR1C3 eGenome AKR1C3 euGene 8644 Genomic and cartography AKR1C3 - 10p15.1 chr10:5126568-5139878 + 10p15-p14 [Description] (hg18- GoldenPath Mar_2006) Ensembl AKR1C3 - 10p15-p14 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene AKR1C3 Gene and transcription Genbank AB018580 [ ENTREZ ] Genbank AF149416 [ ENTREZ ] Genbank AK290365 [ ENTREZ ] Genbank AK296829 [ ENTREZ ] Genbank AK310940 [ ENTREZ ] RefSeq NM_003739 [ SRS ] NM_003739 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq AC_000142 [ SRS ] AC_000142 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_077567 [ SRS ] NT_077567 [ ENTREZ ] RefSeq NW_001837930 [ SRS ] NW_001837930 [ ENTREZ ] RefSeq NW_924584 [ SRS ] NW_924584 [ ENTREZ ] AceView AKR1C3 AceView - NCBI Unigene Hs.78183 [ SRS ] Hs.78183 [ NCBI ] HS78183 [ spliceNest ] Fast-db 720 (alternative variants) Protein : pattern, domain, 3D structure P42330 [ SRS] P42330 [ EXPASY ] P42330 [ INTERPRO ] P42330 SwissProt [ UNIPROT ] PS00798 ALDOKETO_REDUCTASE_1 [ SRS ] PS00798 Prosite ALDOKETO_REDUCTASE_1 [ Expasy ] PS00062 ALDOKETO_REDUCTASE_2 [ SRS ] PS00062 Prosite ALDOKETO_REDUCTASE_2 [ Expasy ] PS00063 ALDOKETO_REDUCTASE_3 [ SRS ] PS00063 Prosite ALDOKETO_REDUCTASE_3 [ Expasy ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 499 Interpro IPR001395 Aldo/ket_red [ SRS ] IPR001395 Aldo/ket_red [ EBI ] CluSTr P42330 PF00248 Aldo_ket_red [ SRS ] PF00248 Aldo_ket_red [ Sanger ] pfam00248 Pfam [ NCBI-CDD ] Prodom PD000288 Aldo/ket_red[INRA-Toulouse]
P42330 AK1C3_HUMAN [ Domain structure ] P42330 AK1C3_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P42330 PDB 1RY0 [ SRS ] 1RY0 [ PdbSum ], 1RY0 [ IMB ] 1RY0 [ RSDB ] PDB 1RY8 [ SRS ] 1RY8 [ PdbSum ], 1RY8 [ IMB ] 1RY8 [ RSDB ] PDB 1S1P [ SRS ] 1S1P [ PdbSum ], 1S1P [ IMB ] 1S1P [ RSDB ] PDB 1S1R [ SRS ] 1S1R [ PdbSum ], 1S1R [ IMB ] 1S1R [ RSDB ] PDB 1S2A [ SRS ] 1S2A [ PdbSum ], 1S2A [ IMB ] 1S2A [ RSDB ] PDB 1S2C [ SRS ] 1S2C [ PdbSum ], 1S2C [ IMB ] 1S2C [ RSDB ] PDB 1XF0 [ SRS ] 1XF0 [ PdbSum ], 1XF0 [ IMB ] 1XF0 [ RSDB ] PDB 1ZQ5 [ SRS ] 1ZQ5 [ PdbSum ], 1ZQ5 [ IMB ] 1ZQ5 [ RSDB ] PDB 2F38 [ SRS ] 2F38 [ PdbSum ], 2F38 [ IMB ] 2F38 [ RSDB ] PDB 2FGB [ SRS ] 2FGB [ PdbSum ], 2FGB [ IMB ] 2FGB [ RSDB ] HPRD 04911 Protein Interaction databases DIP P42330 IntAct P42330 Polymorphism : SNP, mutations, diseases OMIM 603966 [ map ] GENECLINICS 603966 SNP AKR1C3 [dbSNP-NCBI] SNP NM_003739 [SNP-NCI] SNP AKR1C3 [GeneSNPs - Utah] AKR1C3] [HGBASE - SRS] HAPMAP AKR1C3 [HAPMAP] HGMD AKR1C3 General knowledge Family Browser AKR1C3 [UCSC Family Browser] SOURCE NM_003739 SMD Hs.78183 SAGE Hs.78183 1.-.-.- [ Enzyme-Expasy ] 1.-.-.- [ Enzyme-SRS ] 1.-.-.- [ IntEnz-EBI ] 1.-.-.- Enzyme [ BRENDA ] 1.-.-.- [ KEGG ] 1.-.-.- [ WIT ] GO aldo-keto reductase activity [Amigo] aldo-keto reductase activity GO intracellular [Amigo] intracellular GO cytoplasm [Amigo] cytoplasm GO prostaglandin metabolic process [Amigo] prostaglandin metabolic process GO oxidoreductase activity [Amigo] oxidoreductase activity GO prostaglandin-F synthase activity [Amigo] prostaglandin-F synthase activity 3-alpha-hydroxysteroid dehydrogenase (A-specific) activity [Amigo] 3-alpha- GO hydroxysteroid dehydrogenase (A-specific) activity testosterone 17-beta-dehydrogenase (NADP+) activity [Amigo] testosterone 17-beta- GO dehydrogenase (NADP+) activity trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity [Amigo] trans-1,2- GO dihydrobenzene-1,2-diol dehydrogenase activity testosterone 17-beta-dehydrogenase activity [Amigo] testosterone 17-beta- GO dehydrogenase activity GO oxidation reduction [Amigo] oxidation reduction KEGG Arachidonic acid metabolism
Atlas Genet Cytogenet Oncol Haematol 2008; 4 500 KEGG Metabolism of xenobiotics by cytochrome P450 PubGene AKR1C3 TreeFam AKR1C3 CTD 8644 [Comparative ToxicoGenomics Database] Other databases Probes Probe AKR1C3 Related clones (RZPD - Berlin) PubMed PubMed 55 Pubmed reference(s) in LocusLink Bibliography Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution. Lin HK, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM Molecular endocrinology (Baltimore, Md.). 1997 ; 11 (13) : 1971-1984. PMID 9415401
Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. El-Alfy M, Luu-The V, Huang XF, Berger L, Labrie F, Pelletier G Endocrinology. 1999 ; 140 (3) : 1481-1491. PMID 10067877
Immunoelectron microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary gland. Pelletier G, Luu-The V, El-Alfy M, Li S, Labrie F Journal of molecular endocrinology. 2001 ; 26 (1) : 11-19. PMID 11174850
The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Desmond JC, Mountford JC, Drayson MT, Walker EA, Hewison M, Ride JP, Luong QT, Hayden RE, Vanin EF, Bunce CM Cancer research. 2003 ; 63 (2) : 505-512. PMID 12543809
Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Ji Q, Aoyama C, Nien YD, Liu PI, Chen PK, Chang L, Stanczyk FZ, Stolz A Cancer research. 2004 ; 64 (20) : 7610-7617. PMID 15492289
Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. Lewis MJ, Wiebe JP, Heathcote JG BMC cancer. 2004 ; 4 : page 27. PMID 15212687
In situ androgen producing enzymes in human prostate cancer. Nakamura Y, Suzuki T, Nakabayashi M, Endoh M, Sakamoto K, Mikami Y, Moriya T, Ito A, Takahashi S, Yamada S, Arai Y, Sasano H Endocrine-related cancer. 2005 ; 12 (1) : 101-107. PMID 15788642
Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Amin SA, Huang CC, Reierstad S, Lin Z, Arbieva Z, Wiley E, Saborian H, Haynes B, Cotterill H, Dowsett M, Bulun SE
Atlas Genet Cytogenet Oncol Haematol 2008; 4 501 Molecular and cellular endocrinology. 2006 ; 253 (1-2) : 44-55. PMID 16735089
Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta- hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Fung KM, Samara EN, Wong C, Metwalli A, Krlin R, Bane B, Liu CZ, Yang JT, Pitha JV, Culkin DJ, Kropp BP, Penning TM, Lin HK Endocrine-related cancer. 2006 ; 13 (1) : 169-180. PMID 16601286
Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia. Mahadevan D, DiMento J, Croce KD, Riley C, George B, Fuchs D, Mathews T, Wilson C, Lobell M American journal of hematology. 2006 ; 81 (10) : 779-786. PMID 16838325
Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors. Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, Fung KM, Lin HK Molecular and cellular endocrinology. 2006 ; 248 (1-2) : 182-191. PMID 16417966
AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Rizner TL, Smuc T, Rupreht R, Sinkovec J, Penning TM Molecular and cellular endocrinology. 2006 ; 248 (1-2) : 126-135. PMID 16338060
Increased expression of genes converting adrenal androgens to testosterone in androgen- independent prostate cancer. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP Cancer research. 2006 ; 66 (5) : 2815-2825. PMID 16510604
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Contributor(s) Written 11-2007 Hsueh Kung Lin Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, Oklahoma 73104, USA Citation This paper should be referenced as such : Lin HK . AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/AKR1C3ID612ch10p15.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 502 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase))
Identity Other names ICE IL1BC P45 HGNC CASP1 Location 11q22.3 ICEBERG, INCA1, INCA2, COP, Caspase-1, Caspase-5, Caspase-4: The human caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: Local_order cop, inca1, inca2 and iceberg. These decoy caspases are absent in the mouse genome, suggesting their occurrence recently by duplication of caspase-1 during evolution.
Note 11q22.2-q22.3: a site frequently involved in rearrangement in human cancers. DNA/RNA
Atlas Genet Cytogenet Oncol Haematol 2008; 4 503
Description The human caspase-1 gene is comprised of 10 exons, spanning 10.6kb on chromosome 11q22.2-q22.3. Transcription Six alternatively spliced forms of caspase-1 have been identified in Homo sapiens. The longest termed CASP1alpha is 1364bp with an ORF encoding 404 amino acids (aa) and is the most predominant isoform. CASP1beta is 1185bp, lacks entire exon3 (275-338bp; 92-112aa), ORF encoding 383aa. CASP1gamma is 969bp, lacks most of exon2 and entire exon3 (59-338bp; 20-112aa), ORF encoding 291aa. CASP1delta is 825bp, lacks entire exon7 (863-1006bp; 288-335aa), ORF encoding 356aa. CASP1epsilon is 300bp, lacks most of exon2 and exon3exon7 (59-1006bp; 20-335aa), ORF encoding 98aa. CASP1zeta is 1131bp, missing 79bp in prodomain of caspase-1, ORF encoding 365aa. Among these alpha, beta, gamma and zeta forms are proteolytically active and can induce apoptosis. As delta and epsilon lack part of the catalytic domain, they do not induce apoptosis and serve as inhibitors of caspase-1 when overexpressed. Pseudogene COP (Card Only Protein) Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 4 504
Description Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspases-4, caspases-5, and caspases-12. It is also involved in some forms of apoptosis. Caspase-1 protein consists of an N-terminal CARD (caspase activation and recruitment domain), a large P20 subunit and a small P10 subunit. Due to its long N-terminal prodomain, caspase-1 belongs to the initiator group of caspases and is therefore suspected to act proximally in a caspase activation cascade leading to apoptosis. Caspase-1 is synthesized as a proenzyme of 45kDa, which undergoes proteolytic cleavage at Asp residues to produce the active enzyme. The active caspase-1 enzyme is a hetrotetramer comprised of two P20 and two P10 subunits. The catalytic site is formed by amino acids from both P20 and P10 subunits, with the active cysteine located within the P20 subunit. Caspase-1 is activated through interactions with other CARD containing proteins such as ASC, RIP2 and NLRC4 via homotypic CARD-CARD interactions. Bacterial and viral proteins like SipB, IpaB, CrmA, and Serp2 which do not
Atlas Genet Cytogenet Oncol Haematol 2008; 4 505 contain the CARD domain, also regulate caspase-1. Caspase-1 is activated by phosphorylation at serine 376 residue by PAK1 upon Helicobacter pylori infection. Expression Caspase-1 is highly expressed in leukocytes, monocytes and epithelial cells. Caspase-1 gene expression is induced in response to various stimuli such as microbial infections (Mycobacterium avium, Salmonella typhimurium, Legionella pneumophila, Bacillus anthracis, Francisella tularenis and bacterial LPS), cytokines (IFN-gamma and TNF- alpha ), growth factors (TGF-beta), and DNA damaging agents (Doxorubicin, UV radiation and Paclitaxel). Levels of caspase-1 mRNA are high in ischemic tissues. Tumor suppressor p53, p73, SP1, ETS-1, IFT57/HIPPI and IRF-1 activate transcription of full length caspase-1 mRNA by binding to respective sites in the promoter, within a region 550bp upstream of the transcription start site. Localisation Predominantly cytoplasmic. See Table-1 and Table-2. Function The adaptor molecules ASC, NLRC4 and Cryopyrin/Nalp3 regulate caspase-1 within a multiprotein complex known as the "Inflammasome". Caspase-1 activation results in cleavage and activation of proinflammatory cytokines such as IL-1 beta and IL-18. Caspase-1 deficient mice have a defect in the maturation of proIL-1beta and are resistant to the lethal effect of endotoxins. Various pathogens such as S.typhimurium (TypeIII secretion), L.pneumophila (Type IV secretion), B.anthracis (Lethal Toxin), F.tularenis activate caspase-1 through "inflammasomes". Caspase-1 activation also occurs upon exposure to bacterial RNA, imidazoquilone compounds, LPS, extracellular ATP, muramyl dipeptide (MDP), monosodium urate, calcium pyrophosphate dehydrate and other TLR ligands via "inflammasomes". In addition to bacterial pathogens, viral infection also induces caspase-1 activation. Caspase-1 acts apically in neuronal cell death pathways induced by hypoxia and ischaemia. Caspase-1 is also involved in p53- mediated apoptosis in a cell type specific manner. Caspase-1 sensitizes cells to death induced by agents like Fas ligand, radiation and cisplatin. Caspase-1 stimulates membrane biogenesis to repair damage caused by pore-forming toxins, thereby promoting host cell survival. Homology CARD of caspase-1 bears significant homology with the CARDs of Caspase-4, Caspase-5, SFRS2IP/Caspase-11, Caspase-12, ICEBERG, Nod1, NLRC4, NEDD2, cIAP2, cIAP3 and ced3. Mutations Germinal Not Known Somatic Not Known Implicated in Entity Various Diseases Disease In diseases such as ischemic and hypoxia induced brain injury, acute bacterial meningitis, ischemia of the heart and kidney. A role for caspase-1 has been implicated in Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinsons disease, Crohns disease, Age-related cognitive dysfunctions, spinalcord inflammation and gout. Caspase1- activation is enhanced in patients with CINCA syndrome. Entity Cancers Disease In ovarian Cancer and stomach Cancer: there is a decreased expression of caspase-1. External links Nomenclature HGNC CASP1 1499 CASP1 834 caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, Entrez_Gene convertase) Cards Atlas CASP1ID145ch11q22 GeneCards CASP1 Ensembl CASP1 [Search_View] ENSG00000137752 [Gene_View] Genatlas CASP1 GeneLynx CASP1 eGenome CASP1 euGene 834 Genomic and cartography
Atlas Genet Cytogenet Oncol Haematol 2008; 4 506 CASP1 - 11q22.3 chr11:104401447-104411067 - 11q23 [Description] (hg18- GoldenPath Mar_2006) Ensembl CASP1 - 11q23 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CASP1 Gene and transcription Genbank AA761907 [ ENTREZ ] Genbank AB102878 [ ENTREZ ] Genbank AK223503 [ ENTREZ ] Genbank AK290114 [ ENTREZ ] Genbank AK290122 [ ENTREZ ] RefSeq NM_001223 [ SRS ] NM_001223 [ ENTREZ ] RefSeq NM_033292 [ SRS ] NM_033292 [ ENTREZ ] RefSeq NM_033293 [ SRS ] NM_033293 [ ENTREZ ] RefSeq NM_033294 [ SRS ] NM_033294 [ ENTREZ ] RefSeq NM_033295 [ SRS ] NM_033295 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq AC_000143 [ SRS ] AC_000143 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_033899 [ SRS ] NT_033899 [ ENTREZ ] RefSeq NW_001838042 [ SRS ] NW_001838042 [ ENTREZ ] RefSeq NW_925173 [ SRS ] NW_925173 [ ENTREZ ] AceView CASP1 AceView - NCBI Unigene Hs.2490 [ SRS ] Hs.2490 [ NCBI ] HS2490 [ spliceNest ] Fast-db 13477 (alternative variants) Protein : pattern, domain, 3D structure P29466 [ SRS] P29466 [ EXPASY ] P29466 [ INTERPRO ] P29466 SwissProt [ UNIPROT ] Prosite PS50209 CARD [ SRS ] PS50209 CARD [ Expasy ] Prosite PS01122 CASPASE_CYS [ SRS ] PS01122 CASPASE_CYS [ Expasy ] Prosite PS01121 CASPASE_HIS [ SRS ] PS01121 CASPASE_HIS [ Expasy ] Prosite PS50207 CASPASE_P10 [ SRS ] PS50207 CASPASE_P10 [ Expasy ] Prosite PS50208 CASPASE_P20 [ SRS ] PS50208 CASPASE_P20 [ Expasy ] Interpro IPR001315 CARD [ SRS ] IPR001315 CARD [ EBI ] Interpro IPR017350 Caspase_IL-1_beta [ SRS ] IPR017350 Caspase_IL-1_beta [ EBI ] Interpro IPR011029 DEATH_like [ SRS ] IPR011029 DEATH_like [ EBI ] Interpro IPR011600 Pept_C14_cat [ SRS ] IPR011600 Pept_C14_cat [ EBI ] Interpro IPR001309 Pept_C14_ICE_p20 [ SRS ] IPR001309 Pept_C14_ICE_p20 [ EBI ] IPR016129 Pept_C14_ICE_p20_AS [ SRS ] IPR016129 Pept_C14_ICE_p20_AS Interpro [ EBI ] Interpro IPR002138 Pept_C14_p10 [ SRS ] IPR002138 Pept_C14_p10 [ EBI ] Interpro IPR002398 Pept_C14_p45 [ SRS ] IPR002398 Pept_C14_p45 [ EBI ] Interpro IPR015917 Pept_C14_p45_core [ SRS ] IPR015917 Pept_C14_p45_core [ EBI ] CluSTr P29466 Pfam PF00619 CARD [ SRS ] PF00619 CARD [ Sanger ] pfam00619 [ NCBI-CDD ] PF00656 Peptidase_C14 [ SRS ] PF00656 Peptidase_C14 [ Sanger ] pfam00656 Pfam [ NCBI-CDD ] Smart SM00114 CARD [EMBL] Smart SM00115 CASc [EMBL] Blocks P29466 PDB 1BMQ [ SRS ] 1BMQ [ PdbSum ], 1BMQ [ IMB ] 1BMQ [ RSDB ] PDB 1IBC [ SRS ] 1IBC [ PdbSum ], 1IBC [ IMB ] 1IBC [ RSDB ] PDB 1ICE [ SRS ] 1ICE [ PdbSum ], 1ICE [ IMB ] 1ICE [ RSDB ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 507 PDB 1RWK [ SRS ] 1RWK [ PdbSum ], 1RWK [ IMB ] 1RWK [ RSDB ] PDB 1RWM [ SRS ] 1RWM [ PdbSum ], 1RWM [ IMB ] 1RWM [ RSDB ] PDB 1RWN [ SRS ] 1RWN [ PdbSum ], 1RWN [ IMB ] 1RWN [ RSDB ] PDB 1RWO [ SRS ] 1RWO [ PdbSum ], 1RWO [ IMB ] 1RWO [ RSDB ] PDB 1RWP [ SRS ] 1RWP [ PdbSum ], 1RWP [ IMB ] 1RWP [ RSDB ] PDB 1RWV [ SRS ] 1RWV [ PdbSum ], 1RWV [ IMB ] 1RWV [ RSDB ] PDB 1RWW [ SRS ] 1RWW [ PdbSum ], 1RWW [ IMB ] 1RWW [ RSDB ] PDB 1RWX [ SRS ] 1RWX [ PdbSum ], 1RWX [ IMB ] 1RWX [ RSDB ] PDB 1SC1 [ SRS ] 1SC1 [ PdbSum ], 1SC1 [ IMB ] 1SC1 [ RSDB ] PDB 1SC3 [ SRS ] 1SC3 [ PdbSum ], 1SC3 [ IMB ] 1SC3 [ RSDB ] PDB 1SC4 [ SRS ] 1SC4 [ PdbSum ], 1SC4 [ IMB ] 1SC4 [ RSDB ] PDB 2FQQ [ SRS ] 2FQQ [ PdbSum ], 2FQQ [ IMB ] 2FQQ [ RSDB ] PDB 2H48 [ SRS ] 2H48 [ PdbSum ], 2H48 [ IMB ] 2H48 [ RSDB ] PDB 2H4W [ SRS ] 2H4W [ PdbSum ], 2H4W [ IMB ] 2H4W [ RSDB ] PDB 2H4Y [ SRS ] 2H4Y [ PdbSum ], 2H4Y [ IMB ] 2H4Y [ RSDB ] PDB 2H51 [ SRS ] 2H51 [ PdbSum ], 2H51 [ IMB ] 2H51 [ RSDB ] PDB 2H54 [ SRS ] 2H54 [ PdbSum ], 2H54 [ IMB ] 2H54 [ RSDB ] PDB 2HBQ [ SRS ] 2HBQ [ PdbSum ], 2HBQ [ IMB ] 2HBQ [ RSDB ] PDB 2HBR [ SRS ] 2HBR [ PdbSum ], 2HBR [ IMB ] 2HBR [ RSDB ] PDB 2HBY [ SRS ] 2HBY [ PdbSum ], 2HBY [ IMB ] 2HBY [ RSDB ] PDB 2HBZ [ SRS ] 2HBZ [ PdbSum ], 2HBZ [ IMB ] 2HBZ [ RSDB ] HPRD 00977 Protein Interaction databases DIP P29466 IntAct P29466 Polymorphism : SNP, mutations, diseases OMIM 147678 [ map ] GENECLINICS 147678 SNP CASP1 [dbSNP-NCBI] SNP NM_001223 [SNP-NCI] SNP NM_033292 [SNP-NCI] SNP NM_033293 [SNP-NCI] SNP NM_033294 [SNP-NCI] SNP NM_033295 [SNP-NCI] SNP CASP1 [GeneSNPs - Utah] CASP1] [HGBASE - SRS] HAPMAP CASP1 [HAPMAP] COSMIC CASP1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD CASP1 General knowledge Family Browser CASP1 [UCSC Family Browser] SOURCE NM_001223 SOURCE NM_033292 SOURCE NM_033293 SOURCE NM_033294 SOURCE NM_033295 SMD Hs.2490 SAGE Hs.2490 3.4.22.36 [ Enzyme-Expasy ] 3.4.22.36 [ Enzyme-SRS ] 3.4.22.36 [ IntEnz- Enzyme EBI ] 3.4.22.36 [ BRENDA ] 3.4.22.36 [ KEGG ] 3.4.22.36 [ WIT ] GO protein binding [Amigo] protein binding GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO cytoplasm [Amigo] cytoplasm
Atlas Genet Cytogenet Oncol Haematol 2008; 4 508 GO proteolysis [Amigo] proteolysis GO proteolysis [Amigo] proteolysis GO signal transduction [Amigo] signal transduction GO cysteine-type peptidase activity [Amigo] cysteine-type peptidase activity GO caspase activator activity [Amigo] caspase activator activity GO caspase activity [Amigo] caspase activity GO caspase activity [Amigo] caspase activity GO regulation of apoptosis [Amigo] regulation of apoptosis BIOCARTA Caspase Cascade in Apoptosis [Genes] BIOCARTA D4-GDI Signaling Pathway [Genes] BIOCARTA IL 18 Signaling Pathway [Genes] KEGG Neurodegenerative Disorders KEGG MAPK signaling pathway KEGG Huntington's disease KEGG Dentatorubropallidoluysian atrophy (DRPLA) PubGene CASP1 TreeFam CASP1 CTD 834 [Comparative ToxicoGenomics Database] Other databases Probes Probe CASP1 Related clones (RZPD - Berlin) PubMed PubMed 113 Pubmed reference(s) in LocusLink Bibliography A pre-aspartate-specific protease from human leukocytes that cleaves pro-interleukin-1 beta. Black RA, Kronheim SR, Merriam JE, March CJ, Hopp TP The Journal of biological chemistry. 1989 ; 264 (10) : 5323-5326. PMID 2784432
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The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri- induced apoptosis in human monocyte-derived macrophages.
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Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH Jr Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (26) : 15763-15768. PMID 9861044
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Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (5) : 2871-2876. PMID 11226333 p53 associates with and targets Delta Np63 into a protein degradation pathway. Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (4) : 1817-1822. PMID 11172034
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Caspase-1 and caspase-8 cleave and inactivate cellular parkin.
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Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (26) : 16012-16017. PMID 14663141
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Anthrax lethal toxin rapidly activates caspase-1/ICE and induces extracellular release of interleukin (IL)-1beta and IL-18. Cordoba-Rodriguez R, Fang H, Lankford CS, Frucht DM The Journal of biological chemistry. 2004 ; 279 (20) : 20563-20566. PMID 15010463
Caspase-1zeta, a new splice variant of the caspase-1 gene. Feng Q, Li P, Leung PC, Auersperg N Genomics. 2004 ; 84 (3) : 587-591. PMID 15498465
INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. Lamkanfi M, Denecker G, Kalai M, D'hondt K, Meeus A, Declercq W, Saelens X, Vandenabeele P The Journal of biological chemistry. 2004 ; 279 (50) : 51729-51738. PMID 15383541
PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Wang Y, Hasegawa M, Imamura R, Kinoshita T, Kondo C, Konaka K, Suda T International immunology. 2004 ; 16 (6) : 777-786. PMID 15096476
NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. Basak C, Pathak SK, Bhattacharyya A, Mandal D, Pathak S, Kundu M The Journal of biological chemistry. 2005 ; 280 (6) : 4279-4288. PMID 15561713
Caspase-1alpha is down-regulated in human ovarian cancer cells and the overexpression of caspase-1alpha induces apoptosis. Feng Q, Li P, Salamanca C, Huntsman D, Leung PC, Auersperg N Cancer research. 2005 ; 65 (19) : 8591-8596. PMID 16204022
Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.
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Loss of caspase-1 gene expression in human gastric carcinomas and cell lines. Jee CD, Lee HS, Bae SI, Yang HK, Lee YM, Rho MS, Kim WH International journal of oncology. 2005 ; 26 (5) : 1265-1271. PMID 15809717
Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. Mariathasan S, Weiss DS, Dixit VM, Monack DM The Journal of experimental medicine. 2005 ; 202 (8) : 1043-1049. PMID 16230474
Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis. Pei H, Li C, Adereth Y, Hsu T, Watson DK, Li R Cancer research. 2005 ; 65 (16) : 7205-7213. PMID 16103071
IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA Immunity. 2005 ; 23 (5) : 479-490. PMID 16286016
Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia. Syed FM, Hahn HS, Odley A, Guo Y, Vallejo JG, Lynch RA, Mann DL, Bolli R, Dorn GW 2nd Circulation research. 2005 ; 96 (10) : 1103-1109. PMID 15845887
Haplotypes of the caspase-1 gene, plasma caspase-1 levels, and cardiovascular risk. Blankenberg S, Godefroy T, Poirier O, Rupprecht HJ, Barbaux S, Bickel C, Nicaud V, Schnabel R, Kee F, Morrison C, Evans A, Lackner KJ, Cambien F, Munzel T, AtheroGene Investigators, Tiret L Circulation research. 2006 ; 99 (1) : 102-108. PMID 16778130
The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, Kastner DL Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (26) : 9982-9987. PMID 16785446
Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella- infected macrophages. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nunez G Nature immunology. 2006 ; 7 (6) : 576-582. PMID 16648852
Caspase-1 activation of caspase-6 in human apoptotic neurons. Guo H, Petrin D, Zhang Y, Bergeron C, Goodyer CG, LeBlanc AC Cell death and differentiation. 2006 ; 13 (2) : 285-292. PMID 16123779
Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG
Atlas Genet Cytogenet Oncol Haematol 2008; 4 515 Cell. 2006 ; 126 (6) : 1135-1145. PMID 16990137
Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G Nature. 2006 ; 440 (7081) : 233-236. PMID 16407888
Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galan JE The Journal of experimental medicine. 2006 ; 203 (6) : 1407-1412. PMID 16717117
Innate immune response to Francisella tularensis is mediated by TLR2 and caspase-1 activation. Li H, Nookala S, Bina XR, Bina JE, Re F Journal of leukocyte biology. 2006 ; 80 (4) : 766-773. PMID 16895974
Caspase-1 as a radio- and chemo-sensitiser in vitro and in vivo. Martin-Duque P, Quintanilla M, McNeish I, Lopes R, Romero J, Romero D, Lemoine NR, Ramon y Cajal S, Vassaux G International journal of molecular medicine. 2006 ; 17 (5) : 841-847. PMID 16596269
Gout-associated uric acid crystals activate the NALP3 inflammasome. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J Nature. 2006 ; 440 (7081) : 237-241. PMID 16407889
Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A Nature immunology. 2006 ; 7 (6) : 569-575. PMID 16648853
Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Raupach B, Peuschel SK, Monack DM, Zychlinsky A Infection and immunity. 2006 ; 74 (8) : 4922-4926. PMID 16861683
Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE PLoS pathogens. 2006 ; 2 (3) : page e18. PMID 16552444
Caspase-1 builds a new barrier to infection. Saleh M Cell. 2006 ; 126 (6) : 1028-1030. PMID 16990128
Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA Immunity. 2006 ; 24 (3) : 317-327. PMID 16546100
Atlas Genet Cytogenet Oncol Haematol 2008; 4 516 Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis. Thalappilly S, Sadasivam S, Radha V, Swarup G The FEBS journal. 2006 ; 273 (12) : 2766-2778. PMID 16817903
Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, Sagara J, Fernandes-Alnemri T, Alnemri ES Cell death and differentiation. 2006 ; 13 (2) : 236-249. PMID 16037825
The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR Nature immunology. 2006 ; 7 (3) : 318-325. PMID 16444259
Pattern of interleukin-1beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Gattorno M, Tassi S, Carta S, Delfino L, Ferlito F, Pelagatti MA, D'Osualdo A, Buoncompagni A, Alpigiani MG, Alessio M, Martini A, Rubartelli A Arthritis and rheumatism. 2007 ; 56 (9) : 3138-3148. PMID 17763411
Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Gemma C, Bickford PC Reviews in the neurosciences. 2007 ; 18 (2) : 137-148. PMID 17593876
Tumor necrosis factor-alpha-induced caspase-1 gene expression. Role of p73. Jain N, Sudhakar Ch, Swarup G The FEBS journal. 2007 ; 274 (17) : 4396-4407. PMID 17725714
Interaction of HIPPI with putative promoter sequence of caspase-1 in vitro and in vivo. Majumder P, Chattopadhyay B, Sukanya S, Ray T, Banerjee M, Mukhopadhyay D, Bhattacharyya NP Biochemical and biophysical research communications. 2007 ; 353 (1) : 80-85. PMID 17173859
NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Miggin SM, Palsson-McDermott E, Dunne A, Jefferies C, Pinteaux E, Banahan K, Murphy C, Moynagh P, Yamamoto M, Akira S, Rothwell N, Golenbock D, Fitzgerald KA, O'Neill LA Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (9) : 3372-3377. PMID 17360653
Activation of caspase-1 dependent interleukins in developmental brain trauma. Sifringer M, Stefovska V, Endesfelder S, Stahel PF, Genz K, Dzietko M, Ikonomidou C, Felderhoff- Mueser U Neurobiology of disease. 2007 ; 25 (3) : 614-622. PMID 17188500
Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Wickliffe KE, Leppla SH, Moayeri M Cellular microbiology. 2008 ; 10 (2) : 332-343. PMID 17850338
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Atlas Genet Cytogenet Oncol Haematol 2008; 4 517 Last year publications automatic search in PubMed
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Contributor(s) Written 11-2007 Yatender Kumar, Vegesna Radha, Ghanshyam Swarup Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad - 500 007, INDIA Citation This paper should be referenced as such : Kumar Y, Radha V, Swarup G . CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CASP1ID145ch11q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 518 Atlas of Genetics and Cytogenetics in Oncology and Haematology
GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type)
Identity Other names C2GnT-M hC2GnT-M C2GnT2 C2/C4gnT GnT-M mucus type C2GnT HGNC GCNT3 Location 15q21.3 Note GCNT3/C2GnT-M is a single pass type II membrane protein belonging to glycosyltransferase 14 family. DNA/RNA Note Human GCNT3/C2GnT-M is located on chromosome 15 in the region of q21.3, oriented from centromere to telomere.
Schematic representation of Human GCNT3/C2GnT-M gene and transcripts. There are three different sized transcripts. (TIS, Transcription Initiation Site designated as +1; E, Exon; I, Intron; UTR, Untranslated region; ATG, start codon; ORF, Open reading frame). Description Human GCNT3/C2GnT-M gene is approximatively 8.26 kb in size and located in chromosome 15q21.3 at the position of 57,691,415 - 57,699,501. Recently, the GCNT3/C2GnT-M promoter (-417/+187) containing two basal cis-regulatory region (-291/-182 and -62/-43) was identified. The Th2 cytokine and retinoic acid responsive cis-regulatory elements reside in -417/+187 region. Transcription Human GCNT3/C2GnT-M contains three different sized transcripts: 2.3-2.5, 3.6-3.8 and 6.8-7.0 kb. The transcript 1 (approximatively 2.3-2.5kb) is made of 3 exons, exon 1 (69-198 bp), exon 2 (333-401 bp), and exon 3 (1864 bp). Exon 3 contains 59 bp of 5' UTR, 1314 bp of ORF and 491 bp of 3'UTR. It does not contain any introns. Whereas, the intermediate sized transcript (3.6-3.8kb) contains 1.3kb of intron 2 and the large sized transcript (6.8-7.0 kb) contains 4.5kb of intron 1 in addition to all three exons. Exon 1 is heterogeneous in size, which ranges from 69 to 198 bp depending on tissues and cells. Exon 1 is present in all transcripts and has same 3' end but different 5' ends. A 333 bp Exon 2 is identified in most of the mucus secreting tissues and airway epithelial cells while a 401 bp of exon 2 is only detected in A549 cells. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 4 519
The predicted GCNT3/C2GnT-M structure shows a short N-terminal cytoplasmic tail (CT), a transmembrane domain (TM), a stem region and a long catalytic domain at the C-terminal region. Note Human GCNT3/C2GnT-M (EC 2.4.1.102) has 438 amino acids and molecular weight of 50,863 Da. Description GCNT3/C2GnT-M is a type II membrane protein located in the Golgi apparatus. It contains a nine-amino acid peptide tail at the N-terminus located in the cytoplasm, which is followed by a transmembrane domain consisted of 18 amino acids, a stem region, and a catalytic domain located in the Golgi lumen. The protein contains 13 cysteines, including 4 at the N-terminal region, which are conserved among GCNT3/C2GnT-M across species, and 9 at the C-terminal region, which are conserved among all mucin glycan b6GlcNAc branching enzymes. Structural information obtained from bovine GCNT3/C2GnT-M shows that among the 9 conserved cysteines, the second cysteine is unconjugated and the other 8 cysteines form 4 cystine bonds between first and ninth, third and seventh, fourth and fifth, and sixth and eighth. The disulfide bonds formed from the nine conserved cysteines are different between GCNT3/C2GnT-M and C2GnT-L. GCNT3/C2GnT-M contains two potential N- glycosyltaion sites at N-69 and N-289. Expression Human GCNT3/C2GnT-M gene is expressed in mucus-secretory tissues in the following decreasing order of expression: Colon; testis; stomach; small intestine; adrenal gland; kidney; trachea; thyroid gland; Uterus; Ovary; Pancreas; fetal liver; Prostate. Unlike bovine GCNT3/C2GnT-M gene, the type of transcript expressed by hC2GnT-M gene is not tissue specific among the mucus secretory tissues. Expression of GCNT3/C2GnT-M gene is down regulated in colon and colorectal tumors and various colorectal cancer cells. GCNT3/C2GnT-M expression is regulated by various external agent(s). It is inhibited by EGF and enhanced by Th2 cytokines, retinoic acids and sodium butyrate. Localisation Golgi membrane. Function GCNT3/C2GnT-M is responsible for the synthesis of all three branch structures, including core 2, core 4, and I antigen found in the glycans of secreted mucins. These three branch structures are generated by the transfer of GlcNAc from UDP-GlcNAc to core 1, core 3, and I antigen, respectively as shown below. 1. UDP-GlcNAc + Galbeta1-3GalNAca1-S/T gives Galbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP 2. UDP-GlcNAc + GlcNAcbeta1-3GalNAc1a-S/T gives GlcNAcbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP 3. UDP-GlcNAc + GlcNAcbeta1-3Galbeta1-R gives GlcNAcbeta1-3(GlcNAcbeta1-6)Galbeta1-R + UDP(R: sugars) The primary function of secreted mucins is to protect mucus secretory epithelium by retention of water and maintenance of the rheological properties of the mucus, and adherence to airborne and ingested pathogens to facilitate their removal from these tissues. The first two properties depend primarily on the carbohydrate content and this property depends on the heterogeneity of carbohydrate structure. Secreted mucins contain very high carbohydrate content, i.e. 70-90% by weight, and very heterogeneous carbohydrate structure, e.g. up to 100 different oligosaccharides in mucins isolated from a single donor. The three b6GlcNAc branch structures found in the secreted mucins are responsible for the increase of carbohydrate content and structural complexity. Decrease of GCNT3/C2GnT-M in the secretory epithelium can result in dehydration of the mucus and compromise of bacterial clearance. Homology Human GCNT3/C2GnT-M shows a very high level of similarity to other non-human GCNT3/C2GnT-M: bovine (83%), rat (78%) and mouse (77%). Further, it shows moderate level of (48% and 38%) similarity to human C2GnT-L and C2GnT-T, respectively. Implicated in Entity Colorectal cancer Note GCNT3/C2GnT-M enzyme is down regulated in colon and colorectal tumors and most
Atlas Genet Cytogenet Oncol Haematol 2008; 4 520 cancerous cells derived from mucus-secretory tissues. Re-expression of GCNT3/C2GnT-M suppresses tumor growth in the xenografts of nude mice. Disease Colorectal cancer is the 3rd most common form of cancer and the 2nd leading cause of cancer-related death among men and women in the Western world. It causes 655,000 deaths worldwide per year. The survival rate of colorectal cancer is not much higher than 50% even if the disease is diagnosed at an early stage. Colorectal cancer is mostly formed from adenomatous polyps. These polyps can be detected and removed during colonoscopy, which would decrease cancer death by greater than 80%. Metastasis of cancer cells through bowel wall of the colon to lymph nodes is very common. If metastasis is detected, 5 year survival rate is less than 10%. Prognosis Recent reports suggest that deficiency or down regulation of human GCNT3/C2GnT-M expression is associated with development of colitis and colorectal cancer. This enzyme may be used as a prognostic marker for colorectal cancer. Oncogenesis GCNT3/C2GnT-M expression is down regulated in colorectal cancers. Down regulation of GCNT3/C2GnT-M would lead to the production of secreted mucins with lower carbohydrate content and less heterogeneous carbohydrate, which would compromise the protective function of these mucins. As a result, bacteria can not be cleared effectively, which causes irritation of the epithelium and chronic inflammation, and eventually cancer. Its re-expression suppresses tumor cell spreading, adhesion, motility, and invasion. It also inhibits cell growth and colony-forming ability, and induces apoptotic cell death. In addition, expression of C2GnT-M suppresses tumor growth in the xenografts of nude mice. The results suggest that GCNT3/C2GnT-M is important in protecting the normal functional architecture of colon epithelial cells. External links Nomenclature HGNC GCNT3 4205 Entrez_Gene GCNT3 9245 glucosaminyl (N-acetyl) transferase 3, mucin type Cards Atlas GCNT3ID44105ch15q21 GeneCards GCNT3 Ensembl GCNT3 [Search_View] ENSG00000140297 [Gene_View] Genatlas GCNT3 GeneLynx GCNT3 eGenome GCNT3 euGene 9245 Genomic and cartography GCNT3 - 15q21.3 chr15:57696080-57699494 + 15q21.3 [Description] (hg18- GoldenPath Mar_2006) Ensembl GCNT3 - 15q21.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene GCNT3 Gene and transcription Genbank AF038650 [ ENTREZ ] Genbank AF102542 [ ENTREZ ] Genbank AK312852 [ ENTREZ ] Genbank BC017032 [ ENTREZ ] Genbank EF152283 [ ENTREZ ] RefSeq NM_004751 [ SRS ] NM_004751 [ ENTREZ ] RefSeq AC_000058 [ SRS ] AC_000058 [ ENTREZ ] RefSeq AC_000147 [ SRS ] AC_000147 [ ENTREZ ] RefSeq NC_000015 [ SRS ] NC_000015 [ ENTREZ ] RefSeq NT_010194 [ SRS ] NT_010194 [ ENTREZ ] RefSeq NW_001838218 [ SRS ] NW_001838218 [ ENTREZ ] RefSeq NW_925884 [ SRS ] NW_925884 [ ENTREZ ] AceView GCNT3 AceView - NCBI
Atlas Genet Cytogenet Oncol Haematol 2008; 4 521 Unigene Hs.194710 [ SRS ] Hs.194710 [ NCBI ] HS194710 [ spliceNest ] Fast-db 6061 (alternative variants) Protein : pattern, domain, 3D structure O95395 [ SRS] O95395 [ EXPASY ] O95395 [ INTERPRO ] O95395 SwissProt [ UNIPROT ] Interpro IPR003406 Glyco_trans_14 [ SRS ] IPR003406 Glyco_trans_14 [ EBI ] CluSTr O95395 Pfam PF02485 Branch [ SRS ] PF02485 Branch [ Sanger ] pfam02485 [ NCBI-CDD ] Blocks O95395 HPRD 06018 Protein Interaction databases DIP O95395 IntAct O95395 Polymorphism : SNP, mutations, diseases OMIM 606836 [ map ] GENECLINICS 606836 SNP GCNT3 [dbSNP-NCBI] SNP NM_004751 [SNP-NCI] SNP GCNT3 [GeneSNPs - Utah] GCNT3] [HGBASE - SRS] HAPMAP GCNT3 [HAPMAP] HGMD GCNT3 General knowledge Family Browser GCNT3 [UCSC Family Browser] SOURCE NM_004751 SMD Hs.194710 SAGE Hs.194710 2.4.1.102 [ Enzyme-Expasy ] 2.4.1.102 [ Enzyme-SRS ] 2.4.1.102 [ IntEnz- Enzyme EBI ] 2.4.1.102 [ BRENDA ] 2.4.1.102 [ KEGG ] 2.4.1.102 [ WIT ] GO Golgi membrane [Amigo] Golgi membrane beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase GO activity [Amigo] beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N- acetylglucosaminyltransferase activity GO membrane fraction [Amigo] membrane fraction GO Golgi apparatus [Amigo] Golgi apparatus GO carbohydrate metabolic process [Amigo] carbohydrate metabolic process protein amino acid O-linked glycosylation [Amigo] protein amino acid O-linked GO glycosylation N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase activity [Amigo] N- GO acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase activity GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane transferase activity, transferring glycosyl groups [Amigo] transferase activity, GO transferring glycosyl groups PubGene GCNT3 TreeFam GCNT3 CTD 9245 [Comparative ToxicoGenomics Database] Other databases Probes Probe GCNT3 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Control of O-glycan branch formation. Molecular cloning of human cDNA encoding a novel beta1,6-N-acetylglucosaminyltransferase forming core 2 and core 4. Schwientek T, Nomoto M, Levery SB, Merkx G, van Kessel AG, Bennett EP, Hollingsworth MA,
Atlas Genet Cytogenet Oncol Haematol 2008; 4 522 Clausen H The Journal of biological chemistry. 1999 ; 274 (8) : 4504-4512. PMID 9988682
Molecular cloning and expression of a novel beta-1, 6-N-acetylglucosaminyltransferase that forms core 2, core 4, and I branches. Yeh JC, Ong E, Fukuda M The Journal of biological chemistry. 1999 ; 274 (5) : 3215-3221. PMID 9915862
Biosynthesis and function of beta 1,6 branched mucin-type glycans. Beum PV, Cheng PW Advances in experimental medicine and biology. 2001 ; 491 : 279-312. PMID 14533804
Mucin biosynthesis: epidermal growth factor downregulates core 2 enzymes in a human airway adenocarcinoma cell line. Beum PV, Bastola DR, Cheng PW American journal of respiratory cell and molecular biology. 2003 ; 29 (1) : 48-56. PMID 12600830
Identification of disulfide bonds among the nine core 2 N-acetylglucosaminyltransferase-M cysteines conserved in the mucin beta6-N-acetylglucosaminyltransferase family. Singh J, Khan GA, Kinarsky L, Cheng H, Wilken J, Choi KH, Bedows E, Sherman S, Cheng PW The Journal of biological chemistry. 2004 ; 279 (37) : 38969-38977. PMID 15226299
Mucin biosynthesis: upregulation of core 2 beta 1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line. Beum PV, Basma H, Bastola DR, Cheng PW American journal of physiology. Lung cellular and molecular physiology. 2005 ; 288 (1) : L116-L124. PMID 15591039
Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. Ishibashi Y, Inouye Y, Okano T, Taniguchi A Glycoconjugate journal. 2005 ; 22 (1-2) : 53-62. PMID 15864435
C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells. Huang MC, Chen HY, Huang HC, Huang J, Liang JT, Shen TL, Lin NY, Ho CC, Cho IM, Hsu SM Oncogene. 2006 ; 25 (23) : 3267-3276. PMID 16418723
Mucin biosynthesis: molecular cloning and expression of mouse mucus-type core 2 beta1,6 N- acetylglucosaminyltransferase. Hashimoto M, Tan S, Mori N, Cheng H, Cheng PW Glycobiology. 2007 ; 17 (9) : 994-1006. PMID 17591617
Butyrate induces sLex synthesis by stimulation of selective glycosyltransferase genes. Radhakrishnan P, Beum PV, Tan S, Cheng PW Biochemical and biophysical research communications. 2007 ; 359 (3) : 457-462. PMID 17553459
Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene. Tan S, Cheng PW American journal of respiratory cell and molecular biology. 2007 ; 36 (6) : 737-745. PMID 17303715
Atlas Genet Cytogenet Oncol Haematol 2008; 4 523
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Contributor(s) Written 11-2007 Prakash Radhakrishnan, Pi-Wan Cheng Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA Citation This paper should be referenced as such : Radhakrishnan P, Cheng PW . GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/GCNT3ID44105ch15q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 524 Atlas of Genetics and Cytogenetics in Oncology and Haematology
HYAL2 (Hyaluronoglucosaminidase 2)
Identity Other names LuCa-2 LUCA2 HGNC HYAL2 Location 3p21.3 Local_order Telomeric to TUSC2 and centromeric to HAYL1. Note HYAL2 was identified in an EST database search of PH-20 hyaluronidase related sequences. HYAL2 appears to be an inactive hyaluronidase. Characterization of HYAL2 mostly focuses on its role as the cell entry receptor of Jaagsiekte sheep retrovirus (JSRV), and the putative function as a tumor suppressor gene, based on its specific chromosomal location. DNA/RNA
Two alternatively spliced variants (NM_033158.2 and NM_003773.2) of HYAL2 are shown. Both of them contain four exons. Black boxes represent the coding exons of HYAL2. White boxes represent untranslated regions. Description The HYAL2 gene contains 4 exons, spanning 4.99 kb. Transcription The gene encodes two alternatively spliced transcripts (NM_033158 and NM_003773) which differ only in the 5' UTR. Distinct noncoding exon 1 was found in these two transcripts. Both variants encode the same protein. The ORF size is 1422 bp. Pseudogene No known pseudogenes. Protein
The HYAL2 protein contains a N-terminal signal peptide (1-20) and a epidermal growth factor (EGF)-like domain (365-469). Description The 473 amino-acid peptide encodes the HYAL2 protein with a predicted molecular weight of 53.9 KDa. The protein is comprised of a N-terminal signal peptide (amino acids 1-20) and a epidermal growth factor ( EGF )-like domain at amino acids 365-469 (by SMART prediction). Expression High level of HYAL2 expression was detected in most tissues, including liver, kidney, lung and heart. Expression was low or absent in brain. Localisation Originally shown to be lysosomal but subsequently proved to be a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. Function Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix (ECM). The level of hyaluronan is regulated by a balance between hyaluronan synthase and HYAL enzyme activities. Hyaluronan is suggested to be
Atlas Genet Cytogenet Oncol Haematol 2008; 4 525 involved in embryonic development, cell proliferation, migration and wound healing. Although originally supposed to be active at pH 4.0, HYAL2 actually displayed minimal to undetectable hyaluronidase activity in subsequent studies. The hyaluronidase activity of HYAL2 remains controversial. Homology HYAL2 belongs to a family of hyaluronoglucosaminidases. Other members include HYAL1, HYAL3, HYAL4 and Spam1. Mutations Note No germline or somatic mutation is reported. Implicated in Entity Possible in lung cancer and breast cancer. Note HYAL2 is located within a 120-kb minimal deletion region at 3p21.3. a chromosomal segment known to harbor multiple candidate tumor suppressor genes in breast and lung cancers. Nevertheless, HYAL2 does not possess tumor suppressor function, as evident by in vitro and in vivo studies in lung cancer models. HYAL2 serves as the cellular receptor that mediates entry of the Jaagsiekte sheep retrovirus (JSRV), and its receptor function is independent on its catalytic activity. The JSRV envelope (Env) protein is believed to be the active oncogene. The viral Env transforms epithelial cells through activation of RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor ( MST1R ), and followed by activating PI3K/Akt signaling cascade and MAPK signaling cascade. HYAL2 physically interacts and negatively regulates RON. JSRV infects the epithelial cells of the lower airway of sheep and goats, resulting in ovine pulmonary adenocarinoma, sharing features with human bronchioloalveolar carcinoma. Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer. Disease Lung cancer; bronchioloalveolar carcinoma; non-Hodgkin lymphoma ; breast cancer. Prognosis Increased level of HYAL2 deletions in sputum of Stage I non-small-cell lung cancer patients was associated with pack-years of smoking, but independent on patients' age, gender, histologic tumor type and tumor size and location. HYAL2 mRNA expression was inversely correlated with lymphoma aggressiveness. Oncogenesis HYAL2 mRNA expression was lost in lung cancer cell lines. However, expression of HYAL2 was retained in esophageal squamous carcinoma and nasopharyngeal carcinoma cell lines. Highly invasive breast cancer cell lines preferentially express HYAL2. Systemic administration of protamine-complexed vectors expressing HYAL2 inhibited lung metastatic foci in nu/nu mice. Intratumoral injection of same construct failed to suppress primary tumor growth or induce apoptosis, suggesting HYAL2 may function at the level of metastasis. External links Nomenclature HGNC HYAL2 5321 Entrez_Gene HYAL2 8692 hyaluronoglucosaminidase 2 Cards Atlas HYAL2ID40904ch3p21 GeneCards HYAL2 Ensembl HYAL2 [Search_View] ENSG00000068001 [Gene_View] Genatlas HYAL2 GeneLynx HYAL2 eGenome HYAL2 euGene 8692 Genomic and cartography HYAL2 - 3p21.3 chr3:50330244-50335146 - 3p21.3 [Description] (hg18- GoldenPath Mar_2006) Ensembl HYAL2 - 3p21.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 526 HomoloGene HYAL2 Gene and transcription Genbank AF070608 [ ENTREZ ] Genbank AJ000099 [ ENTREZ ] Genbank AJ844619 [ ENTREZ ] Genbank AK092449 [ ENTREZ ] Genbank AK127945 [ ENTREZ ] RefSeq NM_003773 [ SRS ] NM_003773 [ ENTREZ ] RefSeq NM_033158 [ SRS ] NM_033158 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq AC_000135 [ SRS ] AC_000135 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_001838877 [ SRS ] NW_001838877 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView HYAL2 AceView - NCBI Unigene Hs.76873 [ SRS ] Hs.76873 [ NCBI ] HS76873 [ spliceNest ] Fast-db 7166 (alternative variants) Protein : pattern, domain, 3D structure Q12891 [ SRS] Q12891 [ EXPASY ] Q12891 [ INTERPRO ] Q12891 SwissProt [ UNIPROT ] 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 ] Interpro IPR013785 Aldolase_TIM [ SRS ] IPR013785 Aldolase_TIM [ EBI ] Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR001968 Glyco_hydro_56 [ SRS ] IPR001968 Glyco_hydro_56 [ EBI ] IPR017430 Glyco_hydro_56_Hyaluronidase [ SRS ] IPR017430 Interpro Glyco_hydro_56_Hyaluronidase [ EBI ] CluSTr Q12891 PF01630 Glyco_hydro_56 [ SRS ] PF01630 Glyco_hydro_56 Pfam [ Sanger ] pfam01630 [ NCBI-CDD ] Smart SM00181 EGF [EMBL] Prodom PD003549 Glyco_hydro_56[INRA-Toulouse] Q12891 HYAL2_HUMAN [ Domain structure ] Q12891 HYAL2_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q12891 HPRD 04649 Protein Interaction databases DIP Q12891 IntAct Q12891 Polymorphism : SNP, mutations, diseases OMIM 603551 [ map ] GENECLINICS 603551 SNP HYAL2 [dbSNP-NCBI] SNP NM_003773 [SNP-NCI] SNP NM_033158 [SNP-NCI] SNP HYAL2 [GeneSNPs - Utah] HYAL2] [HGBASE - SRS] HAPMAP HYAL2 [HAPMAP] HGMD HYAL2 General knowledge Family Browser HYAL2 [UCSC Family Browser]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 527 SOURCE NM_003773 SOURCE NM_033158 SMD Hs.76873 SAGE Hs.76873 3.2.1.35 [ Enzyme-Expasy ] 3.2.1.35 [ Enzyme-SRS ] 3.2.1.35 [ IntEnz- Enzyme EBI ] 3.2.1.35 [ BRENDA ] 3.2.1.35 [ KEGG ] 3.2.1.35 [ WIT ] GO hyalurononglucosaminidase activity [Amigo] hyalurononglucosaminidase activity GO receptor activity [Amigo] receptor activity GO protein binding [Amigo] protein binding GO lysosome [Amigo] lysosome GO plasma membrane [Amigo] plasma membrane GO carbohydrate metabolic process [Amigo] carbohydrate metabolic process GO metabolic process [Amigo] metabolic process hydrolase activity, acting on glycosyl bonds [Amigo] hydrolase activity, acting on GO glycosyl bonds GO hyaluronan catabolic process [Amigo] hyaluronan catabolic process GO anchored to membrane [Amigo] anchored to membrane KEGG Glycosaminoglycan degradation KEGG Glycan structures - degradation PubGene HYAL2 TreeFam HYAL2 CTD 8692 [Comparative ToxicoGenomics Database] Other databases Probes Probe HYAL2 Related clones (RZPD - Berlin) PubMed PubMed 24 Pubmed reference(s) in LocusLink Bibliography HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. Lepperdinger G, Strobl B, Kreil G The Journal of biological chemistry. 1998 ; 273 (35) : 22466-22470. PMID 9712871
Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI, Minna JD Oncogene. 1998 ; 16 (24) : 3151-3157. PMID 9671394
Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell- surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI, Miller AD Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (8) : 4443-4448. PMID 11296287
Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD Cancer research. 2002 ; 62 (9) : 2715-2720. PMID 11980673
Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates
Atlas Genet Cytogenet Oncol Haematol 2008; 4 528 transformation of epithelial cells by jaagsiekte sheep retrovirus. Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, Lerman MI Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (8) : 4580-4585. PMID 12676986
RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP International journal of cancer. Journal international du cancer. 2004 ; 109 (6) : 839-847. PMID 15027117
Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness. Bertrand P, Courel MN, Maingonnat C, Jardin F, Tilly H, Bastard C International journal of cancer. Journal international du cancer. 2005 ; 113 (2) : 207-212. PMID 15386412
The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. Udabage L, Brownlee GR, Nilsson SK, Brown TJ Experimental cell research. 2005 ; 310 (1) : 205-217. PMID 16125700
Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer. Li R, Todd NW, Qiu Q, Fan T, Zhao RY, Rodgers WH, Fang HB, Katz RL, Stass SA, Jiang F Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 ; 13 (2 Pt 1) : 482-487. PMID 17255269
Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus. Vigdorovich V, Miller AD, Strong RK Journal of virology. 2007 ; 81 (7) : 3124-3129. PMID 17229709
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Contributor(s) Written 11-2007 Lillian SN Chow, Kwok-Wai Lo Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology, and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China Citation This paper should be referenced as such : Chow LSN, Lo KW . HYAL2 (Hyaluronoglucosaminidase 2). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HYAL2ID40904ch3p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 529 Atlas of Genetics and Cytogenetics in Oncology and Haematology
LMO2 (LIM domain only 2 (rhombotin-like 1))
Identity Other names RBTN2 (rhombotin-2) RHOM2 RBTNL1 (rhombotin-like-1) TTG2 (T-cell translocation gene 2) LMO2 (LIM domain only 2) HGNC LMO2 Location 11p13 telomere LMO1 - NUP98 (11p15) - CD59 - FSHB - LMO2 - PAX6 - PDHX (11p13) Local_order centromere. DNA/RNA Description LMO2 belongs to a multigene family, extremely well conserved during evolution, encoding proteins containing two cystein-rich regions referred to as LIM domains: LMO1 (11p15), LMO2 (11p13), LMO3 (12p); 6 exons. Transcription 3 transcripts: LMO2-a and LMO2-b encode the same 158-amino-acid protein; LMO2-c encodes a 151-amino-acid protein. Protein Description Small cystein rich protein with two tandemly arranged Zinc binding LIM domain motifs: named Lom2; 158 amino acids; 18 kDa; 48 % amino-acid identity with LMO1 protein. LMO2 contains two transcription activating domains (one in N-term, in a prolin-rich 19 amino acid region, one in C-term) and two LIM domains as transcription repressing domains, selectively inhibiting the N-term activation domain (no effect on the C-term domain). Expression Early expressed during development, in all tissues (roughly consistent level in central nervous system, low level in thymus). Strongly expressed in the precursors of mixed erythrocyte/macrophage/mast, erythrocyte, megakaryocyte, neutrophil and macrophage colonies, undetectable in the mature progeny. Expressed in early B-cells, in leukemias of both the myeloid and lymphoid lineages. Nuclear marker in normal germinal center B-cells. Also expressed in endothelial cells. High expression in the brain; expressed in the hippocampus during development. Localisation Nuclear. Function Hematopoiesis: LMO2 directly interacts with the basic-loop-helix protein TAL1/SCL and the GATA DNA protein GATA1. They form a transcriptional complex: LMO2 has no direct evidence in DNA binding capacity but could act as a bridging molecule bringing together different DNA binding factors (TAL1, LDB1, E12/E47, GATA1) that are essential for hematopoiesis (e.g. in the erythroid complex). This interaction is critical for the regulation of red blood cell development in early stages of hematopoiesis. TAL1 interacts specifically with the LIM domains of LMO2, which in turn binds LDB1. Because LMO2 can also bind to GATA2, a complex LMO2-GATA2 might occur at earlier stages of hematopoiesis when Gata1 is not expressed. Lmo2 has a central role in adult hematopoietic pathway regulation, on bone marrow pluripotential precursor stem cell mainly. LMO2 and TAL1 are able to partially suppress myeloid differentiation. LMO2 also interacts with retinoblastoma-binding protein 2 and elf-2 (ets transcription factor). LMO2-c expression is regulated by GATA1 and PU.1; LMO2-c acts as an antagonist of LMO2-a/b, therefore blocking the transactivation of LMO2-a/b. In the brain, hBEX2, LMO2, NSCL2 and LDB1 could form a similar complex. Implicated in Entity t(11;14)(p13;q11)/T- cell leukaemia --> LMO2 - TCRD-A Disease Childhood T-cell ALL ; found in 5-10% of T-cell ALL.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 530 Cytogenetics A variant translocation t(7;11)(q35;p13) has been described. Abnormal It was previously believed that LMO2 is activated after chromosomal translocation by Protein association either the T-cell receptor a / T-cell receptor d (14q11) or T-cell receptor b gene (7q35). Chromosome breakpoints occur 25 kb upstream LMO2 gene, in a presumed transcriptional start site, inducing truncation of the promoter/control region and leading to inappropriate Lmo2 level especially in T-cells (abnormal T-cell differentiation). However, it becomes now very likely that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD enhancer, is the main determinant for LMO2 activation in the majority of t(11;14) (p13;q11) translocations. Entity del(11)(p12p13) T-cell leukaemia Disease Childhood T-cell ALL; found in about 5% of T-cell ALL. Cytogenetics Cryptic deletion that varies in size. Abnormal LMO2 is activated through a cryptic intrachromosomal deletion, del(11)(p12p13), in Protein which a negative regulatory element (NRE), situated upstream of the LMO2 gene, is deleted. Removal of this NRE causes activation of the proximal promoter of the LMO2 gene leading to its ectopic expression. Entity Germinal center B-cell lymphomas Disease Diffuse large-B-cell lymphomas, follicular lymphomas, Burkitt lymphomas, less often in other haematological malignancies. Prognosis LMO2 expression, together with BCL6, FN1, CCND2, SCYA3, and BCL2 expressions, is a predictor of outcome in diffuse large-B-cell lymphoma. Entity Prostate cancer Note Expression of LMO2 is higher in prostate tumours samples than in the normal epithelium. Moreover, overexpression of LMO2 is significantly associated with advanced tumour stage, as well as with the development of distant metastasis. Oncogenesis LMO2 may play an important role in prostate cancer progression, possibly via repression of E-cadherin expression. External links Nomenclature HGNC LMO2 6642 Entrez_Gene LMO2 4005 LIM domain only 2 (rhombotin-like 1) Cards Atlas RBTN2ID34 GeneCards LMO2 Ensembl LMO2 [Search_View] ENSG00000135363 [Gene_View] Genatlas LMO2 GeneLynx LMO2 eGenome LMO2 euGene 4005 Genomic and cartography LMO2 - 11p13 chr11:33836699-33870412 - 11p13 [Description] (hg18- GoldenPath Mar_2006) Ensembl LMO2 - 11p13 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene LMO2 Gene and transcription Genbank AF257211 [ ENTREZ ] Genbank BC034041 [ ENTREZ ] Genbank BC035607 [ ENTREZ ] Genbank BC042426 [ ENTREZ ] Genbank BC073973 [ ENTREZ ] RefSeq NM_005574 [ SRS ] NM_005574 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 531 RefSeq AC_000143 [ SRS ] AC_000143 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_009237 [ SRS ] NT_009237 [ ENTREZ ] RefSeq NW_001838022 [ SRS ] NW_001838022 [ ENTREZ ] RefSeq NW_925006 [ SRS ] NW_925006 [ ENTREZ ] AceView LMO2 AceView - NCBI Unigene Hs.34560 [ SRS ] Hs.34560 [ NCBI ] HS34560 [ spliceNest ] Fast-db 4806 (alternative variants) Protein : pattern, domain, 3D structure P25791 [ SRS] P25791 [ EXPASY ] P25791 [ INTERPRO ] P25791 SwissProt [ UNIPROT ] Prosite PS00478 LIM_DOMAIN_1 [ SRS ] PS00478 LIM_DOMAIN_1 [ Expasy ] Prosite PS50023 LIM_DOMAIN_2 [ SRS ] PS50023 LIM_DOMAIN_2 [ Expasy ] Interpro IPR001781 Znf_LIM [ SRS ] IPR001781 Znf_LIM [ EBI ] CluSTr P25791 Pfam PF00412 LIM [ SRS ] PF00412 LIM [ Sanger ] pfam00412 [ NCBI-CDD ] Smart SM00132 LIM [EMBL] Prodom PD000094 LIM[INRA-Toulouse] P25791 RBTN2_HUMAN [ Domain structure ] P25791 RBTN2_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P25791 HPRD 01586 Protein Interaction databases DIP P25791 IntAct P25791 Polymorphism : SNP, mutations, diseases OMIM 180385 [ map ] GENECLINICS 180385 SNP LMO2 [dbSNP-NCBI] SNP NM_005574 [SNP-NCI] SNP LMO2 [GeneSNPs - Utah] LMO2] [HGBASE - SRS] HAPMAP LMO2 [HAPMAP] TICdb LMO2 [Translocation breakpoints In Cancer] HGMD LMO2 General knowledge Family Browser LMO2 [UCSC Family Browser] SOURCE NM_005574 SMD Hs.34560 SAGE Hs.34560 GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO multicellular organismal development [Amigo] multicellular organismal development GO zinc ion binding [Amigo] zinc ion binding GO metal ion binding [Amigo] metal ion binding PubGene LMO2 TreeFam LMO2 CTD 4005 [Comparative ToxicoGenomics Database] Other databases Probes Probe LMO2 Related clones (RZPD - Berlin) PubMed PubMed 40 Pubmed reference(s) in LocusLink Bibliography The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved
Atlas Genet Cytogenet Oncol Haematol 2008; 4 532 in T-cell translocations to human chromosomes 11p15 and 11p13. Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (10) : 4367-4371. PMID 2034676
TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Royer-Pokora B, Loos U, Ludwig WD Oncogene. 1991 ; 6 (10) : 1887-1893. PMID 1923511
Expression of rhombotin 2 in normal and leukaemic haemopoietic cells. Dong WF, Billia F, Atkins HL, Iscove NN, Minden MD British journal of haematology. 1996 ; 93 (2) : 280-286. PMID 8639417
The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH The EMBO journal. 1997 ; 16 (11) : 3145-3157. PMID 9214632
The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (7) : 3890-3895. PMID 9520463
Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. Anguita E, Hughes J, Heyworth C, Blobel GA, Wood WG, Higgs DR The EMBO journal. 2004 ; 23 (14) : 2841-2852. PMID 15215894
Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, Levy R The New England journal of medicine. 2004 ; 350 (18) : 1828-1837. PMID 15115829
Negative regulatory elements are present in the human LMO2 oncogene and may contribute to its expression in leukemia. Hammond SM, Crable SC, Anderson KP Leukemia research. 2005 ; 29 (1) : 89-97. PMID 15541480
Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA- binding complex. Han C, Liu H, Liu J, Yin K, Xie Y, Shen X, Wang Y, Yuan J, Qiang B, Liu YJ, Peng X Nucleic acids research. 2005 ; 33 (20) : 6555-6565. PMID 16314316
The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J, Passier M, van Wering ER, Veerman AJ, Kamps WA, Meijerink JP, Pieters R Blood. 2006 ; 108 (10) : 3520-3529. PMID 16873670
Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 533 Dik WA, Nadel B, Przybylski GK, Asnafi V, Grabarczyk P, Navarro JM, Verhaaf B, Schmidt CA, Macintyre EA, van Dongen JJ, Langerak AW Blood. 2007 ; 110 (1) : 388-392. PMID 17360939
The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation. Hansson A, Zetterblad J, van Duren C, Axelson H, Jonsson JI Biochemical and biophysical research communications. 2007 ; 364 (3) : 675-681. PMID 17964543
Protein stability and transcription factor complex assembly determined by the SCL-LMO2 interaction. Lecuyer E, Lariviere S, Sincennes MC, Haman A, Lahlil R, Todorova M, Tremblay M, Wilkes BC, Hoang T The Journal of biological chemistry. 2007 ; 282 (46) : 33649-33658. PMID 17878155
The significance of LMO2 expression in the progression of prostate cancer. Ma S, Guan XY, Beh PS, Wong KY, Chan YP, Yuen HF, Vielkind J, Chan KW The Journal of pathology. 2007 ; 211 (3) : 278-285. PMID 17167821
The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. Natkunam Y, Zhao S, Mason DY, Chen J, Taidi B, Jones M, Hammer AS, Hamilton Dutoit S, Lossos IS, Levy R Blood. 2007 ; 109 (4) : 1636-1642. PMID 17038524
A novel transcript of the LMO2 gene, LMO2-c, is regulated by GATA-1 and PU.1 and encodes an antagonist of LMO2. Wang Q, Zhang M, Wang X, Yuan W, Chen D, Royer-Pokora B, Zhu T Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2007 ; 21 (5) : 1015-1025. PMID 17361224
A highly conserved regulatory element controls hematopoietic expression of GATA-2 in zebrafish. Yang Z, Jiang H, Zhao F, Shankar DB, Sakamoto KM, Zhang MQ, Lin S BMC developmental biology. 2007 ; 7 : page 97. PMID 17708765
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Contributor(s) Written 06-1998 Chrysthèle Bilhou-Nabera Cytogenetique, Laboratoire d'Hematologie-Pr Raphael, Pav Broca - 4eme étage, 78 rue du General Leclerc, 94275 Le Kremlin-Bicetre, France Updated 11-2007 Pieter Van Vlierberghe, Jean Loup Huret ErasmusMC/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands (PVV); Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Citation This paper should be referenced as such : Bilhou-Nabera C . LMO2 (LIM domain only 2 (rhombotin-like 1)). Atlas Genet Cytogenet Oncol Haematol. June 1998 .
Atlas Genet Cytogenet Oncol Haematol 2008; 4 534 URL : http://AtlasGeneticsOncology.org/Genes/RBTN2ID34.html Van Vlierberghe P, Huret JL . LMO2 (LIM domain only 2 (rhombotin-like 1)). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RBTN2ID34.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 535 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PEBP1 (phosphatidylethanolamine binding protein 1)
Identity Other names HCNP HCNPpp PBP PEBP PEBP-1 RKIP HGNC PEBP1 Location 12q24.23 DNA/RNA
Diagram of the RKIP gene. Exons are depicted as filled boxes and untranslated regions are unfilled boxes. Introns are represented as lines between exons. Intron, exon, and untranslated region sizes are described in base pairs. Description The gene is composed of 4 exons spanning a region of 9,520 base pairs. Transcription The mRNA contains 1507 nucleotides. Alternative splicing has not been described. In prostate cancer cell lines RKIP transcription is repressed by Snail through an E-box in its promoter. Promoter methylation does not seem to cause loss of RKIP expression. Pseudogene RKIP has two putative pseudogenes located on chromosomes 2 and 14. These are intronless sequences with no verified expression to date. Protein
Stereo view of the human RKIP structure prepared with Pymol (Delano, 2002). Pocket residues H86 (left), H118 (right), D70 (top) and Y120 (bottom) are indicated. Note RKIP belongs to a highly conserved family of phospholipid-binding proteins, which have been recognized and studied for several years as PEBP. These proteins are represented in eukaryotes, bacteria, and archae. One of the interesting properties of some PEBP family members is that they are cleaved at the N-terminus to release an undecapeptide which has been named hippocampal cholinergic neurostimulating peptide (HCNP). Description RKIP is an 187 amino acid protein with a molecular mass of 21-23 kDa. The crystal structures of human, bovine and plant PEBPs are solved revealing no homologies to domains of known functions. The structure of RKIP features a b-fold formed by two anti-parallel b-sheets, a small C-terminal aba element, and a cavity at the surface, which could accommodate a small anion such as a phosphoryl group (see diagram
Atlas Genet Cytogenet Oncol Haematol 2008; 4 536 above). Amino acids forming this cavity are conserved among all PEBP family members and constitute the PEB motif. Expression RKIP and its mammalian homologs are widely expressed in tissues; it has been detected in lung, oviduct and ovary, mammary glands, uterus, prostate epithelium, thyroid, mesenteric lymph node, megakaryocytes of the heart; spleen, liver, and epididymis, testis, spermatids, Leydig cells, steroidogenic cells of the adrenal gland zona fasiculata, small intestine, plasma cells, and neural cells such as brain oliodendricytes, Schwann cells, and Pukinje cells. Localisation RKIP is localized in the cytoplasm and at the plasma membrane. Function RKIP inhibits the Raf/MEK/ERK cascade. Identified as a Raf-1 interacting protein in a yeast two-hybrid screen, RKIP was found to inhibit phosphorylation and activation of MEK by Raf-1. RKIP inhibits the phosphorylation of the N-region of Raf-1 by (21- activated kinase) Pak and Src family kinases thereby inhibiting activation of Raf-1. PKC phosphorylation of RKIP following GPCR stimulation causes its release from Raf-1. Classical and atypical PKCs can phosphorylate RKIP at serine 153 causing dissociation of the Raf-1 kinase domain and RKIP, indicating that PKC can mediate ERK activation through RKIP. Once free from Raf-1, RKIP was shown to bind GRK-2 and block its activity, promoting and enhancing G protein signaling and MEK/ERK signaling. RKIP appears to support macrophage differentiation via inhibition of the NFKB pathway. RKIP inhibits the NF-kappaB pathway through interaction with NIK, TAK1, and IKK. RKIP was a novel effector of apoptosis signaling; this may occur by modulation of the NF-kappaB pathway and/or the regulation of the spindle checkpoint via Aurora B kinase and the spindle checkpoint by RKIP. RKIP regulation of Aurora kinase B and the spindle checkpoint through Raf-1/MEK/ERK signaling influences cell cycle fidelity. RKIP has serine protease activity. Purified RKIP was found to inhibit the serine proteases thrombin, chymotrypsin, and neuropsin. HCNP, the N-terminal fragment of RKIP, may play a role in phospholipid organization of the myelin sheath and septal cholinergic development of the hippocampus. HCNP can act on frog cardiac mechanical performance, exerting a negative inotropism. Results of these experiments suggest that RKIP/HCNP may be a new endocrine factor that regulates cardiac physiology. RKIP downregulation may be associated with the congenital heart disease manifested in Down syndrome. RKIP downregulation was found in the rat right ventricle and in the interventricular septum upon cardiac remodeling. RKIP has been found in the male reproductive tract with implications in the organization of sperm membranes during spermiogenesis. It has been identified as a decapacitation factor in mouse spermatozoa. RKIP and other proteins inhibited progesterone-induced acrosome reaction and zona pellucida binding of sperm. Homology No significant sequence homology to other proteins. Humans have two known family members, RKIP and PEBP4. RKIP has high sequence identity to mouse, rat, bovine, and monkey phosphatidylethanolamine binding proteins. Implicated in Entity Breast cancer Oncogenesis Immunohistochemical examination of breast cancer lymph node metastases showed significant loss of RKIP protein expression compared to normal breast duct epithelia and primary tumors. There was a weak negative correlation between RKIP expression and apoptosis in breast tumors that did not have associated lymph node metastases. Low levels of RKIP may allow cancer cells to evade apoptosis. Breast cancer cell lines expressing low levels of RKIP undergo apoptosis following ectopic RKIP addition or Taxol treatment, which induced RKIP expression. Entity Prostate cancer Prognosis Decreased protein expression of RKIP may be a prognostic marker in prostate cancer, with low RKIP levels indicating early PSA failure. Oncogenesis Low levels of RKIP may protect cancer cells against apoptosis. Tumorgenic prostate cancer cell lines expressing low levels of RKIP increase their RKIP expression following treatment with a chemotherapeutic drug, sensitizing the cells to apoptosis. Cell lines with higher RKIP expression can be made resistant to apoptosis when RKIP is knocked
Atlas Genet Cytogenet Oncol Haematol 2008; 4 537 down. RKIP is downregulated in prostate cancer progression and metastasis. Modulation of RKIP expression in prostate cancer cell lines changes invasive ability in vitro as well as development of metastases in vivo, with loss of RKIP corresponding to increased invasiveness and metastatic spread. MEK/ERK activation was associated with low or decreased RKIP expression in vitro, and vice-versa. RKIP mRNA can activate interferon-inducible 2¹,5¹-oligoadenylate synthetases (OAS), leading to RNase L activation. RNase L deficiency in prostate cancer cell lines (PC3, Du145, LNCap) is associated with resistance to apoptosis through OAS activation. Entity Melanoma Note RKIP mRNA and protein expression is reduced in melanoma cell lines versus normal melanocytes. AP-1 activation and ERK1/ERK2 phosphorylation decreased in Mel Im cells stably transfected with RKIP compared to control transfected cells. Immunohistochemical analyses showed reduced RKIP in primary melanoma versus normal normal skin, and further reduction in melanoma metastases. RKIP may act by inhibiting B-Raf kinase activity, as demonstrated in melanoma cell lines in vitro. Entity Hepatocellular carcinoma Note Hepatocellular carcinoma cell lines and HCC liver tissue showed decreased RKIP expression as compared to primary human hepatocytes or adjacent peritumoral tissues. Low RKIP expression was correlated with increased ERK activation and modulation of RKIP expression antagonized MAPK signaling in vitro. Entity Colorectal cancer Note Loss of RKIP, as studied in tissue microarrays of MMR-proficient and deficient colorectal cancer samples, was a marker of tumor progression and metastasis. Diminished RKIP expression was significantly positively associated with worse survival. Entity Insulinoma / Islet neoplasia Note Insulinomas showed decreased or absent RKIP expression as compared to normal nearby islets. ß-cell line HIT-TI5 proliferation, but not apoptotis, was inhibited by RKIP. External links Nomenclature HGNC PEBP1 8630 Entrez_Gene PEBP1 5037 phosphatidylethanolamine binding protein 1 Cards Atlas PEBP1ID44021ch12q24 GeneCards PEBP1 Ensembl PEBP1 [Search_View] ENSG00000089220 [Gene_View] Genatlas PEBP1 GeneLynx PEBP1 eGenome PEBP1 euGene 5037 Genomic and cartography PEBP1 - 12q24.23 chr12:117058253-117067773 + 12q24 [Description] (hg18- GoldenPath Mar_2006) Ensembl PEBP1 - 12q24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PEBP1 Gene and transcription Genbank AK226006 [ ENTREZ ] Genbank AK299414 [ ENTREZ ] Genbank AK308056 [ ENTREZ ] Genbank AK311927 [ ENTREZ ] Genbank BC008714 [ ENTREZ ] RefSeq NM_002567 [ SRS ] NM_002567 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq AC_000144 [ SRS ] AC_000144 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 538 RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_009775 [ SRS ] NT_009775 [ ENTREZ ] RefSeq NW_001838063 [ SRS ] NW_001838063 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView PEBP1 AceView - NCBI Unigene Hs.713526 [ SRS ] Hs.713526 [ NCBI ] HS713526 [ spliceNest ] Fast-db 13937 (alternative variants) Protein : pattern, domain, 3D structure P30086 [ SRS] P30086 [ EXPASY ] P30086 [ INTERPRO ] P30086 SwissProt [ UNIPROT ] Prosite PS01220 PBP [ SRS ] PS01220 PBP [ Expasy ] IPR001858 Phosphotidylethanolamine_bd_CS [ SRS ] IPR001858 Interpro Phosphotidylethanolamine_bd_CS [ EBI ] Interpro IPR008914 PtdEtn-bd_prot_PEBP [ SRS ] IPR008914 PtdEtn-bd_prot_PEBP [ EBI ] CluSTr P30086 Pfam PF01161 PBP [ SRS ] PF01161 PBP [ Sanger ] pfam01161 [ NCBI-CDD ] Prodom PD004330 PBP[INRA-Toulouse] P30086 PEBP1_HUMAN [ Domain structure ] P30086 PEBP1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P30086 PDB 1BD9 [ SRS ] 1BD9 [ PdbSum ], 1BD9 [ IMB ] 1BD9 [ RSDB ] PDB 1BEH [ SRS ] 1BEH [ PdbSum ], 1BEH [ IMB ] 1BEH [ RSDB ] HPRD 06850 Protein Interaction databases DIP P30086 IntAct P30086 Polymorphism : SNP, mutations, diseases OMIM 604591 [ map ] GENECLINICS 604591 SNP PEBP1 [dbSNP-NCBI] SNP NM_002567 [SNP-NCI] SNP PEBP1 [GeneSNPs - Utah] PEBP1] [HGBASE - SRS] HAPMAP PEBP1 [HAPMAP] COSMIC PEBP1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PEBP1 General knowledge Family Browser PEBP1 [UCSC Family Browser] SOURCE NM_002567 SMD Hs.713526 SAGE Hs.713526 GO nucleotide binding [Amigo] nucleotide binding serine-type endopeptidase inhibitor activity [Amigo] serine-type endopeptidase GO inhibitor activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO cytoplasm [Amigo] cytoplasm GO lipid binding [Amigo] lipid binding GO phosphatidylethanolamine binding [Amigo] phosphatidylethanolamine binding BIOCARTA Signal transduction through IL1R [Genes] PubGene PEBP1 TreeFam PEBP1 CTD 5037 [Comparative ToxicoGenomics Database] Other databases Probes
Atlas Genet Cytogenet Oncol Haematol 2008; 4 539 Probe PEBP1 Related clones (RZPD - Berlin) PubMed PubMed 44 Pubmed reference(s) in LocusLink Bibliography Amino acid sequence of the Homo sapiens brain 21-23-kDa protein (neuropolypeptide h3), comparison with its counterparts from Rattus norvegicus and Bos taurus species, and expression of its mRNA in different tissues. Seddiqi N, Bollengier F, Alliel PM, Perin JP, Bonnet F, Bucquoy S, Jolles P, Schoentgen F Journal of molecular evolution. 1994 ; 39 (6) : 655-660. PMID 7807553
Sequence analysis and immunolocalisation of phosphatidylethanolamine binding protein (PBP) in human brain tissue. Moore C, Perry AC, Love S, Hall L Brain research. Molecular brain research. 1996 ; 37 (1-2) : 74-78. PMID 8738137
Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM, Kolch W Nature. 1999 ; 401 (6749) : 173-177. PMID 10490027
Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Kolch W The Biochemical journal. 2000 ; 351 Pt 2 : 289-305. PMID 11023813
Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W Molecular and cellular biology. 2000 ; 20 (9) : 3079-3085. PMID 10757792
The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors. Hengst U, Albrecht H, Hess D, Monard D The Journal of biological chemistry. 2001 ; 276 (1) : 535-540. PMID 11034991
Human phosphatidylethanolamine-binding protein facilitates heterotrimeric G protein- dependent signaling. Kroslak T, Koch T, Kahl E, Hollt V The Journal of biological chemistry. 2001 ; 276 (43) : 39772-39778. PMID 11514577
Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B, Wyche J, Kolch W, Sedivy JM Molecular and cellular biology. 2001 ; 21 (21) : 7207-7217. PMID 11585904
The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family. Simister PC, Banfield MJ, Brady RL Acta crystallographica. Section D, Biological crystallography. 2002 ; 58 (Pt 6 Pt 2) : 1077-1080. PMID 12037323
Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase
Atlas Genet Cytogenet Oncol Haematol 2008; 4 540 inhibitory protein. Corbit KC, Trakul N, Eves EM, Diaz B, Marshall M, Rosner MR The Journal of biological chemistry. 2003 ; 278 (15) : 13061-13068. PMID 12551925
Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET Journal of the National Cancer Institute. 2003 ; 95 (12) : 878-889. PMID 12813171
Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Lorenz K, Lohse MJ, Quitterer U Nature. 2003 ; 426 (6966) : 574-579. PMID 14654844
RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. Chatterjee D, Bai Y, Wang Z, Beach S, Mott S, Roy R, Braastad C, Sun Y, Mukhopadhyay A, Aggarwal BB, Darnowski J, Pantazis P, Wyche J, Fu Z, Kitagwa Y, Keller ET, Sedivy JM, Yeung KC The Journal of biological chemistry. 2004 ; 279 (17) : 17515-17523. PMID 14766752
Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Jazirehi AR, Vega MI, Chatterjee D, Goodglick L, Bonavida B Cancer research. 2004 ; 64 (19) : 7117-7126. PMID 15466208
The role of Raf kinase inhibitor protein (RKIP) in health and disease. Keller ET, Fu Z, Brennan M Biochemical pharmacology. 2004 ; 68 (6) : 1049-1053. PMID 15313400
Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. Keller ET, Fu Z, Yeung K, Brennan M Cancer letters. 2004 ; 207 (2) : 131-137. PMID 15151133
Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis. Odabaei G, Chatterjee D, Jazirehi AR, Goodglick L, Yeung K, Bonavida B Advances in cancer research. 2004 ; 91 : 169-200. PMID 15327891
Reduction in Raf kinase inhibitor protein expression is associated with increased Ras- extracellular signal-regulated kinase signaling in melanoma cell lines. Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK Cancer research. 2004 ; 64 (15) : 5186-5192. PMID 15289323
Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein. Yamazaki T, Nakano H, Hayakari M, Tanaka M, Mayama J, Tsuchida S The Journal of biological chemistry. 2004 ; 279 (31) : 32191-32195. PMID 15155742
Raf kinase inhibitory protein inhibits beta-cell proliferation. Zhang L, Fu Z, Binkley C, Giordano T, Burant CF, Logsdon CD, Simeone DM Surgery. 2004 ; 136 (3) : 708-715. PMID 15349122
Atlas Genet Cytogenet Oncol Haematol 2008; 4 541 Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Hagan S, Al-Mulla F, Mallon E, Oien K, Ferrier R, Gusterson B, Garcia JJ, Kolch W Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (20) : 7392-7397. PMID 16243812
The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein. Keller ET, Fu Z, Brennan M Journal of cellular biochemistry. 2005 ; 94 (2) : 273-278. PMID 15565643
RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Park S, Yeung ML, Beach S, Shields JM, Yeung KC Oncogene. 2005 ; 24 (21) : 3535-3540. PMID 15782137
Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. Trakul N, Menard RE, Schade GR, Qian Z, Rosner MR The Journal of biological chemistry. 2005 ; 280 (26) : 24931-24940. PMID 15886202
Identification and characterization of PEBP as a calpain substrate. Chen Q, Wang S, Thompson SN, Hall ED, Guttmann RP Journal of neurochemistry. 2006 ; 99 (4) : 1133-1141. PMID 17018026
Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR Molecular cell. 2006 ; 23 (4) : 561-574. PMID 16916643
Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D, Keller PJ, Mizokami A, Dunn R, Chinnaiyan AM, Yao Z, Keller ET The Prostate. 2006 ; 66 (3) : 248-256. PMID 16175585
Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Lee HC, Tian B, Sedivy JM, Wands JR, Kim M Gastroenterology. 2006 ; 131 (4) : 1208-1217. PMID 17030190
Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH Nucleic acids research. 2006 ; 34 (22) : 6684-6695. PMID 17145707
Regulation of RKIP binding to the N-region of the Raf-1 kinase. Park S, Rath O, Beach S, Xiang X, Kelly SM, Luo Z, Kolch W, Yeung KC FEBS letters. 2006 ; 580 (27) : 6405-6412. PMID 17097642
Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Beach S, Tang H, Park S, Dhillon AS, Keller ET, Kolch W, Yeung KC Oncogene. 2008 ; 27 (15) : 2243-2248. PMID 17952120
Atlas Genet Cytogenet Oncol Haematol 2008; 4 542
Cross-regulation of VPAC(2) receptor desensitization by M(3) receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2. Huang J, Mahavadi S, Sriwai W, Grider JR, Murthy KS American journal of physiology. Gastrointestinal and liver physiology. 2007 ; 292 (3) : G867-G874. PMID 17170028
Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, Lugli A American journal of clinical pathology. 2007 ; 127 (5) : 820-827. PMID 17439843
MAP kinase meets mitosis: a role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation. Rosner MR Cell division. 2007 ; 2 : page 1. PMID 17214889
Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. Theroux S, Pereira M, Casten KS, Burwell RD, Yeung KC, Sedivy JM, Klysik J Brain research bulletin. 2007 ; 71 (6) : 559-567. PMID 17292798
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Contributor(s) Written 11-2007 Sandy Beach, Kam C Yeung Department of Cancer Biology and Biochemistry, College of Medicine, University of Toledo, Health Science Campus-(formerly Medical University of Ohio), 3035 Arlington Ave., Toledo, OH 43614, USA Citation This paper should be referenced as such : Beach S, Yeung KC . PEBP1 (phosphatidylethanolamine binding protein 1). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PEBP1ID44021ch12q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 543 Atlas of Genetics and Cytogenetics in Oncology and Haematology
RNF7 (RING finger protein-7)
Identity Other names CKBBP1 RBX2 ROC2 SAG (Sensitive to Apoptosis Gene) HGNC RNF7 Location 3q22-24
A) Location. B) Local order DNA/RNA
Description The gene encoding RNF7/SAG consists of four exons and three introns. Transcription About 0.8 kb mRNA with 342 bp open reading frame; three alternative splicing variants; induced by redox compound, tumor promoter (TPA), and hypoxia. Pseudogene Two psuedogenes, SAGp1 and SAGp2. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 4 544
Description 113 amino acids; 14 kDa protein; contains a RING domain (Cys-X2-Cys-X9-39-Cys- X1-3-His-X2-3-Cys/His-X2-Cys-X4-48-Cys-X2-Cys) at the C-terminus (50-102); Subjected to CK2 phosphorylation at Thr-10. Expression Ubiquitously expressed with the highest expression in heart, skeleton muscle, and testis in humans. Localisation Both cytoplasm and nucleus Function 1) In vitro test tube assays using purified protein showed that RNF7/SAG scavenges hydrogen peroxide at the expense of self oligomerization; has thiol-linked peroxidase activity; inhibits peroxynitrite-induced DNA damage. When complexed with the components of SCF E3 ubiquitin ligase, SAG has E3 ubiquitin ligase activity. 2) In cultured cells, SAG over-expression inhibits apoptosis induced by redox, nitric oxide, ischemia/hypoxia, neurotoxin, MPP, and UV-irradiation (unpublished data). SAG over-expression also promotes the S-phase entry and cell growth under serum starved conditions and inhibits TPA-induced neoplastic transformation. Silencing SAG expression by anti-sense or siRNA inhibits tumor cell growth, enhanced apoptosis induced by etoposide and TRAIL, and enhances TPA-induced neoplastic transformation. 3) In whole animals, SAG over-expression via injection of SAG expressing recombinant adenovirus protects mouse brain tissues from ischemia/hypoxia-induced damage. Targeted expression of SAG in mouse skin inhibits tumor formation at the early stage, but enhances tumor growth at the later stage in a SAG-transgenic DMBA-TPA carcinogenesis model. 4) In yeast, SAG is a growth essential gene whose targeted deletion causes death, which can be rescued by human SAG. Homology SAG is an evolutionarily conserved gene with 96% protein sequence identity between human and mouse, 70% identify between human and C-elegans and 50% between human and yeast. Two family members are found in human and mouse, four in Drosophila, three in C-elegans, one in Arabidopsis and in yeast. Mutations Germinal Not known Somatic Not known Implicated in Entity lung and colon cancer Disease SAG/RNF7 over-expression was found in lung cancer and a subset of colon cancer tissues. Prognosis Lung cancer patients with SAG/RNF7 over-expression have a worse prognosis. Oncogenesis Targeted over-expression of SAG/RNF7 in mouse skin by K14 promoter inhibits tumor formation, but enhances tumor growth in DMBA-TPA-induced skin carcinogenesis. External links Nomenclature HGNC RNF7 10070 Entrez_Gene RNF7 9616 ring finger protein 7 Cards Atlas RNF7ID44108ch3q22 GeneCards RNF7 Ensembl RNF7 [Search_View] ENSG00000114125 [Gene_View] Genatlas RNF7 GeneLynx RNF7
Atlas Genet Cytogenet Oncol Haematol 2008; 4 545 eGenome RNF7 euGene 9616 Genomic and cartography GoldenPath RNF7 - chr3:142939741-142947933 + 3q22-q24 [Description] (hg18-Mar_2006) Ensembl RNF7 - 3q22-q24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene RNF7 Gene and transcription Genbank AF092878 [ ENTREZ ] Genbank AF142060 [ ENTREZ ] Genbank AF164679 [ ENTREZ ] Genbank AF312226 [ ENTREZ ] Genbank AK311982 [ ENTREZ ] RefSeq NM_014245 [ SRS ] NM_014245 [ ENTREZ ] RefSeq NM_183237 [ SRS ] NM_183237 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq AC_000135 [ SRS ] AC_000135 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_005612 [ SRS ] NT_005612 [ ENTREZ ] RefSeq NW_001838884 [ SRS ] NW_001838884 [ ENTREZ ] RefSeq NW_921807 [ SRS ] NW_921807 [ ENTREZ ] AceView RNF7 AceView - NCBI Unigene Hs.134623 [ SRS ] Hs.134623 [ NCBI ] HS134623 [ spliceNest ] Fast-db 13582 (alternative variants) Protein : pattern, domain, 3D structure Q9UBF6 [ SRS] Q9UBF6 [ EXPASY ] Q9UBF6 [ INTERPRO ] Q9UBF6 SwissProt [ UNIPROT ] Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ] Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] Interpro IPR013083 Znf_RING/FYVE/PHD [ SRS ] IPR013083 Znf_RING/FYVE/PHD [ EBI ] CluSTr Q9UBF6 PF00097 zf-C3HC4 [ SRS ] PF00097 zf-C3HC4 [ Sanger ] pfam00097 [ NCBI-CDD Pfam ] Smart SM00184 RING [EMBL] Blocks Q9UBF6 PDB 2ECL [ SRS ] 2ECL [ PdbSum ], 2ECL [ IMB ] 2ECL [ RSDB ] HPRD 04840 Protein Interaction databases DIP Q9UBF6 IntAct Q9UBF6 Polymorphism : SNP, mutations, diseases OMIM 603863 [ map ] GENECLINICS 603863 SNP RNF7 [dbSNP-NCBI] SNP NM_014245 [SNP-NCI] SNP NM_183237 [SNP-NCI] SNP RNF7 [GeneSNPs - Utah] RNF7] [HGBASE - SRS] HAPMAP RNF7 [HAPMAP] COSMIC RNF7 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD RNF7 General knowledge Family Browser RNF7 [UCSC Family Browser] SOURCE NM_014245
Atlas Genet Cytogenet Oncol Haematol 2008; 4 546 SOURCE NM_183237 SMD Hs.134623 SAGE Hs.134623 GO copper ion binding [Amigo] copper ion binding GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO anti-apoptosis [Amigo] anti-apoptosis GO redox signal response [Amigo] redox signal response GO zinc ion binding [Amigo] zinc ion binding induction of apoptosis by oxidative stress [Amigo] induction of apoptosis by oxidative GO stress GO metal ion binding [Amigo] metal ion binding PubGene RNF7 TreeFam RNF7 CTD 9616 [Comparative ToxicoGenomics Database] Other databases Probes Probe RNF7 Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Duan H, Wang Y, Aviram M, Swaroop M, Loo JA, Bian J, Tian Y, Mueller T, Bisgaier CL, Sun Y Molecular and cellular biology. 1999 ; 19 (4) : 3145-3155. PMID 10082581
Alterations of SAG mRNA in human cancer cell lines: requirement for the RING finger domain for apoptosis protection. Sun Y Carcinogenesis. 1999 ; 20 (10) : 1899-1903. PMID 10506102
Expression, purification, and biochemical characterization of SAG, a ring finger redox-sensitive protein. Swaroop M, Bian J, Aviram M, Duan H, Bisgaier CL, Loo JA, Sun Y Free radical biology & medicine. 1999 ; 27 (1-2) : 193-202. PMID 10443936
Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation. Swaroop M, Wang Y, Miller P, Duan H, Jatkoe T, Madore SJ, Sun Y Oncogene. 2000 ; 19 (24) : 2855-2866. PMID 10851089
Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. Duan H, Tsvetkov LM, Liu Y, Song Y, Swaroop M, Wen R, Kung HF, Zhang H, Sun Y Molecular carcinogenesis. 2001 ; 30 (1) : 37-46. PMID 11255262
Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth. Huang Y, Duan H, Sun Y Molecular carcinogenesis. 2001 ; 30 (1) : 62-70. PMID 11255265
Atlas Genet Cytogenet Oncol Haematol 2008; 4 547 Expression of the sensitive to apoptosis gene, SAG, as a prognostic marker in nonsmall cell lung cancer. Sasaki H, Yukiue H, Kobayashi Y, Moriyama S, Nakashima Y, Kaji M, Fukai I, Kiriyama M, Yamakawa Y, Fujii Y International journal of cancer. Journal international du cancer. 2001 ; 95 (6) : 375-377. PMID 11668520
SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. Sun Y, Tan M, Duan H, Swaroop M Antioxidants & redox signaling. 2001 ; 3 (4) : 635-650. PMID 11554450
SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes. Swaroop M, Gosink M, Sun Y DNA and cell biology. 2001 ; 20 (7) : 425-434. PMID 11506706
Attenuation of ischemia-induced mouse brain injury by SAG, a redox-inducible antioxidant protein. Yang GY, Pang L, Ge HL, Tan M, Ye W, Liu XH, Huang FP, Wu DC, Che XM, Song Y, Wen R, Sun Y Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2001 ; 21 (6) : 722-733. PMID 11488541
Thiol-linked peroxidase activity of human sensitive to apoptosis gene (SAG) protein. Kim SY, Bae YS, Park JW Free radical research. 2002 ; 36 (1) : 73-78. PMID 11999705
SAG attenuates apoptotic cell death caused by simulated ischaemia/reoxygenation in rat cardiomyocytes. Chanalaris A, Sun Y, Latchman DS, Stephanou A Journal of molecular and cellular cardiology. 2003 ; 35 (3) : 257-264. PMID 12676540
Human sensitive to apoptosis gene protein inhibits peroxynitrite-induced DNA damage. Kim SY, Lee JH, Yang ES, Kil IS, Park JW Biochemical and biophysical research communications. 2003 ; 301 (3) : 671-674. PMID 12565832
Phosphorylation of threonine 10 on CKBBP1/SAG/ROC2/Rbx2 by protein kinase CKII promotes the degradation of IkappaBalpha and p27Kip1. Kim YS, Lee JY, Son MY, Park W, Bae YS The Journal of biological chemistry. 2003 ; 278 (31) : 28462-28469. PMID 12748192
SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection. Tan M, Gallegos JR, Gu Q, Huang Y, Li J, Jin Y, Lu H, Sun Y Neoplasia (New York, N.Y.). 2006 ; 8 (12) : 1042-1054. PMID 17217622
Regulation of nitric oxide-induced apoptosis by sensitive to apoptosis gene protein. Yang ES, Park JW Free radical research. 2006 ; 40 (3) : 279-284. PMID 16484044
SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1
Atlas Genet Cytogenet Oncol Haematol 2008; 4 548 and IkappaB-alpha/NF-kappaB. Gu Q, Bowden GT, Normolle D, Sun Y The Journal of cell biology. 2007 ; 178 (6) : 1009-1023. PMID 17846172
SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Gu Q, Tan M, Sun Y Cancer research. 2007 ; 67 (8) : 3616-3625. PMID 17440073
CK2 phosphorylation of SAG at Thr10 regulates SAG stability, but not its E3 ligase activity. He H, Tan M, Pamarthy D, Wang G, Ahmed K, Sun Y Molecular and cellular biochemistry. 2007 ; 295 (1-2) : 179-188. PMID 16874460
SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. Kim SY, Kim MY, Mo JS, Park JW, Park HS Neuroscience letters. 2007 ; 413 (2) : 132-136. PMID 17240529
SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation. Tan M, Gu Q, He H, Pamarthy D, Semenza GL, Sun Y Oncogene. 2008 ; 27 (10) : 1404-1411. PMID 17828303
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Contributor(s) Written 11-2007 Yi Sun Department of Radiation Oncology, University of Michigan, 4304 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010, USA Citation This paper should be referenced as such : Sun Y . RNF7 (RING finger protein-7). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RNF7ID44108ch3q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 549 Atlas of Genetics and Cytogenetics in Oncology and Haematology
STARD13 (StAR-related lipid transfer (START) domain containing 13)
Identity Other names DLC2 (Deleted in Liver Cancer 2) FLJ37385 GT650 HGNC STARD13 Location 13q13.3 DNA/RNA Note GeneLoc location for GC13M032575: Start: 32,575,307bp from pter; End: 32,757,892; Size: 182,585; Orientation: minus strand
Genomic characterization of human DLC2. (A) chromosomal map location of human DLC2 at 13q 12.3. Arrows underneath the gene symbols indicate the orientation of transcription. RFC3, replication factor C subunit 3; KL, Klotho; AS3, androgen shutoff 3; BRCA2, breast cancer 2, early onset; Tel, telomeric; Cen, centromeric. (B) genomic organization of human DLC2 locus. Non-coding (open boxes) and coding (filled boxes) are shown. (Ching YP,et al. J Biol Chem 2003) Description DLC2 was identified due to striking sequence homology to DLC1. It localizes to a small region of 13q12.3, which is a locus frequently deleted in hepatocellular carcinoma (HCC) as well as in other cancers. Physical mapping of DLC2 in human genome revealed that it is in close proximity to the BRCA2 locus and flanked by microsatellite markers D13S171 and D13S267. The human DLC2 gene spans a region of 182 kb and contains 14 coding exons. Transcription The mRNA of DLC2 is 5886 bp long with an open reading frame of 3342 bp. Using bioinformatic analysis, 4 isoforms of DLC2, namely, DLC2alpha (5886 bp), DLC2beta (5810 bp), DLC2gamma (5784 bp), and DLC2delta (943 bp) have been identified. These 4 isoforms are generated by alternative splicing of the 5' end of the transcript. Northern blot analysis detected 7.2- and 4.2-kb DLC2 transcripts in all tissues examined, with the highest expression in heart, skeletal muscle, kidney, and pancreas. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 4 550
A. DLC2 is a multifunctional protein. Diagram of protein domains in DLC2. SAM, sterile alpha motif; ATP/GTP binding, ATP/GTP-binding site motif A; GAP, RhoGAP domain; START, StAR-related lipid transfer domain. (Ching YP,et al. J Biol Chem 2003) B. Functional domains of the DLC2 isoforms. DLC2alpha and DLC2beta each contains a SAM, a RhoGAP, and a START domain, but they differ in their N-terminal sequence. The difference in the amino acid sequence was located at the first 60 aa in DLC2alpha and the first 52 aa in DLC2beta. DLC2gamma contains a RhoGAP and a START domain. DLC2delta only contains a SAM domain. (Leung TH, et al. Proc Nat Acad Sci USA. 2005) Description DLC2alpha encodes a 1113-amino acid protein which has a calculated molecular mass of 125 kD. DLC2 contains an N-terminal sterile alpha motif (SAM) domain for protein- protein interactions, followed by an ATP/GTP-binding motif, a GTPase-activating protein (GAP) domain, and a C-terminal STAR-related lipid transfer (START) domain. The 4 isoforms of DLC2, DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta, encode proteins of 1113, 1105, 995, and 135 amino acids, respectively. DLC2alpha and DLC2beta encode a protein containing three functional domains, SAM, RhoGAP and START domains. DLC2alpha and DLC2beta differ by only a few N-terminal amino acids. DLC2gamma contains the RhoGAP and START domains, but lacks the N- terminal SAM domain, whereas DLC2delta contains only the SAM domain. Co-immunoprecipitation assay of ectopically expressed DLC2 in cells revealed that DLC1 forms homodimers in vivo and the region 160-672 residues is responsible for the interaction. Expression DLC2 is ubiquitously expressed in human tissues and is more abundant in heart, skeletal muscle, kidney and pancreas. Localisation DLC2alpha, DLC2beta and DLC2gamma are predominantly localized in the cytoplasm in mouse fibroblast and human HCC cells. Cellular fractionation and immunofluorescence microscopy revealed that DLC2 localizes to cytoplasmic speckles overlapping with mitochondria and in structures in close proximity to lipid droplets. The START domain of DLC2 has been demonstrated to be responsible for mitochondria targeting of DLC2. Function DLC2 has been implicated to be a tumor suppressor protein. DLC2 has growth suppressive and anti-metastatic effects on HCC cell line, HepG2 and breast cancer cell line, MCF7. The RhoGAP domain has been demonstrated to be responsible for its biological functions and the RhoGAP activity has been demonstrated in vitro and in vivo. Recombinant DLC2 showed GAP activity specific for small GTPases, RhoA and Cdc42. Using GST-Rhoteckin pull down assay, in vivo RhoA activity has been shown to be negatively regulated by DLC2. However, in cells transfected with DLC2 RhoGAP mutant, the in vivo RhoA activity remained unchanged. Moreover, DLC2 inactivates RhoA activity via its RhoGAP domain and leads to the inhibition of actin stress fiber formation. Ectopic expression of DLC2 changed mouse fibroblast morphology from angular and spindle-shaped to round-shaped with dendritic cellular protrusions. Cells express DLC2 RhoGAP mutants did not exhibit morphological change and the actin stress fiber formation in these cells is unaffected. Introduction of human DLC2 into mouse fibroblasts suppressed Ras signaling and Ras-induced cellular transformation in a GAP-dependent manner. Overexpression of DLC2 also suppressed cell proliferation, motility and anchorage-independent growth in human hepatoma cells.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 551 Collectively, down regulation of RhoA activity in HCC cell line by DLC2 resulted in change of cell morphology, migration rate, proliferation rate and transforming ability. Several proteins were identified as interacting partners of DLC2 by yeast two-hybrid screening. These proteins include SWI/SNF, alpha-tubulin, HMG CoA reductase, and TAX1 binding protein (TAX1BP1). Homology DLC family members: DLC1 is located at chromosome 8p22; DLC3 is located at chromosome Xq13; DLC2 shares 51% and 52% amino acid identities with DLC1 and DLC3, respectively. Implicated in Entity Cancer Note DLC2, with its RhoGAP domain, is able to inhibit the activity of RhoA, which is believed to play a significant role in cell transformation in many cancer types. Down regulation of DLC2 mRNA expression has been reported in various types of cancer including liver, breast, lung, ovarian, renal, uterine, gastric, colon and rectal tumors. DLC2 localizes to a small region of 13q12.3 commonly deleted in HCC. DLC2 is flanked by microsatellite markers D13S171 and D13S267. Loss of heterozygosity on these two markers is frequently found in HCC. Allelic losses at markers D13S171 and D13S267 are detected in 33.3% and 40.7% of the informative cases, respectively. RT- PCR analysis of DLC2 mRNA in 45 HCC samples revealed that 17.8% of the cases showed significant underexpression (more than 2-fold) of DLC2 mRNA when compared with the corresponding non-tumorous liver tissues from the same patients. Studies in human cancers have suggested that small GTPases of the Rho family are critically involved tumorigenesis. Suppression of RhoA activity may be able to reverse the transformation phenotype in cancers. RhoGAP activity of DLC2 has been demonstrated both in vitro and in vivo. Anchorage-independent growth of cancer cells is a hallmark of cellular transformation. Stable expression of DLC2 in liver cancer cell line effectively abolished the anchorage-independent growth ability of the cells. This indicated that DLC2 is capable of reducing the transforming phenotype and supports the view that DLC2 is a functional tumor suppressor. External links Nomenclature HGNC STARD13 19164 Entrez_Gene STARD13 90627 StAR-related lipid transfer (START) domain containing 13 Cards Atlas STARD13ID44051ch13q13 GeneCards STARD13 Ensembl STARD13 [Search_View] ENSG00000133121 [Gene_View] Genatlas STARD13 GeneLynx STARD13 eGenome STARD13 euGene 90627 Genomic and cartography STARD13 - 13q13.3 chr13:32575307-32678143 - 13q12-q13 [Description] GoldenPath (hg18-Mar_2006) Ensembl STARD13 - 13q12-q13 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene STARD13 Gene and transcription Genbank AK091804 [ ENTREZ ] Genbank AK094704 [ ENTREZ ] Genbank AK095114 [ ENTREZ ] Genbank AK308430 [ ENTREZ ] Genbank AK308453 [ ENTREZ ] RefSeq NM_052851 [ SRS ] NM_052851 [ ENTREZ ] RefSeq NM_178006 [ SRS ] NM_178006 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 552 RefSeq NM_178007 [ SRS ] NM_178007 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq AC_000145 [ SRS ] AC_000145 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ] RefSeq NW_001838072 [ SRS ] NW_001838072 [ ENTREZ ] RefSeq NW_925473 [ SRS ] NW_925473 [ ENTREZ ] AceView STARD13 AceView - NCBI Unigene Hs.507704 [ SRS ] Hs.507704 [ NCBI ] HS507704 [ spliceNest ] Fast-db 2847 (alternative variants) Protein : pattern, domain, 3D structure Q6MZG8 [ SRS] Q6MZG8 [ EXPASY ] Q6MZG8 [ INTERPRO ] Q6MZG8 SwissProt [ UNIPROT ] Interpro IPR002913 START_lipid_bd [ SRS ] IPR002913 START_lipid_bd [ EBI ] CluSTr Q6MZG8 Pfam PF01852 START [ SRS ] PF01852 START [ Sanger ] pfam01852 [ NCBI-CDD ] Blocks Q6MZG8 HPRD 11607 Protein Interaction databases DIP Q6MZG8 IntAct Q6MZG8 Polymorphism : SNP, mutations, diseases OMIM 609866 [ map ] GENECLINICS 609866 SNP STARD13 [dbSNP-NCBI] SNP NM_052851 [SNP-NCI] SNP NM_178006 [SNP-NCI] SNP NM_178007 [SNP-NCI] SNP STARD13 [GeneSNPs - Utah] STARD13] [HGBASE - SRS] HAPMAP STARD13 [HAPMAP] HGMD STARD13 General knowledge Family Browser STARD13 [UCSC Family Browser] SOURCE NM_052851 SOURCE NM_178006 SOURCE NM_178007 SMD Hs.507704 SAGE Hs.507704 GO GTPase activator activity [Amigo] GTPase activator activity GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO cytoplasm [Amigo] cytoplasm GO mitochondrion [Amigo] mitochondrion GO lipid particle [Amigo] lipid particle GO signal transduction [Amigo] signal transduction GO membrane [Amigo] membrane GO mitochondrial membrane [Amigo] mitochondrial membrane monolayer-surrounded lipid storage body outer lipid monolayer [Amigo] monolayer- GO surrounded lipid storage body outer lipid monolayer GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle PubGene STARD13 TreeFam STARD13 CTD 90627 [Comparative ToxicoGenomics Database] Other databases
Atlas Genet Cytogenet Oncol Haematol 2008; 4 553 Probes Probe STARD13 Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO The Journal of biological chemistry. 2003 ; 278 (12) : 10824-10830. PMID 12531887
Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. Nagaraja GM, Kandpal RP Biochemical and biophysical research communications. 2004 ; 313 (3) : 654-665. PMID 14697242
Rho GTPase activating protein cDNA on chromosome 13q12 is the deleted in liver cancer (DLC2) gene. Popescu NC, Durkin ME Biochemical and biophysical research communications. 2004 ; 315 (4) : page 781. PMID 14985079
Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY, Ng IO Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (42) : 15207-15212. PMID 16217026
Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. Ng DC, Chan SF, Kok KH, Yam JW, Ching YP, Ng IO, Jin DY FEBS letters. 2006 ; 580 (1) : 191-198. PMID 16364308
Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Ullmannova V, Popescu NC International journal of oncology. 2006 ; 29 (5) : 1127-1132. PMID 17016643
DLC-1:a Rho GTPase-activating protein and tumour suppressor. Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC Journal of cellular and molecular medicine. 2007 ; 11 (5) : 1185-1207. PMID 17979893
The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle. Kwan JJ, Donaldson LW BMC structural biology. 2007 ; 7 : page 34. PMID 17519008
Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2. Li H, Fung KL, Jin DY, Chung SS, Ching YP, Ng IO, Sze KH, Ko BC, Sun H Proteins. 2007 ; 67 (4) : 1154-1166. PMID 17380510
Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Qian X, Li G, Asmussen HK, Asnaghi L, Vass WC, Braverman R, Yamada KM, Popescu NC,
Atlas Genet Cytogenet Oncol Haematol 2008; 4 554 Papageorge AG, Lowy DR Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (21) : 9012-9017. PMID 17517630
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Contributor(s) Written 11-2007 Thomas Ho-Yin Leung, Judy Wai Ping Yam, Irene Oi-lin Ng Departments of Pathology, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Citation This paper should be referenced as such : Leung THY, Yam JWP, Ng IOL . STARD13 (StAR-related lipid transfer (START) domain containing 13). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/STARD13ID44051ch13q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 555 Atlas of Genetics and Cytogenetics in Oncology and Haematology
TTL (Twelve-thirteen Translocation Leukemia)
Identity Other names FLJ21437 LOC646982 TTL/TEL TTL-T TTL-B1 TTL-B2 HGNC Location 13q14.11 Note Not to be confused with: TTL : tubulin tyrosine ligase (2q13), nor with "transthyretin-like (TTL) gene family", a family to which belongs TTR (transthyretin, 18q12). DNA/RNA Description Start at 39,822,377 bp from pter; the gene spans 119,929 bases on minus strand. Transcription Three splicing forms, namely: TTL-T, TTL-B1 and -B2. TTL-T is 2090 bp long and composed of exons 1-8. The longest open-reading frame contains exons 4, 5, and part of exon 6; it encods a 133 amino acids peptid. TTL-B1 transcript is 3450 bp long and is composed of exons 4, 5, and part of exon 9. TTL-B2, 3588 bp long is composed of exons 4, 5, and part of exon 8a. Protein Note This gene/protein remains poorly known: there has been no study on it since the princeps paper by Qiao et al (2003). Expression Ubiquitous expression (lung, liver, spleen, thymus, and bone marrow); major expression in brain and testis. Homology TTL has no homology to known genes. Implicated in Entity t(12;13)(p13;q14) in B-cell acute lymphoblastic leukaemia (B-ALL) --> ETV6 /TTL. Note Only one case to date. Hybrid/Mutated Both reciprocal transcripts, TTL/ETV6 and ETV6/TTL, were detected. ETV6/TTL fusion Gene transcript The other transcript, TTL/ETV6, comprises 5' TTL exons 1 to 5 or to 8a, fused to ETV6 from exon 2. The predicted 530 amino acids fusion protein consists mostly of ETV6 with both HLH and ETS domains, and could have modified transcriptional activities. On the other hand, a loss of function of ETV6 and/or of TTL.could play the critical role in leukemogenesis. External links Nomenclature HGNC - - Entrez_Gene LOC646982 646982 TTL/TEL fusion protein TTL-T Cards Atlas TTLID529ch13q14 GeneCards LOC646982 Ensembl LOC646982 [Search_View] [Gene_View] Genatlas LOC646982 GeneLynx LOC646982 eGenome LOC646982 euGene 646982 Genomic and cartography LOC646982 - 13q14.11 chr13:39941672-39945084 - 13q14.11 [Description] GoldenPath (hg18-Mar_2006)
Atlas Genet Cytogenet Oncol Haematol 2008; 4 556 Ensembl LOC646982 - 13q14.11 [CytoView] NCBI Mapview HomoloGene LOC646982 Gene and transcription Genbank AK025090 [ ENTREZ ] Genbank AY116214 [ ENTREZ ] Genbank AY116215 [ ENTREZ ] Genbank AY116216 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ] RefSeq NW_925473 [ SRS ] NW_925473 [ ENTREZ ] AceView LOC646982 AceView - NCBI Unigene Hs.287664 [ SRS ] Hs.287664 [ NCBI ] HS287664 [ spliceNest ] Protein : pattern, domain, 3D structure Q8NEU1 [ SRS] Q8NEU1 [ EXPASY ] Q8NEU1 [ INTERPRO ] Q8NEU1 SwissProt [ UNIPROT ] CluSTr Q8NEU1 Blocks Q8NEU1 Protein Interaction databases DIP Q8NEU1 IntAct Q8NEU1 Polymorphism : SNP, mutations, diseases SNP LOC646982 [dbSNP-NCBI] SNP LOC646982 [GeneSNPs - Utah] LOC646982] [HGBASE - SRS] HAPMAP LOC646982 [HAPMAP] HGMD - General knowledge Family LOC646982 [UCSC Family Browser] Browser SMD Hs.287664 SAGE Hs.287664 PubGene LOC646982 TreeFam - CTD 646982 [Comparative ToxicoGenomics Database] Other databases Probes PubMed Bibliography Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;q14), and its implication in leukemogenesis. Qiao Y, Ogawa S, Hangaishi A, Yuji K, Izutsu K, Kunisato A, Imai Y, Wang L, Hosoya N, Nannya Y, Sato Y, Maki K, Mitani K, Hirai H. Leukemia. 2003 Jun; 17(6): 1112-20. PMID 12764377
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Contributor(s) Written 11-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Atlas Genet Cytogenet Oncol Haematol 2008; 4 557 Citation This paper should be referenced as such : Huret JL . TTL (Twelve-thirteen Translocation Leukemia). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/TTLID529ch13q14.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 558 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ZFP36L1 (Zinc finger protein 36, C3H type-like 1)
Identity Other names Berg36 BRF1 cMG1 ERF1 TIS11B HGNC ZFP36L1 Location 14q24.1 Note The rat clone of ZFP36L1, cMG1, was the first cloned member of the tristetraprolin (TTP, TIS11, NUP475, GOS24) family of CCCH tandem zinc finger proteins. There are 4 mammalian members of this family, TTP, ZFP36L1, ZFP36L2 (TIS11D, ERF2, BRF2), and ZFP36L3. ZFP36L3 is the only family member that is rodent-specific. These proteins have been shown to bind (via their conserved tandem zinc finger domain) directly to class II AU-rich elements (ARE) in the 3'-untranslated region (UTR) of mRNA leading to deadenylation and destabilization of the mRNA. DNA/RNA
Diagram of the human ZFP36L1 gene. Exons are represented by gray boxes; intron by the hatched box. The translation start site is indicated by the arrow and the translation stop site by the double line. The dark box represents the CCCH tandem zinc finger domain. Description The human ZFP36L1 has 2 exons spanning 5411 bp on chromosome 14 (NC_000014.7; NT_026437.11). The first exon, which is small (186 bp), is separated from the larger second exon (2834 bp) by a 2388 bp intron. Transcription 3022 bp human transcript (NM_004926.2) with 1014 bp (338 amino acids) of coding region. Pseudogene None known. Protein Description Human ZFP36L1 is a 338 amino acid protein with a predicted molecular weight of 36.3 kDa. Expression In the adult mouse, expression appears to be ubiquitous. Based on northern blots, mRNA expression is highest in mouse kidney, spleen, ovary and lung, with lower levels of expression in thymus and heart, and still lower levels in brain, liver and testis. In the embryonic mouse, mRNA was barely detectable at embryonic day 7.5 (E7.5), but increased dramatically by E9.5 and E10.5. In situ hybridization histochemistry demonstrated that there was high level expression in the allantois at E8.0, immediately before fusion with the chorion. Expression is also seen in mouse embryonic stem cells. Localisation Transfection studies using a GFP-tagged protein have shown diffuse cytoplasmic expression. There is good evidence that the protein can shuttle between the nucleus and the cytoplasm in a CRM1 (nuclear export receptor)-dependent, leptomycin B- inhibitable manner. Function ZFP36L1 is a member of the TTP (ZFP36) family of CCCH tandem zinc finger proteins. These proteins have been shown to bind to target mRNAs through their AU-rich elements present in the 3'-untranslated regions of the mRNA. The binding of these proteins to mRNA leads to deadenylation and destabilization of the mRNA. All four family members have been shown to bind directly to single stranded RNA probes (RNA gel shift assays), destabilize target mRNA (co-transfection assays), and deadenylate ARE-containing RNA probes (cell-free deadenylation assays). Physiological target mRNAs have been identified for TTP which include tumor necrosis factor alpha (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF),
Atlas Genet Cytogenet Oncol Haematol 2008; 4 559 interleukin-2b (IL-2), and immediate early response gene 3 (IER3, IEX-1, gly96). To date, one physiological target mRNA has been identified for ZFP36L1; however, this target mRNA is not destabilized by ZFP36L1 (see below). Two reports of ZFP36L1 knockout mice have been published. In one report, knockout embryos died around embryonic day 11 mainly due to failure of chorioallantoic fusion. When fusion did occur, there was increased apoptosis throughout the neural tube, as well as placental failure due to atrophy of the trophoblast layers. In a second report, knockout embryos also died at mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, the extraembryonic mesoderm failed to invaginate the trophoblast layer. This phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A (in the embryo and in mouse embryonic fibroblasts). This elevated level of expression was not due to increased stability of the VEGF-A mRNA, but rather due to enhanced association with polyribosomes. This is in contrast to a prior report using co-transfection studies showing that ZFP36L1 was able to bind to two AU-rich motifs in the 3' UTR of VEGF mRNA that led to destabilization of the mRNA. Mouse ZFP36L1 has been shown to interact with 14-3-3 proteins in a phosphorylation-dependent manner. This interaction causes ZFP36L1 to be sequestered in the cytoplasm preventing it from regulating mRNA decay. Several studies have suggested that ZFP36L1 may function as a pro-apoptotic protein. Homology Four members of the TTP family of CCCH tandem zinc finger proteins, TTP (ZFP36), ZFP36L1, ZFP36L2 and the rodent-specific ZFP36L3, have been identified. They all share a highly conserved tandem zinc finger domain. Mutations Note Eight polymorphisms have been identified. The functional significance of these polymorphisms has not been determined. 1) G change into T at base 644 in the 5' UTR 2) AG change into GC at base 706 in the first coding region 3) G change into A at base 729 in the intron 4) C change into CC at base 772 in the intron 5) A change into G at base 804 in the intron 6) G change into C at base 845 in the intron 7) G change into A at base 3685 in the second coding region 8) C change into A at base 3915 in the second coding region Implicated in Entity Cisplatin sensitivity in head and neck squamous cell carcinoma (HNSCC). Note A common feature in HNSCC is cisplatin sensitivity. Microarray analysis identified mouse ZFP36L1 to be differentially expressed by cisplatin treatment. Cisplatin-sensitive HNSCC cell lines expressed elevated levels of ZFP36L1 compared to cisplatin-resistant HNSCC cell lines. Downregulation of ZFP36L1 (using antisense oligonucleotides) in cisplatin-sensitive cell lines made the cells cisplatin-resistant. Conversely, overexpression of ZFP36L1 reverted cisplatin-resistant cells to cisplatin-sensitive cells. There was an inverse correlation between the expression levels of ZFP36L1 and the human inhibitor of apoptosis protein-2, cIAP2 (Birc3, baculoviral IAP repeat-containing 3). Increased expression of ZFP36L1 also correlated with increased caspase-3 activity and increased cisplatin-induced apoptosis. These results suggested that expression of ZFP36L1 enhanced cisplatin sensitivity in HNSCC cells by reducing cIAP2 mRNA levels. Entity t(8;21) translocation Note The AML1-MTG8 fusion transcription factor generated by t(8;21) translocation is thought to affect the normal regulation of genes that are needed for differentiation and proliferation of hematopoietic progenitors leading to acute myelogenous leukemia (AML). ZFP36L1 was identified as an up-regulated gene in t(8;21) leukemic cells suggesting that it may be important to AML1-MTG8-mediated leukemogenesis. Entity Human T-lymphotropic virus 1(HTLV-1) Note ZFP36L1 expression is also up-regulated in human T-lymphotropic virus 1(HTLV-1)- infected cells. HTLV-1 is associated with adult T-cell leukemia/lymphoma and the Tax oncoprotein encoded by the 3' region of HTLV-1 has been proposed to dysregulate the expression of many genes that are important for cell proliferation. The Tax
Atlas Genet Cytogenet Oncol Haematol 2008; 4 560 transactivator was shown to bind to two ZFP36L1 upstream elements (a novel transcription factor-binding site labeled BRF1 Tax-responsive site or BTRS and a second consensus cAMP-responsive site or CRE). Entity Various cancers. Note Increased expression of ZFP36L1 has been seen in several cancers including lymph node (+) primary breast tumors and hepatocellular carcinomas. Increased expression has also been demonstrated in a number of the NCI 60 panel of human cancer cell lines. These include the mammary gland cancer cell lines BT549, MDA-MB-231, and NCI/ADR-RES; ovarian cell lines OVCAR-5, OVCAR-8 and SK-OV-3; lung cell line NCI- H226; skin cell lines LOXMVI, M14, MALME-3M, and SK-MEL-2; brain cell lines SF268 and SF295; prostate cell line PC-3; kidney cell lines A498, ACHN, CAKI-1, SN12C, TK10, and UO31; and colon cell line HT29. External links Nomenclature HGNC ZFP36L1 1107 Entrez_Gene ZFP36L1 677 zinc finger protein 36, C3H type-like 1 Cards Atlas ZFP36L1ID42866ch14q22 GeneCards ZFP36L1 Ensembl ZFP36L1 [Search_View] ENSG00000185650 [Gene_View] Genatlas ZFP36L1 GeneLynx ZFP36L1 eGenome ZFP36L1 euGene 677 Genomic and cartography ZFP36L1 - 14q24.1 chr14:68324128-68329538 - 14q22-q24 [Description] (hg18- GoldenPath Mar_2006) Ensembl ZFP36L1 - 14q22-q24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene ZFP36L1 Gene and transcription Genbank BC018340 [ ENTREZ ] Genbank BT019468 [ ENTREZ ] Genbank CR592455 [ ENTREZ ] Genbank DQ891349 [ ENTREZ ] Genbank DQ894529 [ ENTREZ ] RefSeq NM_004926 [ SRS ] NM_004926 [ ENTREZ ] RefSeq AC_000057 [ SRS ] AC_000057 [ ENTREZ ] RefSeq AC_000146 [ SRS ] AC_000146 [ ENTREZ ] RefSeq NC_000014 [ SRS ] NC_000014 [ ENTREZ ] RefSeq NT_026437 [ SRS ] NT_026437 [ ENTREZ ] RefSeq NW_001838112 [ SRS ] NW_001838112 [ ENTREZ ] RefSeq NW_925561 [ SRS ] NW_925561 [ ENTREZ ] AceView ZFP36L1 AceView - NCBI Unigene Hs.707091 [ SRS ] Hs.707091 [ NCBI ] HS707091 [ spliceNest ] Fast-db 2550 (alternative variants) Protein : pattern, domain, 3D structure Q07352 [ SRS] Q07352 [ EXPASY ] Q07352 [ INTERPRO ] Q07352 SwissProt [ UNIPROT ] Prosite PS50103 ZF_C3H1 [ SRS ] PS50103 ZF_C3H1 [ Expasy ] Interpro IPR007635 Tis11B_N [ SRS ] IPR007635 Tis11B_N [ EBI ] Interpro IPR000571 Znf_CCCH [ SRS ] IPR000571 Znf_CCCH [ EBI ] CluSTr Q07352 Pfam PF04553 Tis11B_N [ SRS ] PF04553 Tis11B_N [ Sanger ] pfam04553 [ NCBI-CDD
Atlas Genet Cytogenet Oncol Haematol 2008; 4 561 ] Pfam PF00642 zf-CCCH [ SRS ] PF00642 zf-CCCH [ Sanger ] pfam00642 [ NCBI-CDD ] Smart SM00356 ZnF_C3H1 [EMBL] Blocks Q07352 PDB 1W0V [ SRS ] 1W0V [ PdbSum ], 1W0V [ IMB ] 1W0V [ RSDB ] PDB 1W0W [ SRS ] 1W0W [ PdbSum ], 1W0W [ IMB ] 1W0W [ RSDB ] HPRD 03041 Protein Interaction databases DIP Q07352 IntAct Q07352 Polymorphism : SNP, mutations, diseases OMIM 601064 [ map ] GENECLINICS 601064 SNP ZFP36L1 [dbSNP-NCBI] SNP NM_004926 [SNP-NCI] SNP ZFP36L1 [GeneSNPs - Utah] ZFP36L1] [HGBASE - SRS] HAPMAP ZFP36L1 [HAPMAP] HGMD ZFP36L1 General knowledge Family Browser ZFP36L1 [UCSC Family Browser] SOURCE NM_004926 SMD Hs.707091 SAGE Hs.707091 nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay GO [Amigo] nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay GO vasculogenesis [Amigo] vasculogenesis GO transcription factor activity [Amigo] transcription factor activity GO mRNA binding [Amigo] mRNA binding GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO cytosol [Amigo] cytosol GO mRNA catabolic process [Amigo] mRNA catabolic process GO regulation of translation [Amigo] regulation of translation GO zinc ion binding [Amigo] zinc ion binding GO regulation of mRNA stability [Amigo] regulation of mRNA stability GO metal ion binding [Amigo] metal ion binding PubGene ZFP36L1 TreeFam ZFP36L1 CTD 677 [Comparative ToxicoGenomics Database] Other databases Probes Probe ZFP36L1 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Identification of a mRNA rapidly induced in an intestinal epithelial cell line by epidermal growth factor. Gomperts M, Pascall JC, Brown KD Biochemical Society transactions. 1990 ; 18 (4) : 568-569. PMID 2276442
The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 562 Varnum BC, Ma QF, Chi TH, Fletcher B, Herschman HR Molecular and cellular biology. 1991 ; 11 (3) : 1754-1758. PMID 1996120
Cloning and characterization of ERF-1, a human member of the Tis11 family of early-response genes. Bustin SA, Nie XF, Barnard RC, Kumar V, Pascall JC, Brown KD, Leigh IM, Williams NS, McKay IA DNA and cell biology. 1994 ; 13 (5) : 449-459. PMID 8024689
Distinct mechanisms for rescue from apoptosis in Ramos human B cells by signaling through CD40 and interleukin-4 receptor: role for inhibition of an early response gene, Berg36. Ning ZQ, Norton JD, Li J, Murphy JJ European journal of immunology. 1996 ; 26 (10) : 2356-2363. PMID 8898945
Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Carballo E, Lai WS, Blackshear PJ Science (New York, N.Y.). 1998 ; 281 (5379) : 1001-1005. PMID 9703499
The product of the primary response gene BRF1 inhibits the interaction between 14-3-3 proteins and cRaf-1 in the yeast trihybrid system. Bustin SA, McKay IA DNA and cell biology. 1999 ; 18 (8) : 653-661. PMID 10463061
Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony- stimulating factor messenger RNA deadenylation and stability. Carballo E, Lai WS, Blackshear PJ Blood. 2000 ; 95 (6) : 1891-1899. PMID 10706852
Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival. Johnson BA, Geha M, Blackwell TK Oncogene. 2000 ; 19 (13) : 1657-1664. PMID 10763822
Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. Lai WS, Carballo E, Thorn JM, Kennington EA, Blackshear PJ The Journal of biological chemistry. 2000 ; 275 (23) : 17827-17837. PMID 10751406
Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF. Shimada H, Ichikawa H, Nakamura S, Katsu R, Iwasa M, Kitabayashi I, Ohki M Blood. 2000 ; 96 (2) : 655-663. PMID 10887131
Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms. Johnson BA, Stehn JR, Yaffe MB, Blackwell TK The Journal of biological chemistry. 2002 ; 277 (20) : 18029-18036. PMID 11886850
Members of the tristetraprolin family of tandem CCCH zinc finger proteins exhibit CRM1- dependent nucleocytoplasmic shuttling. Phillips RS, Ramos SB, Blackshear PJ
Atlas Genet Cytogenet Oncol Haematol 2008; 4 563 The Journal of biological chemistry. 2002 ; 277 (13) : 11606-11613. PMID 11796723
Polymorphisms in the genes encoding members of the tristetraprolin family of human tandem CCCH zinc finger proteins. Blackshear PJ, Phillips RS, Vazquez-Matias J, Mohrenweiser H Progress in nucleic acid research and molecular biology. 2003 ; 75 : 43-68. PMID 14604009
Expression of butyrate response factor 1 in HTLV-1-transformed cells and its transactivation by tax protein. Li B, Fink T, Ebbesen P, Liu XD, Zachar V Archives of virology. 2003 ; 148 (9) : 1787-1804. PMID 14505090
Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Ciais D, Cherradi N, Bailly S, Grenier E, Berra E, Pouyssegur J, Lamarre J, Feige JJ Oncogene. 2004 ; 23 (53) : 8673-8680. PMID 15467755
Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family. Stumpo DJ, Byrd NA, Phillips RS, Ghosh S, Maronpot RR, Castranio T, Meyers EN, Mishina Y, Blackshear PJ Molecular and cellular biology. 2004 ; 24 (14) : 6445-6455. PMID 15226444
Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins. Blackshear PJ, Phillips RS, Ghosh S, Ramos SB, Richfield EK, Lai WS Biology of reproduction. 2005 ; 73 (2) : 297-307. PMID 15814898
Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines. Lee SK, Kim SB, Kim JS, Moon CH, Han MS, Lee BJ, Chung DK, Min YJ, Park JH, Choi DH, Cho HR, Park SK, Park JW International journal of cancer. Journal international du cancer. 2005 ; 117 (1) : 32-40. PMID 15880358
Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR Journal of immunology (Baltimore, Md. : 1950). 2005 ; 174 (2) : 953-961. PMID 15634918
The RNA binding protein Zfp36l1 is required for normal vascularisation and post- transcriptionally regulates VEGF expression. Bell SE, Sanchez MJ, Spasic-Boskovic O, Santalucia T, Gambardella L, Burton GJ, Murphy JJ, Norton JD, Clark AR, Turner M Developmental dynamics : an official publication of the American Association of Anatomists. 2006 ; 235 (11) : 3144-3155. PMID 17013884
BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites. Benjamin D, Schmidlin M, Min L, Gross B, Moroni C Molecular and cellular biology. 2006 ; 26 (24) : 9497-9507. PMID 17030608
Atlas Genet Cytogenet Oncol Haematol 2008; 4 564 Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts. Lai WS, Parker JS, Grissom SF, Stumpo DJ, Blackshear PJ Molecular and cellular biology. 2006 ; 26 (24) : 9196-9208. PMID 17030620
Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis. Zindy PJ, L'Helgoualc'h A, Bonnier D, Le Bechec A, Bourd-Boitin K, Zhang CX, Musso O, Glaise D, Troadec MB, Loreal O, Turlin B, Leger J, Clement B, Theret N Hepatology (Baltimore, Md.). 2006 ; 44 (5) : 1296-1307. PMID 17058241
Breast cancer molecular signatures as determined by SAGE: correlation with lymph node status. Abba MC, Sun H, Hawkins KA, Drake JA, Hu Y, Nunez MI, Gaddis S, Shi T, Horvath S, Sahin A, Aldaz CM Molecular cancer research : MCR. 2007 ; 5 (9) : 881-890. PMID 17855657
Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines. Carrick DM, Blackshear PJ Archives of biochemistry and biophysics. 2007 ; 462 (2) : 278-285. PMID 17517366
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Contributor(s) Written 11-2007 Deborah J Stumpo, Perry J Blackshear Laboratory of Neurobiology, NIEHS MD A2-05, 111 Alexander Drive, Research Triangle Park, NC 27709, USA Citation This paper should be referenced as such : Stumpo DJ, Blackshear PJ . ZFP36L1 (Zinc finger protein 36, C3H type-like 1). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ZFP36L1ID42866ch14q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 565 Atlas of Genetics and Cytogenetics in Oncology and Haematology
ZNF384 (Zinc Finger protein 384)
Identity Other names CAGH1 CAGH1A CIZ ERDA2 NMP4 NP TNRC1 HGNC ZNF384 Location 12p13.31 Local_order centromere 5'-ZNF384- 3' telomere DNA/RNA Note GeneLoc location for GC12M006646: Start: 6,645,904 bp from pter; End: 6,668,930 bp from pter; Size: 23,026 bases (23Kb); Orientation: minus strand
The diagram shows all genes (including ZNF384), with their orientation from centromere to telomere, which are localized in a region going from 6,590 Kbp to 6,720 Kbp at 12p13. Transcription Transcript Variant: different alternative splicing isoforms are described. Protein
Schematic representation of CIZ protein. LZ: leucine-rich domain SR: serine rich domain PR: Proline rich domain NLS: Nuclear Localization signal ZFs: Kruppel-type C2H2 zinc finger domains QA: Gln-Ala repeat (See also Martini et al., Cancer Research 2002). Note Similarity: belongs to the Kruppel C2H2-type zinc-finger protein family; contains 8 C2H2-type zinc fingers. Description Nucleocytoplasmic shuttling protein and transcription factor which appear to bind and regulate the promoter of MMP1, MMP3, MMP7 and COL1A1. Multiple transcript variants encoding several protein isoforms have been found. Localisation Nucleus Implicated in Entity Acute lymphoblastic leukemia with t(12;17)(p13;q11) --> TAF15-ZNF384 Disease pro-B Acute lymphoblastic leukemia with expression of myeloid antigens ( ANPEP/CD13 and/or CD33, and less frequently FUT4/CD15); acute myeloid leukemia. Prognosis Relatively good prognosis.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 566
A) Schematic representation of the reciprocal t(12;17)(p13;q11) translocation; B) Break-a-part FISH: RP11-369N23 maps telomeric to the 3' ZNF384 while RP11-101F21 partially overlaps with the 5' end of ZNF384 (RP11 clones belong to the Peter De Jong library and were kindly provided by M Rocchi). Abnormal TAF15-ZNF384 Protein
Schematic representation of the TAF15-ZNF384 fusion protein. SYQG, Ser-Tyr-Gln-Gly transactivating domain; RGG, Arg-Gly-Gly rich region, (RNA binding domain); LZ, leucine-rich domain; SR, serine rich domain; PR, Proline rich domain; NLS, Nuclear Localization signal; ZFs, Kruppel-type C2H2 zinc finger domains QA: Gln-Ala repeat (see also Martini et al., Cancer Res 2002). Entity Acute lymphoblastic leukemia with t(12;19)(p13;p13) --> E2A-ZNF384 Disease pro-B Acute Lymphoblastic Leukemia with expression of myeloid antigens. Prognosis Relatively good prognosis. Cytogenetics The t(12;19)(p13;p13) is cryptic
A) Schematic representation of the reciprocal t(12;19)(p13;p13) translocation; B) Break-a-part FISH: RP11-369N23 maps telomeric to the 3'ZNF384 while RP11-101F21 partially overlaps with the 5' end of ZNF384 (RP11 clones belong to the Peter De Jong library and were kindly provided by M Rocchi).
Atlas Genet Cytogenet Oncol Haematol 2008; 4 567 Abnormal ZNF384-E2A Protein Entity Acute lymphoblastic leukemia with t(12;22)(p13;q12) --> EWSR1-ZNF384 Disease pro-B Acute Lymphoblastic Leukemia with expression of myeloid antigens; biphenotypic leukemia. Prognosis Relatively good prognosis.
Schematic representation of the reciprocal t(12;22)(p13;q12) translocation producing the EWSR1-ZNF384 fusion gene. Abnormal EWSR1-ZNF384 Protein
Schematic representation of the EWSR1-ZNF384 fusion protein. SYQG, Ser-Tyr-Gln-Gly transactivating domain; LZ, leucine-rich domain; SR, serine rich domain; PR, Proline rich domain; NLS, Nuclear Localization signal; ZFs, Kruppel-type C2H2 zinc finger domains; QA, Gln-Ala repeat (see also Martini et al., Cancer Res 2002). Breakpoints
External links Nomenclature HGNC ZNF384 11955 Entrez_Gene ZNF384 171017 zinc finger protein 384 Cards Atlas ZNF384ID42881ch12p13 GeneCards ZNF384 Ensembl ZNF384 [Search_View] ENSG00000126746 [Gene_View] Genatlas ZNF384 GeneLynx ZNF384
Atlas Genet Cytogenet Oncol Haematol 2008; 4 568 eGenome ZNF384 euGene 171017 Genomic and cartography ZNF384 - 12p13.31 chr12:6645904-6668086 - 12p12 [Description] (hg18- GoldenPath Mar_2006) Ensembl ZNF384 - 12p12 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene ZNF384 Gene and transcription Genbank AK095734 [ ENTREZ ] Genbank AL047622 [ ENTREZ ] Genbank BC053361 [ ENTREZ ] Genbank BP312309 [ ENTREZ ] Genbank BP363856 [ ENTREZ ] RefSeq NM_001039916 [ SRS ] NM_001039916 [ ENTREZ ] RefSeq NM_001039917 [ SRS ] NM_001039917 [ ENTREZ ] RefSeq NM_001039918 [ SRS ] NM_001039918 [ ENTREZ ] RefSeq NM_001039919 [ SRS ] NM_001039919 [ ENTREZ ] RefSeq NM_001039920 [ SRS ] NM_001039920 [ ENTREZ ] RefSeq NM_133476 [ SRS ] NM_133476 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq AC_000144 [ SRS ] AC_000144 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_009759 [ SRS ] NT_009759 [ ENTREZ ] RefSeq NW_001838050 [ SRS ] NW_001838050 [ ENTREZ ] RefSeq NW_925295 [ SRS ] NW_925295 [ ENTREZ ] AceView ZNF384 AceView - NCBI Unigene Hs.708126 [ SRS ] Hs.708126 [ NCBI ] HS708126 [ spliceNest ] Fast-db 1262 (alternative variants) Protein : pattern, domain, 3D structure Q7Z722 [ SRS] Q7Z722 [ EXPASY ] Q7Z722 [ INTERPRO ] Q7Z722 SwissProt [ UNIPROT ] 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 Q7Z722 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00355 ZnF_C2H2 [EMBL] Prodom PD000003 Znf_C2H2[INRA-Toulouse] Q7Z722 Q7Z722_HUMAN [ Domain structure ] Q7Z722 Q7Z722_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks Q7Z722 HPRD 18332 Protein Interaction databases DIP Q7Z722 IntAct Q7Z722 Polymorphism : SNP, mutations, diseases OMIM 609951 [ map ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 569 GENECLINICS 609951 SNP ZNF384 [dbSNP-NCBI] SNP NM_001039916 [SNP-NCI] SNP NM_001039917 [SNP-NCI] SNP NM_001039918 [SNP-NCI] SNP NM_001039919 [SNP-NCI] SNP NM_001039920 [SNP-NCI] SNP NM_133476 [SNP-NCI] SNP ZNF384 [GeneSNPs - Utah] ZNF384] [HGBASE - SRS] HAPMAP ZNF384 [HAPMAP] COSMIC ZNF384 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD ZNF384 General knowledge Family Browser ZNF384 [UCSC Family Browser] SOURCE NM_001039916 SOURCE NM_001039917 SOURCE NM_001039918 SOURCE NM_001039919 SOURCE NM_001039920 SOURCE NM_133476 SMD Hs.708126 SAGE Hs.708126 GO nucleic acid binding [Amigo] nucleic acid binding GO DNA binding [Amigo] DNA binding 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 GO metal ion binding [Amigo] metal ion binding PubGene ZNF384 TreeFam ZNF384 CTD 171017 [Comparative ToxicoGenomics Database] Other databases Probes Probe ZNF384 Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Involvement of the nuclear matrix in the control of skeletal genes: the NMP1 (YY1), NMP2 (Cbfa1), and NMP4 (Nmp4/CIZ) transcription factors. Bidwell JP, Torrungruang K, Alvarez M, Rhodes SJ, Shah R, Jones DR, Charoonpatrapong K, Hock JM, Watt AJ Critical reviews in eukaryotic gene expression. 2001 ; 11 (4) : 279-297. PMID 12067068
Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A, Somers R, Aventin A, Foa R, Hagemeijer A, Mecucci C, Marynen P Cancer research. 2002 ; 62 (19) : 5408-5412. PMID 12359745
Identifying genes that regulate bone remodeling as potential therapeutic targets.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 570 Krane SM The Journal of experimental medicine. 2005 ; 201 (6) : 841-843. PMID 15781576
CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. La Starza R, Aventin A, Crescenzi B, Gorello P, Specchia G, Cuneo A, Angioni A, Bilhou-Nabera C, Boque C, Foa R, Uyttebroeck A, Talmant P, Cimino G, Martelli MF, Marynen P, Mecucci C, Hagemeijer A Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (9) : 1696-1699. PMID 15990865
Identification in human osteoarthritic chondrocytes of proteins binding to the novel regulatory site AGRE in the human matrix metalloprotease 13 proximal promoter. Fan Z, Tardif G, Boileau C, Bidwell JP, Geng C, Hum D, Watson A, Pelletier JP, Lavigne M, Martel- Pelletier J Arthritis and rheumatism. 2006 ; 54 (8) : 2471-2480. PMID 16868967
Interaction partners for human ZNF384/CIZ/NMP4--zyxin as a mediator for p130CAS signaling? Janssen H, Marynen P Experimental cell research. 2006 ; 312 (7) : 1194-1204. PMID 16510139
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Contributor(s) Written 11-2007 Paolo Gorello, Roberta La Starza, Cristina Mecucci Hematology, University of Perugia, via Brunamonti, 06122 Perugia, Italy Citation This paper should be referenced as such : Gorello P, La Starza R, Mecucci C . ZNF384 (Zinc Finger protein 384). Atlas Genet Cytogenet Oncol Haematol. November 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ZNF384ID42881ch12p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 571 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CD53 (CD53 molecule)
Identity Other names TSPAN25 Tetraspanin-25 Tspan-25 tetraspanin-25 CD53 glycoprotein CD53 tetraspan antigen MOX44 HGNC CD53 Location 1p13.3 Telomere-KCNA3--Q8NHC3---CD53---C1orf103---TMEM77---CEPT1---DENND2D- Local_order Centromere
Map of chromosomal region 1p13.3 DNA/RNA
Exon-Intron structure of human CD53 gene. Description Gene size: 26,77 Kbp; 8 exons. Transcription Transcript length: 1,567 bps. Protein
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The CD53 protein has four transmembrane domains. Several residues are conserved and define the tetraspanin protein family. The protein is glycosylated (green) in its second extracellular loop. Internally the protein is palmitoylated (red lines). EC: extracellular. Note Size: 219 amino acids; 24341 Da; Four transmembrane domains. Subcellular location: Plasma Membrane; endosomes. Localisation Plasma membrane; endosomes; exoxomes. Function Modifier of signal transduction. Homology Member of the tetraspanin protein family. Implicated in Entity T-cell acute lymphoblastic leukemia Cytogenetics t(1;22)(p13;q13)
Location of breakpoint in chromosome region 1p13.3 in a case of T-ALL with a t(1;22)(p13;q13). The CD53 gene is not structurally altered. It is not known if its level of expression is affected. Abnormal None Protein External links Nomenclature HGNC CD53 1686 Entrez_Gene CD53 963 CD53 molecule Cards Atlas CD53ID983ch1p13 GeneCards CD53 Ensembl CD53 [Search_View] ENSG00000143119 [Gene_View]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 573 Genatlas CD53 GeneLynx CD53 eGenome CD53 euGene 963 Genomic and cartography CD53 - 1p13.3 chr1:111217245-111244081 + 1p13 [Description] (hg18- GoldenPath Mar_2006) Ensembl CD53 - 1p13 [CytoView] NCBI Mapview OMIM Disease map [OMIM]
HomoloGene CD53 Gene and transcription Genbank AK298723 [ ENTREZ ] Genbank AK313582 [ ENTREZ ] Genbank BC035456 [ ENTREZ ] Genbank BC040693 [ ENTREZ ] Genbank BG536920 [ ENTREZ ] RefSeq NM_000560 [ SRS ] NM_000560 [ ENTREZ ] RefSeq NM_001040033 [ SRS ] NM_001040033 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_019273 [ SRS ] NT_019273 [ ENTREZ ] RefSeq NW_001838594 [ SRS ] NW_001838594 [ ENTREZ ] RefSeq NW_922462 [ SRS ] NW_922462 [ ENTREZ ] AceView CD53 AceView - NCBI Unigene Hs.443057 [ SRS ] Hs.443057 [ NCBI ] HS443057 [ spliceNest ] Fast-db 17030 (alternative variants) Protein : pattern, domain, 3D structure P19397 [ SRS] P19397 [ EXPASY ] P19397 [ INTERPRO ] P19397 SwissProt [ UNIPROT ] Prosite PS00421 TM4_1 [ SRS ] PS00421 TM4_1 [ Expasy ] Interpro IPR000301 Transmem_4 [ SRS ] IPR000301 Transmem_4 [ EBI ] CluSTr P19397 PF00335 Tetraspannin [ SRS ] PF00335 Tetraspannin [ Sanger ] pfam00335 Pfam [ NCBI-CDD ] Blocks P19397 HPRD 01054 Protein Interaction databases DIP P19397 IntAct P19397 Polymorphism : SNP, mutations, diseases OMIM 151525 [ map ] GENECLINICS 151525 SNP CD53 [dbSNP-NCBI] SNP NM_000560 [SNP-NCI] SNP NM_001040033 [SNP-NCI] SNP CD53 [GeneSNPs - Utah] CD53] [HGBASE - SRS] HGMD CD53 General knowledge Family Browser CD53 [UCSC Family Browser] SOURCE NM_000560 SOURCE NM_001040033
Atlas Genet Cytogenet Oncol Haematol 2008; 4 574 SMD Hs.443057 SAGE Hs.443057 GO plasma membrane [Amigo] plasma membrane GO signal transduction [Amigo] signal transduction GO integral to membrane [Amigo] integral to membrane PubGene CD53 TreeFam CD53 CTD 963 [Comparative ToxicoGenomics Database] Other databases Probes Probe CD53 Related clones (RZPD - Berlin) PubMed PubMed 32 Pubmed reference(s) in LocusLink Bibliography The human CD53 gene, coding for a four transmembrane domain protein, maps to chromosomal region 1p13. Gonzalez ME, Pardo-Manuel de Villena F, Fernandez-Ruiz E, Rodriguez de Cordoba S, Lazo PA Genomics. 1993 ; 18 (3) : 725-728. PMID 8307585
Genomic structure of the human CD53 gene. Korinek V, HorejsiV Immunogenetics. 1993 ; 38 (4) : 272-279. PMID 8319976
CD53, a protein with four membrane-spanning domains, mediates signal transduction in human monocytes and B cells. Olweus J, Lund-Johansen F, Horejsi V Journal of immunology (Baltimore, Md. : 1950). 1993 ; 151 (2) : 707-716. PMID 8335905
Chromosomal localization of the Ox-44 (CD53) leukocyte antigen gene in man and rodents. Taguchi T, Bellacosa A, Zhou JY, Gilbert DJ, Lazo PA, Copeland NG, Jenkins NA, Tsichlis PN, Testa JR Cytogenetics and cell genetics. 1993 ; 64 (3-4) : 217-221. PMID 8404042
HindIII RFLP in the human CD53 gene on 1p13. Gallego MI, Varas F, Lazo PA Human molecular genetics. 1994 ; 3 (9) : page 1711. PMID 7833942
Cross-linking of CD53 promotes activation of resting human B lymphocytes. Rasmussen AM, Blomhoff HK, Stokke T, Horejsi V, Smeland EB Journal of immunology (Baltimore, Md. : 1950). 1994 ; 153 (11) : 4997-5007. PMID 7963560
Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). Mannion BA, Berditchevski F, Kraeft SK, Chen LB, Hemler ME Journal of immunology (Baltimore, Md. : 1950). 1996 ; 157 (5) : 2039-2047. PMID 8757325
Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. Szollosi J, Horejsi V, Bene L, Angelisova P, Damjanovich S Journal of immunology (Baltimore, Md. : 1950). 1996 ; 157 (7) : 2939-2946. PMID 8816400
Atlas Genet Cytogenet Oncol Haematol 2008; 4 575 Recurrent infectious diseases in human CD53 deficiency. Mollinedo F, Fontan G, Barasoain I, Lazo PA Clinical and diagnostic laboratory immunology. 1997 ; 4 (2) : 229-231. PMID 9067662
Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes. Nichols TC, Guthridge JM, Karp DR, Molina H, Fletcher DR, Holers VM European journal of immunology. 1998 ; 28 (12) : 4123-4129. PMID 9862348
Increased expression of the tetraspanins CD53 and CD63 on apoptotic human neutrophils. Beinert T, Munzing S, Possinger K, Krombach F Journal of leukocyte biology. 2000 ; 67 (3) : 369-373. PMID 10733097
Differential cooperation between regulatory sequences required for human CD53 gene expression. Hernandez-Torres J, Yunta M, Lazo PA The Journal of biological chemistry. 2001 ; 276 (38) : 35405-35413. PMID 11443129
Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Hemler ME Annual review of cell and developmental biology. 2003 ; 19 : 397-422. PMID 14570575
Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ, Fero M, Pollack JR, van de Rijn M, Brooks JD The American journal of pathology. 2003 ; 162 (3) : 925-932. PMID 12598325
Apoptosis protection and survival signal by the CD53 tetraspanin antigen. Yunta M, Lazo PA Oncogene. 2003 ; 22 (8) : 1219-1224. PMID 12606948
Discrimination of biclonal B-cell chronic lymphoproliferative neoplasias by tetraspanin antigen expression. Barrena S, Almeida J, Yunta M, Lopez A, Diaz-Mediavilla J, Orfao A, Lazo PA Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (9) : 1708-1709. PMID 15973446
Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Barrena S, Almeida J, Yunta M, Lopez A, Fernandez-Mosteirin N, Giralt M, Romero M, Perdiguer L, Delgado M, Orfao A, Lazo PA Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (8) : 1376-1383. PMID 15931266
Tetraspanin functions and associated microdomains. Hemler ME Nature reviews. Molecular cell biology. 2005 ; 6 (10) : 801-811. PMID 16314869
Atlas Genet Cytogenet Oncol Haematol 2008; 4 576 Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO, Israel MA Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (16) : 5814-5819. PMID 15827123
Determination of stromal signatures in breast carcinoma. West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP, Montgomery K, Zhu S, Patel R, Hernandez-Boussard T, Goldblum JR, Brown PO, van de Vijver M, van de Rijn M PLoS biology. 2005 ; 3 (6) : page e187. PMID 15869330
Interleukin-2 receptor beta chain locus rearrangement in a T-cell acute lymphoblastic leukemia. Berger R, Bernard OA Pathologie-biologie. 2007 ; 55 (1) : 56-58. PMID 16697123
Functional implications of tetraspanin proteins in cancer biology. Lazo PA Cancer science. 2007 ; 98 (11) : 1666-1677. PMID 17727684
The CD53 and CEACAM-1 genes are genetic targets for early B cell factor. Mansson R, Lagergren A, Hansson F, Smith E, Sigvardsson M European journal of immunology. 2007 ; 37 (5) : 1365-1376. PMID 17429843
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Contributor(s) Written 12-2007 Pedro A Lazo Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, campus Miguel de Unamuno, E-37007 Salamanca, Spain Citation This paper should be referenced as such : Lazo PA . CD53 (CD53 molecule). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CD53ID983ch1p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 577 Atlas of Genetics and Cytogenetics in Oncology and Haematology
EVI1 (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1)
Identity Other names PRDM3 HGNC EVI1 Location 3q26.2 DNA/RNA
Genomic locus of the human EVI1 gene and EVI1 mRNA variants. Asterisk, translation initiation codon; diamond, translation stop codon. (This figure was reprinted from Gene 396, R. Wieser, 'The oncogene and developmental regulator EVI1: Expression, biochemical properties, and biological functions', pages 346-357, Copyright Elsevier (2007), with permission from Elsevier. Gene homepage: http://www.sciencedirect.com/science/journal/03781119) Description The human EVI1 gene spans approximately 65 kb of genomic DNA. 14 of its 16 exons are coding (Fig. 1A). Transcription can initiate from alternative exons 1a, 1b, 1c, 1d, or 3L (Fig. 1B), and several alternative splice variants of the EVI1 mRNA have been described (Delta324, -Rp9, Delta105; Fig. 1A). The human MDS1 gene consists of 4 exons spread over a genomic region of more than 500 kb. MDS1 exon 4 is located less than 2 kb upstream of EVI1 exon1a. The MDS1-EVI1 mRNA presumably results from splicing of the second exon of MDS1 to the second exon of EVI1 (Fig. 1B). Transcription Telomere to centromere. Protein
A) EVI1 and B) MDS1/EVI1 protein domains and EVI1 interacting proteins. Black boxes, zinc finger motifs; RD, repression domain, with binding motifs for the transcriptional corepressor CtBP depicted as black bars; ac, acidic region; PR, PR domain. This figure was reprinted from Gene 396, R. Wieser, 'The oncogene and developmental regulator EVI1: Expression, biochemical properties, and biological functions', pages 346-357, Copyright Elsevier (2007), with permission from Elsevier. Gene homepage: http://www.sciencedirect.com/science/journal/03781119. Description Exon 3 of the human EVI1 gene contains two closely spaced ATG codons, either of which may serve as the translation initiation site. Depending on which ATG is used, proteins of 1051 or 1041 amino acids will be formed. EVI1 contains two domains of
Atlas Genet Cytogenet Oncol Haematol 2008; 4 578 seven and three zinc finger motifs, respectively, a repression domain between the two sets of zinc fingers, and an acidic domain of unknown function at its C-terminus. It is a 145 kDa protein that is capable of binding to DNA in a sequence specific manner, and that interacts with transcriptional coactivators (P/CAF, CBP) and corepressors (CtBP, HDAC) as well as other sequence specific transcription factors (GATA1, Smad3). Predicted translation of MDS1-EVI1 adds 188 amino acids to the N-terminus of EVI1. 63 of these additional amino acids are derived from the untranslated second exon and the untranslated part of the third exon of EVI1, and the remaining 125 from the MDS1 gene. MDS1-EVI1 contains a PR domain, which is about 40% homologous to the N- terminus of the retinoblastoma-binding protein, RIZ, and the PRDI-BF1 transcription factor. Some biological functions of MDS1/EVI1 are different from, or even antagonistic to, those of EVI1. Expression In human tissues/organs, the EVI1 mRNA is expressed abundantly in kidney, lung, pancreas, stomach, ovaries, uterus, and prostate, to a lesser extent in the small intestine, colon, thymus, spleen, heart, brain, testis, and placenta, and at very low levels in skeletal muscle and bone marrow. The pattern of expression of MDS1-EVI1 is very similar to that of EVI1. In the adult mouse, the Evi1 mRNA is expressed, at varying levels, in the kidney, lung, stomach, ovary, uterus, intestine, thymus, spleen, heart, brain, and liver. In the mouse embryo, Evi1 mRNA levels are high in the urinary system and Mullerian ducts, the lung, the heart, and the emerging limb buds. Similar Evi1 expression patterns were also observed in Xenopus, chicken, and zebrafish. Localisation Nuclear; in part in speckles. Function Because of the spatially and temporally restricted expression of EVI1, it has been suggested that this gene plays an important role in development and could be involved in organogenesis, cell migration, cell growth, and differentiation. In the mouse, homozygous disruption of the 6th exon of the Evi1 gene lead to embryonic lethality, with widespread hypocellularity, reduced body size, small or absent limb buds, a pale yolk sac and placenta, abnormal development of the nervous system and the heart, and massive haemorrhaging. EVI1 is thought to exert its biological functions mainly by acting as a transcription factor. In addition, however, EVI1 has been reported to inhibit c-jun N-terminal kinase, and to stimulate PI3K/AKT signalling. Homology EVI1 orthologs are present in many species. Evi1 proteins from other mammals share more than 90% amino acid sequence identity with the human protein, and Xenopus Evi1 is 77% identical to its human counterpart. MDS1-EVI1 shares an overall homology with the C. elegans Egl 43 protein that includes the PR domain at the N-terminus and the two zinc-finger domains. An MDS1/EVI1 ortholog, hamlet, is also present in Drosophila. Implicated in Entity t(3;3)(q21;q26) or inv(3)(q21q26) Note 3q21q26 syndrome. Chromosomal rearrangements located either 5' or 3' of the EVI1 gene can activate its transcription in haematopoietic cells. Usually, t(3;3)(q21;q26) breakpoints are located 5' of EVI1, and inv(3) (q21q26) breakpoints 3' of it. Nevertheless, in both cases aberrant expression of the EVI1 gene may be due to its juxtaposition to the enhancer of the constitutively expressed housekeeping gene ribophorin 1 at 3q21. Disease Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS), and Chronic Myelogenous Leukemia (CML). Prognosis Patients with EVI1 rearrangements have elevated platelet counts, marked hyperplasia with dysplasia of megakaryocytes, and a poor prognosis. Cytogenetics Rearrangements at 3q26 may occur as a sole anomaly, but are often associated with monosomy 7 or deletion of the long arm of chromosome 7, and, less frequently, deletion in chromosome 5.
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Normal and leukemia-associated EVI1 protein variants. Oncogenesis Inappropriate expression of EVI1 in haematopoietic cells alters differentiation into granulocytes, erythrocytes and megakaryocytes. EVI1 promotes the proliferation of certain cell types, but inhibits the growth of others. It interferes with growth inhibition by TGF-b and with apoptosis elicited by a variety of stimuli. In a murine bone marrow transduction/transplantation model, EVI1 caused a disease resembling human myelodysplastic syndrome. Additional coexpression of Hoxa9 and Meis 1 lead to overt leukemia. Entity t(3;21)(q26;q22) Disease Therapy-related MDS/AML and CML during the blast crisis. Prognosis Poor. Cytogenetics Complex. Abnormal AML1 -MDS1-EVI1 Protein Oncogenesis AML1-MDS1-EVI1 is a chimeric transcription factor that interferes with AML1 functions in a dominant negative manner, but shares some biological effects with EVI1. Entity t(3;12)(q26;p13) Disease CML during the blast crisis and MDS in transformation. Prognosis Poor. Cytogenetics Complex. Abnormal Overexpression of a fusion protein between the amino terminus of TEL, Protein which does not contain any functional domains, and the entire MDS1/EVI1 protein is driven by the TEL promoter. Entity AML without 3q26 rearrangements. Note EVI1 may also be overexpressed in AML, MDS, or CML in blast crisis in the absence of any cytogenetically detectable 3q26 rearrangements. Disease AML, MDS, CML. Prognosis Poor (AML). Oncogenesis as above. Breakpoints
Atlas Genet Cytogenet Oncol Haematol 2008; 4 580
Note Other chromosomal rearrangements that results in the inappropriate expression of EVI1 include t(2;3)(p13;q26), t(2;3)(q23;q26), t(3;7)(q27;q22), t(3;8)(q26;q24), t(3;13) (q26;q13-14), and t(3;17)(q26;q22). External links Nomenclature HGNC EVI1 3498 Entrez_Gene EVI1 2122 ecotropic viral integration site 1 Cards Atlas EVI103q26ID19 GeneCards EVI1 Ensembl EVI1 [Search_View] ENSG00000085276 [Gene_View] Genatlas EVI1 GeneLynx EVI1 eGenome EVI1 euGene 2122 Genomic and cartography EVI1 - 3q26.2 chr3:170283981-170346761 - 3q26 [Description] (hg18- GoldenPath Mar_2006) Ensembl EVI1 - 3q26 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene EVI1 Gene and transcription Genbank AA043944 [ ENTREZ ] Genbank AF164155 [ ENTREZ ] Genbank AF164156 [ ENTREZ ] Genbank AF164157 [ ENTREZ ] Genbank AF487422 [ ENTREZ ] RefSeq NM_001105077 [ SRS ] NM_001105077 [ ENTREZ ] RefSeq NM_001105078 [ SRS ] NM_001105078 [ ENTREZ ] RefSeq NM_005241 [ SRS ] NM_005241 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq AC_000135 [ SRS ] AC_000135 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_005612 [ SRS ] NT_005612 [ ENTREZ ] RefSeq NW_001838884 [ SRS ] NW_001838884 [ ENTREZ ] RefSeq NW_921807 [ SRS ] NW_921807 [ ENTREZ ] AceView EVI1 AceView - NCBI Unigene Hs.656395 [ SRS ] Hs.656395 [ NCBI ] HS656395 [ spliceNest ] Fast-db 14505 (alternative variants) Protein : pattern, domain, 3D structure
Atlas Genet Cytogenet Oncol Haematol 2008; 4 581 Q03112 [ SRS] Q03112 [ EXPASY ] Q03112 [ INTERPRO ] Q03112 SwissProt [ UNIPROT ] 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 Q03112 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00355 ZnF_C2H2 [EMBL]
Prodom PD000003 Znf_C2H2[INRA-Toulouse] Q03112 EVI1_HUMAN [ Domain structure ] Q03112 EVI1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q03112 HPRD 01310 Protein Interaction databases DIP Q03112 IntAct Q03112 Polymorphism : SNP, mutations, diseases OMIM 165215 [ map ] GENECLINICS 165215 SNP EVI1 [dbSNP-NCBI] SNP NM_001105077 [SNP-NCI] SNP NM_001105078 [SNP-NCI] SNP NM_005241 [SNP-NCI] SNP EVI1 [GeneSNPs - Utah] EVI1] [HGBASE - SRS] HAPMAP EVI1 [HAPMAP] COSMIC EVI1 [Somatic mutation (COSMIC-CGP-Sanger)] TICdb EVI1 [Translocation breakpoints In Cancer] HGMD EVI1 General knowledge Family Browser EVI1 [UCSC Family Browser] SOURCE NM_001105077 SOURCE NM_001105078 SOURCE NM_005241 SMD Hs.656395 SAGE Hs.656395 GO molecular_function [Amigo] molecular_function GO DNA binding [Amigo] DNA binding GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO multicellular organismal development [Amigo] multicellular organismal development GO biological_process [Amigo] biological_process GO zinc ion binding [Amigo] zinc ion binding GO metal ion binding [Amigo] metal ion binding KEGG MAPK signaling pathway PubGene EVI1 TreeFam EVI1
Atlas Genet Cytogenet Oncol Haematol 2008; 4 582 CTD 2122 [Comparative ToxicoGenomics Database] Other databases Probes Probe EVI1 Related clones (RZPD - Berlin) PubMed PubMed 33 Pubmed reference(s) in LocusLink Bibliography Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN Cell. 1988 ; 54 (6) : 831-840. PMID 2842066
Alternative splicing of the Evi-1 zinc finger gene generates mRNAs which differ by the number of zinc finger motifs. Bordereaux D, Fichelson S, Tambourin P, Gisselbrecht S Oncogene. 1990 ; 5 (6) : 925-927. PMID 2113669
Unique expression of the human Evi-1 gene in an endometrial carcinoma cell line: sequence of cDNAs and structure of alternatively spliced transcripts. Morishita K, Parganas E, Douglass EC, Ihle JN Oncogene. 1990 ; 5 (7) : 963-971. PMID 2115646
Patterns of Evi-1 expression in embryonic and adult tissues suggest that Evi-1 plays an important regulatory role in mouse development. Perkins AS, Mercer JA, Jenkins NA, Copeland NG Development (Cambridge, England). 1991 ; 111 (2) : 479-487. PMID 1893871
Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Nucifora G, Birn DJ, Espinosa R 3rd, Erickson P, LeBeau MM, Roulston D, McKeithan TW, Drabkin H, Rowley JD Blood. 1993 ; 81 (10) : 2728-2734. PMID 8490181
Induction of two alternatively spliced evi-1 proto-oncogene transcripts by cAMP in kidney cells. Bartholomew C, Clark AM Oncogene. 1994 ; 9 (3) : 939-942. PMID 8108138
Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M, Hirai H The EMBO journal. 1994 ; 13 (3) : 504-510. PMID 8313895
Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN, Rowley JD Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (9) : 4004-4008. PMID 8171026
Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 583 Russell M, List A, Greenberg P, Woodward S, Glinsmann B, Parganas E, Ihle J, Taetle R Blood. 1994 ; 84 (4) : 1243-1248. PMID 8049440
Identification of a breakpoint cluster region 3' of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3) (q21q26). Suzukawa K, Parganas E, Gajjar A, Abe T, Takahashi S, Tani K, Asano S, Asou H, Kamada N, Yokota J Blood. 1994 ; 84 (8) : 2681-2688. PMID 7919381 t(2;3)(p23;q26) in a patient with AML M2. Levaltier X, Penther D, Bastard C, Troussard X British journal of haematology. 1996 ; 92 (4) : page 1027. PMID 8616064
Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud N, Marynen P Blood. 1996 ; 88 (2) : 682-689. PMID 8695816
Expression of EVI1 and the Retinoblastoma genes in acute myelogenous leukemia with t(3;13) (q26;q13-14). Yufu Y, Sadamura S, Ishikura H, Abe Y, Katsuno M, Nishimura J, Nawata H American journal of hematology. 1996 ; 53 (1) : 30-34. PMID 8813093
The Evi1 proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development. Hoyt PR, Bartholomew C, Davis AJ, Yutzey K, Gamer LW, Potter SS, Ihle JN, Mucenski ML Mechanisms of development. 1997 ; 65 (1-2) : 55-70. PMID 9256345
The EVI1 gene in myeloid leukemia. Nucifora G Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1997 ; 11 (12) : 2022-2031. PMID 9447815
Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P Cancer research. 1997 ; 57 (4) : 564-569. PMID 9044825
The EVI-1 gene--its role in pathogenesis of human leukemias. Jolkowska J, Witt M Leukemia research. 2000 ; 24 (7) : 553-558. PMID 10867128
The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, Ogawa S, Moriguchi T, Nishida E, Yazaki Y, Hirai H The EMBO journal. 2000 ; 19 (12) : 2958-2968. PMID 10856240
Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-
Atlas Genet Cytogenet Oncol Haematol 2008; 4 584 localization in nuclear speckles. Chakraborty S, Senyuk V, Sitailo S, Chi Y, Nucifora G The Journal of biological chemistry. 2001 ; 276 (48) : 44936-44943. PMID 11568182
High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel- van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lowenberg B, Delwel R Blood. 2003 ; 101 (3) : 837-845. PMID 12393383
Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: case report and review of the literature. Voutsadakis IA, Maillard N American journal of hematology. 2003 ; 72 (2) : 135-137. PMID 12555218
Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia. Vinatzer U, Mannhalter C, Mitterbauer M, Gruener H, Greinix H, Schmidt HH, Fonatsch C, Wieser R Genes, chromosomes & cancer. 2003 ; 36 (1) : 80-89. PMID 12461752
Interphase fluorescence in situ hybridization assay for the detection of rearrangements of the EVI-1 locus in chromosome band 3q26 in myeloid malignancies. Wieser R, Schreiner U, Rieder H, Pirc-Danoewinata H, Gruner H, Loncarevic IF, Fonatsch C Haematologica. 2003 ; 88 (1) : 25-30. PMID 12551823
EVI1 induces myelodysplastic syndrome in mice. Buonamici S, Li D, Chi Y, Zhao R, Wang X, Brace L, Ni H, Saunthararajah Y, Nucifora G The Journal of clinical investigation. 2004 ; 114 (5) : 713-719. PMID 15343390
Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: report of 21 new cases, clinical, cytogenetic and molecular genetic features. Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij-Philipsen M, Geurts van Kessel A, Slater R, Hamers G, Michaux L, Speleman F, Hagemeijer A Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 ; 18 (6) : 1108-1114. PMID 15085164
Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'- ends. Aytekin M, Vinatzer U, Musteanu M, Raynaud S, Wieser R Gene. 2005 ; 356 : 160-168. PMID 16014322
Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Du Y, Jenkins NA, Copeland NG Blood. 2005 ; 106 (12) : 3932-3939. PMID 16109773
The Evi1 proto-oncoprotein blocks endomitosis in megakaryocytes by inhibiting sustained cyclin-dependent kinase 2 catalytic activity. Kilbey A, Alzuherri H, McColl J, Cales C, Frampton J, Bartholomew C British journal of haematology. 2005 ; 130 (6) : 902-911.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 585 PMID 16156860
Evi-1 expression in Xenopus. Mead PE, Parganas E, Ohtsuka S, Morishita K, Gamer L, Kuliyev E, Wright CV, Ihle JN Gene expression patterns : GEP. 2005 ; 5 (5) : 601-608. PMID 15905132
Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression. Yuasa H, Oike Y, Iwama A, Nishikata I, Sugiyama D, Perkins A, Mucenski ML, Suda T, Morishita K The EMBO journal. 2005 ; 24 (11) : 1976-1987. PMID 15889140
Conservation and expression of a novel alternatively spliced Evi1 exon. Alzuherri H, McGilvray R, Kilbey A, Bartholomew C Gene. 2006 ; 384 : 154-162. PMID 17014970
Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M Nature medicine. 2006 ; 12 (4) : 401-409. PMID 16582916
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 (4) : 349-356. PMID 16342172
Evi1 is specifically expressed in the distal tubule and duct of the Xenopus pronephros and plays a role in its formation. Van Campenhout C, Nichane M, Antoniou A, Pendeville H, Bronchain OJ, Marine JC, Mazabraud A, Voz ML, Bellefroid EJ Developmental biology. 2006 ; 294 (1) : 203-219. PMID 16574097 t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D Cancer. 2006 ; 106 (8) : 1730-1738. PMID 16532439
An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML British journal of haematology. 2007 ; 136 (6) : 806-813. PMID 17341266
Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T, Miyata S, Nakamura T Blood. 2007 ; 109 (9) : 3998-4005. PMID 17227832
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R
Atlas Genet Cytogenet Oncol Haematol 2008; 4 586 Gene. 2007 ; 396 (2) : 346-357. PMID 17507183
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Contributor(s) Written 05-2003 Soumen Chakraborty, Silvia Buonamici, Vitalyi Senyuk, Giuseppina Nucifora Dept. of Pathology(Rm.3314), Molecular Biology and Research Building University Of Illinois At Chicago 900 South Ashland Avenue Chicago, IL-60607, USA Updated 12-2007 Rotraud Wieser Medizinische Universitaet Wien, Department fuer Medizinische Genetik, Waehringerstr. 10, A-1090 Wien, Austria Citation This paper should be referenced as such : Chakraborty S, Buonamici S, Senyuk V, Nucifora G . EVI1 (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1). Atlas Genet Cytogenet Oncol Haematol. May 2003 . URL : http://AtlasGeneticsOncology.org/Genes/EVI103q26ID19.html Wieser R . EVI1 (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)- EVI1). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/EVI103q26ID19.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 587 Atlas of Genetics and Cytogenetics in Oncology and Haematology
KIF14 (kinesin family member 14)
Identity Other names KIAA0042 HUMORFW MGC142302 HGNC KIF14 Location 1q32.1 Genes flanking KIF14 at 1q32.1 are (centromeric to telomeric): ZNF281 (zinc finger Local_order protein 281), KIF14, DDX59 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 59). DNA/RNA Description Gene spans 68.5 kbp on the minus strand at 1q32.1. Transcription One known 6586 base transcript, 30 exons. The KIF14 promoter is bound by p130/ E2F4 under growth arrest conditions; further details of transcriptional regulation are currently lacking. Protein
Schematic representation of the KIF14 protein (not to scale). KIF14 contains two major effector domains. The first is a highly conserved 274 aa kinesin motor domain containing an ATP-binding site (aa 447-454) which is involved in microtubule-dependent ATPase activity, and a microtubule binding site (aa 455-628) involved in ATP-dependent protein transport. The second is a 67 aa forkhead-associated (FHA) domain (aa 825-891) which has similarity to the SMAD Mad Homology 2 (MH2) domain, and is involved in mediating protein- protein interactions with phosphoproteins, although no such interactions have been documented for KIF14. In addition to the highly conserved N-type neck region (N) adjacent to the motor domain, KIF14 also contains 4 other C-terminal regions predicted to form coiled-coil structures (1-4). Phosphorylation sites have been identified on Tyr-196, Ser-1200 and Ser-1292 (P), and a ubiquitination site identified on Lys-275 (U). The kinesin motor and FHA domains are flanked by a 354 aa N-terminal extension, and a 758 aa C-terminal stalk and tail region. The N-terminal extension is involved in the binding of PRC1 (protein-regulating cytokinesis 1), a protein crucial for the proper formation of the central spindle structure during cytokinesis. Citron kinase has been shown to interact with the C-terminal stalk and tail of KIF14, and this interaction is required for proper localization of KIF14 to the mitotic spindle. Description KIF14 is a 186 kDa, 1648 aa protein, containing kinesin motor and forkhead-associated (FHA) domains. It is a member of the N-3 family of kinesins. High-throughput studies have identified phosphorylations on Tyr-196; Ser-1200 and Ser-1292, and ubiquitination on Lys-275. Expression KIF14 was cloned from an immature myeloid cell line, KG-1. By qRT-PCR, KIF14 is expressed at low levels in normal adult tissues and at higher levels in placenta and fetal tissues; highest expression is in fetal thymus and liver. KIF14 expression varies with the cell cycle, with highest expression at G2-M. Localisation In HeLa cells, KIF14 is localized to the cytoplasm during interphase, and becomes tightly localized to the midbody and central spindle during cytokinesis. Function KIF14 is a mitotic kinesin motor protein with ATPase activity. It interacts with protein regulator of cytokinesis 1 (PRC1) and is essential for localizing citron kinase to the mitotic spindle. KIF14 knockdown results in failure of cytokinesis, leading to multinucleation and/or apoptosis, but no chromosome segregation defects. Homology There are KIF14 orthologs in several mammalian species. The closest Drosophila melanogaster gene, with 40% amino acid identity, is nebbish/tiovivo, encoding Klp38B
Atlas Genet Cytogenet Oncol Haematol 2008; 4 588 (kinesin-like protein 38B). Klp38B is a mitotic kinesin that binds to chromatin and microtubules in the formation of the bipolar spindle and attachment of chromosomes to the spindle, and/or acts in cytokinesis. Mutations Germinal None yet identified. Somatic None yet identified. Implicated in Entity Retinoblastoma Prognosis KIF14 mRNA and protein expression is greatly increased in tumors versus normal adult and fetal retina. mRNA expression is higher in older patients' tumors than younger. Cytogenetics KIF14 lies in a "hotspot" of genomic gain at 1q31.3-1q32.1. Low-level genomic gain (3-5 copies) of the gene is observed in 50% of tumors. High-level amplification has been observed in one tumor (along with, but independent of, MYCN amplification). Entity Breast carcinoma Prognosis mRNA expression increases with grade, and is higher in ductal than lobular carcinoma, and in estrogen receptor (ER) negative over ER positive tumors. Expression correlates with proliferation, and overexpression is prognostic for poor overall and disease-free survival. Cytogenetics KIF14 lies in a "hotspot" of genomic gain at 1q31.3-1q32.1. Low-level genomic gain of the gene is observed in 50% of breast cancer cell lines. Entity Non-small-cell lung carcinoma Prognosis mRNA expression decreases with differentiation, and is higher in squamous cell than adenocarcinoma. Overexpression is independently prognostic for poor disease-free survival, and prognostic for poor overall survival. Oncogenesis Knockdown of KIF14 decreases proliferation of H1299 NSCLC cells, and decreases their ability to form colonies in soft agar. Entity Hepatocellular carcinoma Cytogenetics Low-level gain of the KIF14 locus is seen in 58% tumors. To be noted Numerous microarray studies indexed in Oncomine document overexpression of KIF14 in other cancers, including brain tumors, seminoma, prostate and tongue cancers. External links Nomenclature HGNC KIF14 19181 Entrez_Gene KIF14 9928 kinesin family member 14 Cards Atlas KIF14ID44138ch1q32 GeneCards KIF14 Ensembl KIF14 [Search_View] ENSG00000118193 [Gene_View] Genatlas KIF14 GeneLynx KIF14 eGenome KIF14 euGene 9928 Genomic and cartography KIF14 - 1q32.1 chr1:198787930-198856485 - 1q32.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl KIF14 - 1q32.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene KIF14 Gene and transcription Genbank BC098582 [ ENTREZ ] Genbank BC113742 [ ENTREZ ] Genbank D26361 [ ENTREZ ] RefSeq NM_014875 [ SRS ] NM_014875 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 589 RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004487 [ SRS ] NT_004487 [ ENTREZ ] RefSeq NW_001838533 [ SRS ] NW_001838533 [ ENTREZ ] RefSeq NW_926128 [ SRS ] NW_926128 [ ENTREZ ] AceView KIF14 AceView - NCBI Unigene Hs.3104 [ SRS ] Hs.3104 [ NCBI ] HS3104 [ spliceNest ] Fast-db 17688 (alternative variants) Protein : pattern, domain, 3D structure Q15058 [ SRS] Q15058 [ EXPASY ] Q15058 [ INTERPRO ] Q15058 SwissProt [ UNIPROT ] Prosite PS50006 FHA_DOMAIN [ SRS ] PS50006 FHA_DOMAIN [ Expasy ] PS00411 KINESIN_MOTOR_DOMAIN1 [ SRS ] PS00411 Prosite KINESIN_MOTOR_DOMAIN1 [ Expasy ] PS50067 KINESIN_MOTOR_DOMAIN2 [ SRS ] PS50067 Prosite KINESIN_MOTOR_DOMAIN2 [ Expasy ] Interpro IPR000253 FHA [ SRS ] IPR000253 FHA [ EBI ] Interpro IPR001752 Kinesin_motor [ SRS ] IPR001752 Kinesin_motor [ EBI ] CluSTr Q15058 Pfam PF00498 FHA [ SRS ] PF00498 FHA [ Sanger ] pfam00498 [ NCBI-CDD ] Pfam PF00225 Kinesin [ SRS ] PF00225 Kinesin [ Sanger ] pfam00225 [ NCBI-CDD ] Smart SM00240 FHA [EMBL] Smart SM00129 KISc [EMBL] Blocks Q15058 HPRD 06605 Protein Interaction databases DIP Q15058 IntAct Q15058 Polymorphism : SNP, mutations, diseases OMIM 611279 [ map ] GENECLINICS 611279 SNP KIF14 [dbSNP-NCBI] SNP NM_014875 [SNP-NCI] SNP KIF14 [GeneSNPs - Utah] KIF14] [HGBASE - SRS] HAPMAP KIF14 [HAPMAP] HGMD KIF14 General knowledge Family Browser KIF14 [UCSC Family Browser] SOURCE NM_014875 SMD Hs.3104 SAGE Hs.3104 GO nucleotide binding [Amigo] nucleotide binding GO microtubule motor activity [Amigo] microtubule motor activity GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO spindle [Amigo] spindle GO microtubule [Amigo] microtubule GO microtubule associated complex [Amigo] microtubule associated complex GO microtubule-based movement [Amigo] microtubule-based movement PubGene KIF14 TreeFam KIF14 CTD 9928 [Comparative ToxicoGenomics Database] Other databases
Atlas Genet Cytogenet Oncol Haematol 2008; 4 590 Probes Probe KIF14 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S DNA research : an international journal for rapid publication of reports on genes and genomes. 1994 ; 1 (5) : 223-229. PMID 7584044
A chromatin-associated kinesin-related protein required for normal mitotic chromosome segregation in Drosophila. Molina I, Baars S, Brill JA, Hales KG, Fuller MT, Ripoll P The Journal of cell biology. 1997 ; 139 (6) : 1361-1371. PMID 9396743
Mutation of a gene for a Drosophila kinesin-like protein, Klp38B, leads to failure of cytokinesis. Ohkura H, Torok T, Tick G, Hoheisel J, Kiss I, Glover DM Journal of cell science. 1997 ; 110 ( Pt 8) : 945-954. PMID 9152020
The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Durocher D, Taylor IA, Sarbassova D, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB Molecular cell. 2000 ; 6 (5) : 1169-1182. PMID 11106755
The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Durocher D, Taylor IA, Sarbassova D, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB Molecular cell. 2000 ; 6 (5) : 1169-1182. PMID 11106755
KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers. Corson TW, Huang A, Tsao MS, Gallie BL Oncogene. 2005 ; 24 (30) : 4741-4753. PMID 15897902
Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. Zhu C, Zhao J, Bibikova M, Leverson JD, Bossy-Wetzel E, Fan JB, Abraham RT, Jiang W Molecular biology of the cell. 2005 ; 16 (7) : 3187-3199. PMID 15843429
RNA interference-mediated silencing of mitotic kinesin KIF14 disrupts cell cycle progression and induces cytokinesis failure. Carleton M, Mao M, Biery M, Warrener P, Kim S, Buser C, Marshall CG, Fernandes C, Annis J, Linsley PS Molecular and cellular biology. 2006 ; 26 (10) : 3853-3863. PMID 16648480
KIF14 mRNA expression is a predictor of grade and outcome in breast cancer. Corson TW, Gallie BL International journal of cancer. Journal international du cancer. 2006 ; 119 (5) : 1088-1094. PMID 16570270
Atlas Genet Cytogenet Oncol Haematol 2008; 4 591 KIF14 and citron kinase act together to promote efficient cytokinesis. Gruneberg U, Neef R, Li X, Chan EH, Chalamalasetty RB, Nigg EA, Barr FA The Journal of cell biology. 2006 ; 172 (3) : 363-372. PMID 16431929
Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB, Gallie BL Genes, chromosomes & cancer. 2007 ; 46 (2) : 118-129. PMID 17099872
KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS, Gallie BL Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 ; 13 (11) : 3229-3234. PMID 17545527
High expression of KIF14 in retinoblastoma: association with older age at diagnosis. Madhavan J, Coral K, Mallikarjuna K, Corson TW, Amit N, Khetan V, George R, Biswas J, Gallie BL, Kumaramanickavel G Investigative ophthalmology & visual science. 2007 ; 48 (11) : 4901-4906. PMID 17962437
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Contributor(s) Written 12-2007 Brigitte L Thériault, Timothy W Corson Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada (BLT); Department of Molecular, Cellular and Developmental Biology, Yale (TWC) Citation This paper should be referenced as such : Thériault BL, Corson TW . KIF14 (kinesin family member 14). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/KIF14ID44138ch1q32.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 592 Atlas of Genetics and Cytogenetics in Oncology and Haematology
NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
Identity Other names GP145-TrkB TRKB Trk-B HGNC NTRK2 Location 9q21.33 NTRK2 is located between solute carrier family 28, sodium-coupled nucleoside Local_order transporter member 3 (SLC28A3) and ATP/GTP binding protein 1 (AGTPBP1). DNA/RNA
Figure 1: The horizontal bar represents NTRK2 gene (355,039 bp). Vertical bars depict the exons 1-24 (red: translated regions, blue: 5' and 3' UTR regions). Table 1: NTRK2 exons and size (bp). Description NTRK2 gene is comprised between 86,473,286-86,828,325 bp of chromosome 9, with plus strand orientation. The start codon is located on exon 5. Alternative stop codons are placed on terminal exons 16, 19 and 24. Transcription According to AceView (NCBI), six alternative promoters may control transcription of the complex NTRK2 locus. There are at least 18 mRNA variants supported by cDNA clones, potentially encoding 12 complete proteins. Variants may include 8 different terminal exons with alternative polyadenylation sites. Truncation at the 5' end or 3' end, alternative splicing, intron retention, occurrence of 5 cassette exons, and different exon boundaries introduce additional differences. Five confirmed mRNA variants (a, b, c, d, e) are reported (NCBI accessions: NM_006180.3; NM_001007097.1; NM_001018064.1; NM_001018065.1; NM_001018066.1). The mRNA variant (a) encodes the full-length protein; variant (c) is slightly shorter excluding the small internal exon 17. Of particular importance are the truncated isoforms lacking the catalytic tyrosine kinase domain generated by the inclusion of alternate terminal exon 16 (b) or exon 19 (d) and (e). Pseudogene None Protein
The predicted domains of TrkB (variant c): Signal Peptide (SP, AA 1-31); Leucine Rich Repeat N-Terminal
Atlas Genet Cytogenet Oncol Haematol 2008; 4 593 domain (LRRNT, AA 31-65); Leucine-rich Repeats (LRR, AA 72-93, 96-117, 116-138); Leucine Rich Repeat C-Terminal domain (LRRCT, AA 148-195); Immunoglobulin C-2 Type 1 domain (IGC2-1, AA 197-282); Immunoglobulin C-2-type 2 domain (IGC2-2, AA 295-365); Transmembrane (TM, AA 431-454); the Protein Kinase domain (TyrKc, AA 538-807). In addition the site of interaction with SHC1 (Shc, AA 516) and with Phospho-Lipase C-gamma-1 (AA PLC-gamma, 817) are indicated. Note Three TrkB isoforms are reported by UniProt/Swiss-Prot: 1. The long isoform TrkB, including the tyrosine kinase domain (ID Q16620-1; variant c). 2. The truncated isoform TrkB-T1 lacking the tyrosine kinase domain (ID Q16620-2; variant b). 3. The truncated isoform TrkB-T-Shc lacking the tyrosine kinase domain but retaining the Shc site (ID Q16620-3; variant e). Description The unprocessed precursor of the full-length TrkB (a) consists of 838 AA. Variant (c) excludes 16 AA of unknown function, located downstream of the transmembrane segment. The N-terminal portion (AA 32-430) is potentially extracellular and includes several N- glycosylation sites (AA 67, 121, 254). It follows a single transmembrane segment (AA 432-454). The C-terminal portion is cytosolic (AA 455-822) and comprises the Protein Kinase domain. This region includes the ATP binding site (AA 544-552) and several sites of autophosphorylation such as Tyr-516/702/706/707/817 (AA position refers to variant c). The truncated Trkb-T1 (b) is composed of 477 AA. TrkB-T-Shc variants d and e consist of 553 AA and 537 AA, respectively. Truncated isoforms TrkB-T1 and TrkB-T-Shc include C-terminal sequence variations of 10 and 9 AA, respectively. Expression NTRK2 gene is preferentially expressed in brain, spinal cord, cranial and spinal ganglia. Expression is most prominent in the following brain regions: amygdale, caudate nucleus, cerebellum, choroid plexus, corpus callosum, cortex, hippocampus, hypothalamus and thalamus. In addition, a variety of cranial structures such as eyes, ophthalmic nerves, various facial districts and vestibular system indicate significant expression. Lower expression is described in several other tissues such as heart, kidney, lung, ovaries, pancreas, pituitary gland, prostate, salivary glands, skeletal muscle, spleen, thymus and thyroid. Isoforms TrkB and TrkB-T1 are expressed in brain as well as in several peripheral areas, whereas TrkB-T-Shc is primarily expressed in brain. AceView (NCBI) analysis of cDNA clones supports the expression pattern suggested by the evaluation of mRNA described above. In addition suggests elevated expression in several tumor tissues. Localisation Neuronal activity promotes TrkB translocation from intracellular vesicles to the plasma membrane where it becomes available for neurotrophins. The N-terminal segment is extracellular and is involved in neurotrophin binding and cell adhesion. A single transmembrane segment is located in the central portion of the polypeptide. The C- terminal segment is intracellular and comprises the protein kinase domain. Function TrkB specifically binds brain-derived neurotrophic factor (BDNF) and neurotrophin4/5. It can also bind neurotrophin-3 with low affinity but it excludes nerve growth factor (NGF). Neurotrophin binding triggers receptor dimerization and consequent trans- phosphorylation of tyrosine residues of the TyrKc domain. Phosphorylated receptor undergoes conformational changes, which promote the recruitment of intracellular substrates such SHC1, PI-3 kinase, and PLC-gamma-1. The signaling cascades consequently activated support neuronal survival during development and following injuries, promote neuronal differentiation and maintenance, control short-term and long- term synaptic activity. TrkB can also form heterodimers with the pan-neurotrophin receptor p75NTR or with truncated TrkB. This influences the establishment of specific connections with signaling pathways. Homology TrkB belongs to the large family of protein kinase comprising a conserved kinase domain. It is included in the subfamily of tyrosine protein kinase. For the presence of a highly conserved intracellular TyrKc domain it is most related to growth factor receptors, and particularly to the neurotrophic factor receptors TrkA and TrkC. The homology with tyrosine kinase receptors is extended to the IGC-2 and LRRs domains, however, these are also present in cell-adhesion molecules. Mutations
Atlas Genet Cytogenet Oncol Haematol 2008; 4 594 Germinal Heterozygous missense mutations leading to substitution of highly conserved residues have been linked to Obesity, Hyperphagia and Developmental Delay. Recurrent SNPs of the NTRK2 locus are associated with Eating Disorders (Anorexia and Bulimia nervosa). Somatic Tumor-specific mutations in the kinase domain have been identified in Colorectal Cancer cells. Implicated in Entity Various diseases Disease Obesity, Hyperphagia and Developmental Delay. Neuroblastomas, Pancreatic Ductal Adenocarcinomas, Wilms's tumors, Colorectal Cancer. Oncogenesis Overexpression of full-length TrkB is generally associated with malignant transformation. Excessive TrkB signaling through MAPK, PI3K and mTOR pathways support tumor development and metastasis. In highly malignant tumors the overexpression of TrkB enhances angiogenesis and invasive potential by upregulating VEGF and matrix proteases. Furthermore TrkB overcomes apoptosis caused by loss of cell-matrix interactions (anoikis), which is a natural barrier to metastasis. In contrast with the oncogenic activity of TrkB, the truncated isoforms TrkB-T1 and TrkB-T-Shc, lacking the tyrosine kinase domain, behave as dominant-negative inhibitors and counteract tumor growth.
To be noted NTRK2 gene is comprised in the region, del(9q), commonly deleted in acute myeloid leukemia, this disease is believed to arise by heterozygous loss of tumor suppressor genes. Numerous structural abnormalities of the region 9q22 are associated with cancer cases reported by The Cancer Genome Anatomy Project (CGAP). External links Nomenclature HGNC NTRK2 8032 Entrez_Gene NTRK2 4915 neurotrophic tyrosine kinase, receptor, type 2 Cards Atlas NTRK2ID41589ch9q21 GeneCards NTRK2 Ensembl NTRK2 [Search_View] ENSG00000148053 [Gene_View] Genatlas NTRK2 GeneLynx NTRK2 eGenome NTRK2 euGene 4915 Genomic and cartography NTRK2 - 9q21.33 chr9:86474446-86620441 + 9q22.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl NTRK2 - 9q22.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene NTRK2 Gene and transcription Genbank AB209118 [ ENTREZ ] Genbank AF086101 [ ENTREZ ] Genbank AF400441 [ ENTREZ ] Genbank AF410898 [ ENTREZ ] Genbank AF410899 [ ENTREZ ] RefSeq NM_001007097 [ SRS ] NM_001007097 [ ENTREZ ] RefSeq NM_001018064 [ SRS ] NM_001018064 [ ENTREZ ] RefSeq NM_001018065 [ SRS ] NM_001018065 [ ENTREZ ] RefSeq NM_001018066 [ SRS ] NM_001018066 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 595 RefSeq NM_006180 [ SRS ] NM_006180 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq AC_000141 [ SRS ] AC_000141 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_023935 [ SRS ] NT_023935 [ ENTREZ ] RefSeq NW_001839221 [ SRS ] NW_001839221 [ ENTREZ ] RefSeq NW_924484 [ SRS ] NW_924484 [ ENTREZ ] AceView NTRK2 AceView - NCBI Unigene Hs.712776 [ SRS ] Hs.712776 [ NCBI ] HS712776 [ spliceNest ] Fast-db 10067 (alternative variants) Protein : pattern, domain, 3D structure Q16620 [ SRS] Q16620 [ EXPASY ] Q16620 [ INTERPRO ] Q16620 SwissProt [ UNIPROT ] Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP Prosite [ Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM Prosite [ Expasy ] PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR Prosite [ Expasy ] PS00239 RECEPTOR_TYR_KIN_II [ SRS ] PS00239 RECEPTOR_TYR_KIN_II Prosite [ Expasy ] Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] Interpro IPR013783 Ig-like_fold [ SRS ] IPR013783 Ig-like_fold [ EBI ] Interpro IPR013098 Ig_I-set [ SRS ] IPR013098 Ig_I-set [ EBI ] Interpro IPR003598 Ig_sub2 [ SRS ] IPR003598 Ig_sub2 [ EBI ] Interpro IPR001611 LRR [ SRS ] IPR001611 LRR [ EBI ] Interpro IPR000483 LRR_C [ SRS ] IPR000483 LRR_C [ EBI ] Interpro IPR000372 LRR_cys_N [ SRS ] IPR000372 LRR_cys_N [ EBI ] Interpro IPR000719 Prot_kinase_core [ SRS ] IPR000719 Prot_kinase_core [ EBI ] IPR017441 Protein_kinase_ATP_bd_CS [ SRS ] IPR017441 Interpro Protein_kinase_ATP_bd_CS [ EBI ] IPR002011 Recept_tyr_kinase-II_CS [ SRS ] IPR002011 Recept_tyr_kinase-II_CS Interpro [ EBI ] Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ] Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr Q16620 Pfam PF07679 I-set [ SRS ] PF07679 I-set [ Sanger ] pfam07679 [ NCBI-CDD ] Pfam PF00560 LRR_1 [ SRS ] PF00560 LRR_1 [ Sanger ] pfam00560 [ NCBI-CDD ] Pfam PF01462 LRRNT [ SRS ] PF01462 LRRNT [ Sanger ] pfam01462 [ NCBI-CDD ] PF07714 Pkinase_Tyr [ SRS ] PF07714 Pkinase_Tyr [ Sanger ] pfam07714 Pfam [ NCBI-CDD ] Smart SM00408 IGc2 [EMBL] Smart SM00082 LRRCT [EMBL] Smart SM00013 LRRNT [EMBL] Smart SM00219 TyrKc [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse] Q16620 NTRK2_HUMAN [ Domain structure ] Q16620 NTRK2_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks Q16620 PDB 1HCF [ SRS ] 1HCF [ PdbSum ], 1HCF [ IMB ] 1HCF [ RSDB ] PDB 1WWB [ SRS ] 1WWB [ PdbSum ], 1WWB [ IMB ] 1WWB [ RSDB ] HPRD 02712 Protein Interaction databases
Atlas Genet Cytogenet Oncol Haematol 2008; 4 596 DIP Q16620 IntAct Q16620 Polymorphism : SNP, mutations, diseases OMIM 600456 [ map ] GENECLINICS 600456 SNP NTRK2 [dbSNP-NCBI] SNP NM_001007097 [SNP-NCI] SNP NM_001018064 [SNP-NCI] SNP NM_001018065 [SNP-NCI] SNP NM_001018066 [SNP-NCI] SNP NM_006180 [SNP-NCI] SNP NTRK2 [GeneSNPs - Utah] NTRK2] [HGBASE - SRS] HAPMAP NTRK2 [HAPMAP] COSMIC NTRK2 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD NTRK2 General knowledge Family Browser NTRK2 [UCSC Family Browser] SOURCE NM_001007097 SOURCE NM_001018064 SOURCE NM_001018065 SOURCE NM_001018066 SOURCE NM_006180 SMD Hs.712776 SAGE Hs.712776 2.7.10.1 [ Enzyme-Expasy ] 2.7.10.1 [ Enzyme-SRS ] 2.7.10.1 [ IntEnz- Enzyme EBI ] 2.7.10.1 [ BRENDA ] 2.7.10.1 [ KEGG ] 2.7.10.1 [ WIT ] GO nucleotide binding [Amigo] nucleotide binding transmembrane receptor protein tyrosine kinase activity [Amigo] transmembrane GO receptor protein tyrosine kinase activity GO receptor activity [Amigo] receptor activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO integral to plasma membrane [Amigo] integral to plasma membrane GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway GO [Amigo] transmembrane receptor protein tyrosine kinase signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway GO [Amigo] transmembrane receptor protein tyrosine kinase signaling pathway transmembrane receptor protein tyrosine kinase signaling pathway GO [Amigo] transmembrane receptor protein tyrosine kinase signaling pathway GO activation of adenylate cyclase activity [Amigo] activation of adenylate cyclase activity GO multicellular organismal development [Amigo] multicellular organismal development GO nervous system development [Amigo] nervous system development GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO kinase activity [Amigo] kinase activity GO transferase activity [Amigo] transferase activity GO cell differentiation [Amigo] cell differentiation GO neurotrophin binding [Amigo] neurotrophin binding KEGG MAPK signaling pathway PubGene NTRK2 TreeFam NTRK2 CTD 4915 [Comparative ToxicoGenomics Database] Other databases
Atlas Genet Cytogenet Oncol Haematol 2008; 4 597 Probes Probe NTRK2 Related clones (RZPD - Berlin) PubMed PubMed 85 Pubmed reference(s) in LocusLink Bibliography trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. Klein R, Parada LF, Coulier F, Barbacid M The EMBO journal. 1989 ; 8 (12) : 3701-3709. PMID 2555172
Signal transduction by receptors with tyrosine kinase activity. Ullrich A, Schlessinger J Cell. 1990 ; 61 (2) : 203-212. PMID 2158859
A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors. Schneider R, Schweiger M Oncogene. 1991 ; 6 (10) : 1807-1811. PMID 1656363
The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, Burton LE, Stanton BR, Kaplan DR, Hunter T Cell. 1991 ; 65 (5) : 895-903. PMID 1645620 trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C, Glass DJ, Masiakowski P, Furth ME, Valenzuela DM Cell. 1991 ; 65 (5) : 885-893. PMID 1710174
Identification of TrkB autophosphorylation sites and evidence that phospholipase C-gamma 1 is a substrate of the TrkB receptor. Middlemas DS, Meisenhelder J, Hunter T The Journal of biological chemistry. 1994 ; 269 (7) : 5458-5466. PMID 8106527
Expression and function of TRK-B and BDNF in human neuroblastomas. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM Molecular and cellular biology. 1994 ; 14 (1) : 759-767. PMID 8264643
Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2). Nakagawara A, Liu XG, Ikegaki N, White PS, Yamashiro DJ, Nycum LM, Biegel JA, Brodeur GM Genomics. 1995 ; 25 (2) : 538-546. PMID 7789988
Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants. Aoyama M, Asai K, Shishikura T, Kawamoto T, Miyachi T, Yokoi T, Togari H, Wada Y, Kato T, Nakagawara A Cancer letters. 2001 ; 164 (1) : 51-60. PMID 11166915
Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual
Atlas Genet Cytogenet Oncol Haematol 2008; 4 598 gene length, and splicing mechanism. Stoilov P, Castren E, Stamm S Biochemical and biophysical research communications. 2002 ; 290 (3) : 1054-1065. PMID 11798182
Mutational analysis of the tyrosine kinome in colorectal cancers. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE Science (New York, N.Y.). 2003 ; 300 (5621) : page 949. PMID 12738854
Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS Nature. 2004 ; 430 (7003) : 1034-1039. PMID 15329723
A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS Nature neuroscience. 2004 ; 7 (11) : 1187-1189. PMID 15494731
The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. Hecht M, Schulte JH, Eggert A, Wilting J, Schweigerer L Carcinogenesis. 2005 ; 26 (12) : 2105-2115. PMID 16051641 p75NTR--live or let die. Nykjaer A, Willnow TE, Petersen CM Current opinion in neurobiology. 2005 ; 15 (1) : 49-57. PMID 15721744
Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, harm avoidance and minimum body mass index. Ribases M, Gratacos M, Badia A, Jimenez L, Solano R, Vallejo J, Fernandez-Aranda F, Estivill X Molecular psychiatry. 2005 ; 10 (9) : 851-860. PMID 15838534
Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Sclabas GM, Fujioka S, Schmidt C, Li Z, Frederick WA, Yang W, Yokoi K, Evans DB, Abbruzzese JL, Hess KR, Zhang W, Fidler IJ, Chiao PJ Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (2 Pt 1) : 440-449. PMID 15701826
Delineation of the minimal commonly deleted segment and identification of candidate tumor- suppressor genes in del(9q) acute myeloid leukemia. Sweetser DA, Peniket AJ, Haaland C, Blomberg AA, Zhang Y, Zaidi ST, Dayyani F, Zhao Z, Heerema NA, Boultwood J, Dewald GW, Paietta E, Slovak ML, Willman CL, Wainscoat JS, Bernstein ID, Daly SB Genes, chromosomes & cancer. 2005 ; 44 (3) : 279-291. PMID 16015647
Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ Cancer research. 2006 ; 66 (8) : 4249-4255. PMID 16618748
Atlas Genet Cytogenet Oncol Haematol 2008; 4 599 Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Geiger TR, Peeper DS Cancer research. 2007 ; 67 (13) : 6221-6229. PMID 17616679
Neurotrophic receptor TrkB: Is it a predictor of poor prognosis for carcinoma patients? Han L, Zhang Z, Qin W, Sun W Medical hypotheses. 2007 ; 68 (2) : 407-409. PMID 17008023
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Contributor(s) Written 12-2007 Nadia Gabellini University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3; 35131, Padua, Italy Citation This paper should be referenced as such : Gabellini N . NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/NTRK2ID41589ch9q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 600 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast))
Identity Other names Alpha-PAK MGC130000 MGC130001 P65-PAK PAK-1 PAKalpha HGNC PAK1 Location 11q13.5 centromere - MYO7A GDPD4 LOC387791 PAK1 DFFZp434E1119 FLJ38894 Local_order AQP11 Note PAK1 encodes a serine/threonine specific protein kinase that is a member of the PAK branch of the STE20 family. PAK1 plays a role in cell survival, polarity, and motility, and may have oncogenic function when overexpressed. DNA/RNA
The alignment of PAK1 mRNA to its genomic sequence. Description The PAK1 gene contains 14 exons. The sizes of the exons 1-14 are 189, 100, 129, 147, 37, 119, 174, 63, 48, 112, 117, 99, 196, 137, and 86 bps. Exon 2 contains the translation initation ATG, and a few additional codons. Exon 13 contains the stop codon. Other features of the PAK1 gene, such as promoters or enhancer elements, have not been described. Transcription PAK1 expression is particularly high in the brain. Other tissues which have reasonably high levels of PAK1 expression include spleen and skeletal muscle. The mRNA size is 1945 bps. Protein
Description PAK1 is a highly conserved serine/threonine protein kinase of 545 amino acids and is a member of the PAK group of the STE20 family of serine/threonine protein kinases. Pak1 is active in a monomeric form; the non-active form is an autoinhibited homodimer. Pak1 contains a regulatory N-terminal regulatory domain and C-terminal catalytic domain The regulatory domain consists of a p21 GTPase-binding domain (PBD), an inhibitory domain (PID); five SH3-domains; and one non-classical SH3-binding site for the PIX family of proteins (PXP). Pak1 binds to activated forms of the GTPases Cdc42 and Rac. Pak1 homodimerizes through a motif adjacent to the p21-binding domain, and is autoinhibited. Upon binding to Cdc42 or Rac, Pak1 is activated and autophosphorylates. Pak1 has dozens of substrates, activating cytoskeletal and transcription pathways that enhance cell motility, proliferation, and survival. Expression PAK1 is highly expressed in epithelium of tongue and larynx and in thyroid gland,
Atlas Genet Cytogenet Oncol Haematol 2008; 4 601 expression also found in central nervous system (brain). Localisation Under basal conditions, Pak1 localizes to the cytosol. Upon growth factor stimulation, Pak1 is recruited to the plasma membrane as well as the nucleus. Function Cell survival and proliferation Homology Similar to STE20 in budding yeast and PAK1 in fission yeast. Human PAK1 complements both these yeast genes. Mutations Note No mutations in the PAK1 gene have been reported Implicated in Entity Cancers Disease There is emerging evidence that the Pak family may play a key role in several human malignancies, including breast, ovarian, head and neck, colon, thyroid, and renal cancer. In human breast cancer, the expression level of Pak1 correlates with the tumor grade, with higher expression in less differentiated ductal carcinomas of the breast (grade III tumors) than in grade II and grade I tumors. Pak1 overexpression is also associated with tamoxifen resistance in breast cancer. In human tumors, Pak1 is not itself activated by mutation: rather, Pak1 is overexpressed by unknown mechanisms. Pak1 may also play a role in transformation by Kaposi's sarcoma-associated herpes virus, which induces Kaposi's sarcoma and primary effusion lymphomas. Prognosis Recently, it has been shown that the level of phosphorylated (activated) Pak1 Level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. As noted above, Pak1 expression may also correlate with tamoxifen resistance in breast cancer. External links Nomenclature HGNC PAK1 8590 Entrez_Gene PAK1 5058 p21 protein (Cdc42/Rac)-activated kinase 1 Cards Atlas PAK1ID41633ch11q13 GeneCards PAK1 Ensembl PAK1 [Search_View] ENSG00000149269 [Gene_View] Genatlas PAK1 GeneLynx PAK1 eGenome PAK1 euGene 5058 Genomic and cartography PAK1 - 11q13.5 chr11:76710708-76862756 - 11q13-q14 [Description] (hg18- GoldenPath Mar_2006) Ensembl PAK1 - 11q13-q14 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PAK1 Gene and transcription Genbank AF071884 [ ENTREZ ] Genbank AK055228 [ ENTREZ ] Genbank AK293098 [ ENTREZ ] Genbank BC050377 [ ENTREZ ] Genbank BC109298 [ ENTREZ ] RefSeq NM_001128620 [ SRS ] NM_001128620 [ ENTREZ ] RefSeq NM_002576 [ SRS ] NM_002576 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq AC_000143 [ SRS ] AC_000143 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_033927 [ SRS ] NT_033927 [ ENTREZ ] RefSeq NW_001838028 [ SRS ] NW_001838028 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 602 RefSeq NW_925106 [ SRS ] NW_925106 [ ENTREZ ] AceView PAK1 AceView - NCBI Unigene Hs.435714 [ SRS ] Hs.435714 [ NCBI ] HS435714 [ spliceNest ] Fast-db 12220 (alternative variants) Protein : pattern, domain, 3D structure Q13153 [ SRS] Q13153 [ EXPASY ] Q13153 [ INTERPRO ] Q13153 SwissProt [ UNIPROT ] Prosite PS50108 CRIB [ SRS ] PS50108 CRIB [ Expasy ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP Prosite [ Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM Prosite [ Expasy ] PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 PROTEIN_KINASE_ST [ Expasy Prosite ] Interpro IPR000095 PAK_box_Rho_bd [ SRS ] IPR000095 PAK_box_Rho_bd [ EBI ] Interpro IPR015750 Pak_like [ SRS ] IPR015750 Pak_like [ EBI ] Interpro IPR000719 Prot_kinase_core [ SRS ] IPR000719 Prot_kinase_core [ EBI ] IPR017441 Protein_kinase_ATP_bd_CS [ SRS ] IPR017441 Interpro Protein_kinase_ATP_bd_CS [ EBI ] Interpro IPR017442 Se/Thr_pkinase-rel [ SRS ] IPR017442 Se/Thr_pkinase-rel [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ] Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr Q13153 Pfam PF00786 PBD [ SRS ] PF00786 PBD [ Sanger ] pfam00786 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ] Smart SM00285 PBD [EMBL] Smart SM00220 S_TKc [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse] Q13153 PAK1_HUMAN [ Domain structure ] Q13153 PAK1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q13153 PDB 1F3M [ SRS ] 1F3M [ PdbSum ], 1F3M [ IMB ] 1F3M [ RSDB ] PDB 1YHV [ SRS ] 1YHV [ PdbSum ], 1YHV [ IMB ] 1YHV [ RSDB ] PDB 1YHW [ SRS ] 1YHW [ PdbSum ], 1YHW [ IMB ] 1YHW [ RSDB ] PDB 1ZSG [ SRS ] 1ZSG [ PdbSum ], 1ZSG [ IMB ] 1ZSG [ RSDB ] PDB 2HY8 [ SRS ] 2HY8 [ PdbSum ], 2HY8 [ IMB ] 2HY8 [ RSDB ] HPRD 03995 Protein Interaction databases DIP Q13153 IntAct Q13153 Polymorphism : SNP, mutations, diseases OMIM 602590 [ map ] GENECLINICS 602590 SNP PAK1 [dbSNP-NCBI] SNP NM_001128620 [SNP-NCI] SNP NM_002576 [SNP-NCI] SNP PAK1 [GeneSNPs - Utah] PAK1] [HGBASE - SRS] HAPMAP PAK1 [HAPMAP] COSMIC PAK1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PAK1 General knowledge Family Browser PAK1 [UCSC Family Browser] SOURCE NM_001128620 SOURCE NM_002576
Atlas Genet Cytogenet Oncol Haematol 2008; 4 603 SMD Hs.435714 SAGE Hs.435714 2.7.11.1 [ Enzyme-Expasy ] 2.7.11.1 [ Enzyme-SRS ] 2.7.11.1 [ IntEnz- Enzyme EBI ] 2.7.11.1 [ BRENDA ] 2.7.11.1 [ KEGG ] 2.7.11.1 [ WIT ] GO MAPKKK cascade [Amigo] MAPKKK cascade GO nucleotide binding [Amigo] nucleotide binding GO protein serine/threonine kinase activity [Amigo] protein serine/threonine kinase activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO cytoplasm [Amigo] cytoplasm GO plasma membrane [Amigo] plasma membrane GO apoptosis [Amigo] apoptosis GO ER-nuclear signaling pathway [Amigo] ER-nuclear signaling pathway cytoskeleton organization and biogenesis [Amigo] cytoskeleton organization and GO biogenesis GO transferase activity [Amigo] transferase activity GO cell junction [Amigo] cell junction GO positive regulation of JNK activity [Amigo] positive regulation of JNK activity protein amino acid autophosphorylation [Amigo] protein amino acid GO autophosphorylation Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent BIOCARTA signaling [Genes] BIOCARTA Influence of Ras and Rho proteins on G1 to S Transition [Genes] BIOCARTA Agrin in Postsynaptic Differentiation [Genes] Role of PI3K subunit p85 in regulation of Actin Organization and Cell BIOCARTA Migration [Genes] BIOCARTA fMLP induced chemokine gene expression in HMC-1 cells [Genes] BIOCARTA FAS signaling pathway ( CD95 ) [Genes] BIOCARTA MAPKinase Signaling Pathway [Genes] BIOCARTA Signaling of Hepatocyte Growth Factor Receptor [Genes] BIOCARTA Ras-Independent pathway in NK cell-mediated cytotoxicity [Genes] BIOCARTA Links between Pyk2 and Map Kinases [Genes] BIOCARTA Rac 1 cell motility signaling pathway [Genes] BIOCARTA TNFR1 Signaling Pathway [Genes] KEGG MAPK signaling pathway KEGG Axon guidance KEGG Focal adhesion KEGG Natural killer cell mediated cytotoxicity KEGG T cell receptor signaling pathway KEGG Epithelial cell signaling in Helicobacter pylori infection PubGene PAK1 TreeFam PAK1 CTD 5058 [Comparative ToxicoGenomics Database] Other databases Probes Probe PAK1 Related clones (RZPD - Berlin) PubMed PubMed 171 Pubmed reference(s) in LocusLink Bibliography A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L Nature. 1994 ; 367 (6458) : 40-46. PMID 8107774
Emerging from the Pak: the p21-activated protein kinase family.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 604 Sells MA, Chernoff J Trends in cell biology. 1997 ; 7 (4) : 162-167. PMID 17708935
Pak to the future. Bagrodia S, Cerione RA Trends in cell biology. 1999 ; 9 (9) : 350-355. PMID 10461188
The Ste20 group kinases as regulators of MAP kinase cascades. Dan I, Watanabe NM, Kusumi A Trends in cell biology. 2001 ; 11 (5) : 220-230. PMID 11316611 p21-activated kinases: three more join the Pak. Jaffer ZM, Chernoff J The international journal of biochemistry & cell biology. 2002 ; 34 (7) : 713-717. PMID 11950587
Biology of the p21-activated kinases. Bokoch GM Annual review of biochemistry. 2003 ; 72 : 743-781. PMID 12676796
The genetics of Pak. Hofmann C, Shepelev M, Chernoff J Journal of cell science. 2004 ; 117 (Pt 19) : 4343-4354. PMID 15331659 p21-activated kinases in cancer. Kumar R, Gururaj AE, Barnes CJ Nature reviews. Cancer. 2006 ; 6 (6) : 459-471. PMID 16723992
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Contributor(s) Written 12-2007 Dina Stepanova, Jonathan Chernoff Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA Citation This paper should be referenced as such : Stepanova D, Chernoff J . PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PAK1ID41633ch11q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 605 Atlas of Genetics and Cytogenetics in Oncology and Haematology
POU4F1 (POU class 4 homeobox 1)
Identity Other names BRN3A Brn-3a FLJ13449 Oct-T1 RDC-1 HGNC POU4F1 Location 13q31.1 Local_order Gene orientation: minus strand Note Member of class IV POU domain transcription factor. DNA/RNA Description The gene is about 4,468 bases encoded by two exons separated by a short intron. Transcription 5', upstream promoter drives expression of longer Brn-3a transcript encoding for Brn-3a(l) protein which includes exons 1 and 2. Regulatory sequences within the intron control expression of short Brn-3a transcript entirely from exon 2, which encodes Brn-3a(s) protein. Protein
Schematic diagram showing the two isoforms of Brn3-a protein that can be derived from the Brn-3a gene as a result of alternative promoter usage (P1 and P2). AD refers to N-terminal activation domain present only in Brn-3a(l). POU domain found at the C' terminal of the protein is common to both Brn-3a(l) and Brn-3a(s). Description Protein product for Brn-3a(l) is 423 amino acids with estimated molecular weight of about 42.9 kDa whereas Brn-3a(s) protein is 339 amino acids; about 32 kDa. Expression Nervous System: Originally isolated from brain cDNA, Brn-3a is expressed in specific neurons of midbrain and hindbrain in CNS and in peripheral sensory neurons (trigeminal ganglia, dorsal root ganglia, spinal cord). It is first seen in neural crest cells that are destined to form sensory neurons and expression persists in mature neurones. Brn-3a is also expressed in retinal ganglion cells and vestibular somatosensory cells, where it cooperates with Brn-3b and Brn-3c respectively to determine cell fate. Non-neuronal cell: Brn-3a is also expressed in T-cells, heart, testis, ovary, breast epithelium. Cancers: implicated in neuroblastoma, Ewing sarcoma, cervical cancers, prostate cancers. Localisation Nuclear Function Brn-3a proteins act as transcription factors to regulate the expression of target genes, which can alter cell fate. In neuron, Brn-3a protects cells from apoptosis (by transactivating anti-apoptotic genes while repressing expression of pro-apoptotic proteins -see below). Brn-3a also enhances differentiation of neuronal cells in vitro and in-vivo by its ability to transactivate multiple neuronal target promoters. Brn-3a is required for the generation of proprioceptors in trigeminal ganglia. The POU domain found at the C' terminal end of Brn-3a proteins is a bipartite DNA binding domain that can recognize and bind with high affinity and specificity to specific DNA sequences present in the promoters of target genes. DNA consensus sites recognized by Brn-3a include a core A/T rich octamer sequence e.g. ATAATTAAT with
Atlas Genet Cytogenet Oncol Haematol 2008; 4 606 the POU-homeodomain (POU-HD) facilitating high affinity binding, whilst the POU- specific (POU-s) domain enhances specificity. The POU domain of Brn-3a protein also has transactivation function and since Brn-3a(l) and Brn-3a(s) are identical in this region, both proteins can regulate specific subsets of target genes that require POU domain transactivation function e.g. neurofilament, SNAP 25, synaptophysin, Hsp-27. However, some Brn-3a target genes require the N' terminal transactivation domain that is found only in Brn-3a(l) protein and therefore these target genes can only be activated by Brn-3a(l) protein e.g. Bcl-2, Bcl- XL, alpha-internexin. Other target genes regulated by Brn-3a include TrkA, neuroD1 and neuroD4, Nav1.7 sodium channel, Doppel glycoprotein, iNOS, p53, NGFI-A, Hsp-27, tyrosine hydroxylase. Brn-3a also auto-regulate its own expression. In addition to its direct effects on specific target genes, Brn-3a can also alter gene expression by its interaction with other cellular factors. For example, Brn-3a interacts physically with p53 protein, and modifies its effects on specific target genes that regulate cell fate. Thus Brn-3a cooperates with p53 to increase the expression of the cell cycle regulator, p21cip1/waf1 whilst antagonising p53 mediated expression of pro- apoptotic target genes, Bax and Noxa. Brn-3a other interacting partner includes Rin1 (on target gene, Egr1), HIPK1 (alters TrkA expression), EWS- Fli1 fusion protein (represses Brn-3a mediated effects on survival / differentiation genes). In addition to cellular target genes, Brn-3a also controls expression of viral genes such as those encoding the human papilloma virus (HPV) immediate early E6/E7 gene (required for HPV transformation of cervical cells) by binding to and transactivating the viral promoter. It is thought that the ability of Brn-3a to transactivate this promoter contributes to its effects in transformation of cervical cancer cells. Homology High homology with other POU4 family members in the POU domain (C' terminal end of the protein), and in the POU4 box (region of homology within the N' terminal transactivation domain, present only in Brn-3a(l)). Family members include mammalian POU4f2 (Brn-3b), POU4f3 (Brn-3c), drosophila I-POU and nematode, unc-86. Implicated in Entity Normal development of sensory neurons in CNS and PNS Note Loss of Brn-3a by homologous recombination in mice resulted in significant loss of sensory neurons (e.g. in the midbrain, trigeminal ganglia, dorsal root ganglia) during development. Mutants die within the first day of birth. Studies using cultured neural crest cells demonstrate that Brn-3a expressing cells are destined for sensory lineage. Brn-3a is required for the survival of these cells and achieves this partly by inhibiting expression of p53 mediated, pro-apoptotic target genes. Neural crest cells cultured from Brn-3a knockout mice, undergo significant apoptosis as a result of increased expression of p53 pro-apoptotic target genes, bax and Noxa. Entity Neuroblastomas Oncogenesis Brn-3a mRNA is significantly reduced in neuroblastoma tumour biopsies. Studies undertaken using neuroblastoma cell lines showed that Brn-3a is expressed at low levels when the cells are actively proliferating. However, when cells are induced to cease dividing and undergo differentiation, Brn-3a is significantly increased in cells. Forced over-expression of Brn-3a protects cells from apoptosis but also induces differentiation and neurite outgrowth. Therefore, the significant decrease of Brn-3 in neuroblastoma tumours may contribute to the oncogenic changes in the cells. Entity Neuroendocrine tumours Oncogenesis Brn-3a was shown to be elevated in highly aggressive neuroendocrine tumours SCCL tumours and ACTH producing pituitary tumours. Entity Ewing sarcoma Oncogenesis Brn-3a was detected in some Ewing sarcomas, which are tumours derived from primitive neural ectodermal lineage. These tumours are characterised by rearrangement of genes encoding the Ewing sarcoma (EWS) protein, and members of the Ets family of transcription factors. The most common fusion protein, EWS/Fli1, produces cellular transformation. Brn-3a interacts with the EWS/Fli1 fusion protein, and this interaction prevents Brn-3a mediated transactivation of genes required for cell cycle arrest e.g. p21cip1/waf1 and neurite outgrowth e.g. SNAP-25. Entity Cervical cancer
Atlas Genet Cytogenet Oncol Haematol 2008; 4 607 Oncogenesis Brn-3a is expressed at high levels in high-grade cervical intra-epithelial neoplasia (CIN 3) compared to normal cervical biopsies. In this context, Brn-3a may contribute to tissue formation by binding to regulatory regions of Human Papilloma Viruses, HPV-16 and HPV18 and regulate expression of their oncogenic E6 and E7 genes. Entity Prostate cancer Oncogenesis Brn-3a was also detected in prostate cancers with up to 50% of tumours showing significant increase in expression of Brn-3a short isoforms. Entity Systemic lupus erythematosus Note Brn-3a is elevated in approximately 43% of patients with SLE and this correlates with enhanced levels of auto-antibodies to the protein. Increased Brn-3a also correlates with enhanced expression of HSP 90 protein in serum of SLE patients. External links Nomenclature HGNC POU4F1 9218 Entrez_Gene POU4F1 5457 POU class 4 homeobox 1 Cards Atlas POU4F1ID44173ch13q31 GeneCards POU4F1 Ensembl POU4F1 [Search_View] ENSG00000152192 [Gene_View] Genatlas POU4F1 GeneLynx POU4F1 eGenome POU4F1 euGene 5457 Genomic and cartography POU4F1 - 13q31.1 chr13:78071231-78075696 - 13q31.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl POU4F1 - 13q31.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene POU4F1 Gene and transcription Genbank BC148330 [ ENTREZ ] Genbank BC148792 [ ENTREZ ] Genbank BM714015 [ ENTREZ ] Genbank BM726529 [ ENTREZ ] Genbank L20433 [ ENTREZ ] RefSeq NM_006237 [ SRS ] NM_006237 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ] RefSeq NW_925506 [ SRS ] NW_925506 [ ENTREZ ] AceView POU4F1 AceView - NCBI Unigene Hs.654522 [ SRS ] Hs.654522 [ NCBI ] HS654522 [ spliceNest ] Fast-db 7053 (alternative variants) Protein : pattern, domain, 3D structure Q01851 [ SRS] Q01851 [ EXPASY ] Q01851 [ INTERPRO ] Q01851 SwissProt [ UNIPROT ] Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ] Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ] Prosite PS00035 POU_1 [ SRS ] PS00035 POU_1 [ Expasy ] Prosite PS00465 POU_2 [ SRS ] PS00465 POU_2 [ Expasy ] Prosite PS51179 POU_3 [ SRS ] PS51179 POU_3 [ Expasy ] Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ] Interpro IPR012287 Homeodomain-rel [ SRS ] IPR012287 Homeodomain-rel [ EBI ]
Atlas Genet Cytogenet Oncol Haematol 2008; 4 608 Interpro IPR013847 POU [ SRS ] IPR013847 POU [ EBI ] Interpro IPR015584 POU_4_related [ SRS ] IPR015584 POU_4_related [ EBI ] Interpro IPR000327 POU_specific [ SRS ] IPR000327 POU_specific [ EBI ] CluSTr Q01851 PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger ] pfam00046 [ NCBI- Pfam CDD ] Pfam PF00157 Pou [ SRS ] PF00157 Pou [ Sanger ] pfam00157 [ NCBI-CDD ] Smart SM00389 HOX [EMBL] Smart SM00352 POU [EMBL] Prodom PD000010 Homeobox[INRA-Toulouse] Q01851 PO4F1_HUMAN [ Domain structure ] Q01851 PO4F1_HUMAN [ sequences Prodom sharing at least 1 domain ] Prodom PD000010[INRA-Toulouse] Q01851 PO4F1_HUMAN [ Domain structure ] Q01851 PO4F1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q01851 HPRD 03379 Protein Interaction databases DIP Q01851 IntAct Q01851 Polymorphism : SNP, mutations, diseases OMIM 601632 [ map ] GENECLINICS 601632 SNP POU4F1 [dbSNP-NCBI] SNP NM_006237 [SNP-NCI] SNP POU4F1 [GeneSNPs - Utah] POU4F1] [HGBASE - SRS] HAPMAP POU4F1 [HAPMAP] HGMD POU4F1 General knowledge Family Browser POU4F1 [UCSC Family Browser] SOURCE NM_006237 SMD Hs.654522 SAGE Hs.654522 GO suckling behavior [Amigo] suckling behavior GO transcription factor activity [Amigo] transcription factor activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus regulation of transcription from RNA polymerase II promoter [Amigo] regulation of GO transcription from RNA polymerase II promoter GO multicellular organismal development [Amigo] multicellular organismal development GO axonogenesis [Amigo] axonogenesis GO synaptogenesis [Amigo] synaptogenesis GO cell migration in hindbrain [Amigo] cell migration in hindbrain central nervous system neuron differentiation [Amigo] central nervous system neuron GO differentiation GO positive regulation of apoptosis [Amigo] positive regulation of apoptosis GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding peripheral nervous system neuron differentiation [Amigo] peripheral nervous system GO neuron differentiation GO proprioception during equilibrioception [Amigo] proprioception during equilibrioception PubGene POU4F1 TreeFam POU4F1 CTD 5457 [Comparative ToxicoGenomics Database] Other databases
Atlas Genet Cytogenet Oncol Haematol 2008; 4 609 Probes Probe POU4F1 Related clones (RZPD - Berlin) PubMed PubMed 20 Pubmed reference(s) in LocusLink Bibliography Expression of a large family of POU-domain regulatory genes in mammalian brain development. He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG Nature. 1989 ; 340 (6228) : 35-41. PMID 2739723
A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system. Collum RG, Fisher PE, Datta M, Mellis S, Thiele C, Huebner K, Croce CM, Israel MA, Theil T, Moroy T Nucleic acids research. 1992 ; 20 (18) : 4919-4925. PMID 1357630
A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells. Lillycrop KA, Budrahan VS, Lakin ND, Terrenghi G, Wood JN, Polak JM, Latchman DS Nucleic acids research. 1992 ; 20 (19) : 5093-5096. PMID 1383937
Differential expression of four members of the POU family of proteins in activated and phorbol 12-myristate 13-acetate-treated Jurkat T cells. Bhargava AK, Li Z, Weissman SM Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (21) : 10260-10264. PMID 8234287
The DNA target site for the Brn-3 POU family transcription factors can confer responsiveness to cyclic AMP and removal of serum in neuronal cells. Budhram-Mahadeo V, Theil T, Morris PJ, Lillycrop KA, Moroy T, Latchman DS Nucleic acids research. 1994 ; 22 (15) : 3092-3098. PMID 8065921
The levels of the antagonistic POU family transcription factors Brn-3a and Brn-3b in neuronal cells are regulated in opposite directions by serum growth factors. Budhram-Mahadeo V, Lillycrop KA, Latchman DS Neuroscience letters. 1995 ; 185 (1) : 48-51. PMID 7731552
Activation of the alpha-internexin promoter by the Brn-3a transcription factor is dependent on the N-terminal region of the protein. Budhram-Mahadeo V, Morris PJ, Lakin ND, Theil T, Ching GY, Lillycrop KA, Moroy T, Liem RK, Latchman DS The Journal of biological chemistry. 1995 ; 270 (6) : 2853-2858. PMID 7852360
Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors. Fedtsova NG, Turner EE Mechanisms of development. 1995 ; 53 (3) : 291-304. PMID 8645597
Regulation of neurite outgrowth and SNAP-25 gene expression by the Brn-3a transcription factor. Lakin ND, Morris PJ, Theil T, Sato TN, Moroy T, Wilson MC, Latchman DS The Journal of biological chemistry. 1995 ; 270 (26) : 15858-15863. PMID 7797590
Atlas Genet Cytogenet Oncol Haematol 2008; 4 610 Activation of the herpes simplex virus immediate-early gene promoters by neuronally expressed POU family transcription factors. Lillycrop KA, Liu YZ, Theil T, Moroy T, Latchman DS The Biochemical journal. 1995 ; 307 ( Pt 2) : 581-584. PMID 7733899
The neuronal nicotinic acetylcholine receptor alpha 2 subunit gene promoter is activated by the Brn-3b POU family transcription factor and not by Brn-3a or Brn-3c. Milton NG, Bessis A, Changeux JP, Latchman DS The Journal of biological chemistry. 1995 ; 270 (25) : 15143-15147. PMID 7797498
The different activities of the two activation domains of the Brn-3a transcription factor are dependent on the context of the binding site. Budhram-Mahadeo V, Morris PJ, Lakin ND, Dawson SJ, Latchman DS The Journal of biological chemistry. 1996 ; 271 (15) : 9108-9113. PMID 8621561
Activation and repression of gene expression by POU family transcription factors. Latchman DS Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 1996 ; 351 (1339) : 511-515. PMID 8735273
Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells. Liu YZ, Dawson SJ, Latchman DS Journal of molecular neuroscience : MN. 1996 ; 7 (1) : 77-85. PMID 8835784
Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG Nature. 1996 ; 384 (6609) : 574-577. PMID 8955272
Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors. Milton NG, Bessis A, Changeux JP, Latchman DS The Biochemical journal. 1996 ; 317 ( Pt 2) : 419-423. PMID 8713067
Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors. Morris PJ, Lakin ND, Dawson SJ, Ryabinin AE, Kilimann MW, Wilson MC, Latchman DS Brain research. Molecular brain research. 1996 ; 43 (1-2) : 279-285. PMID 9037543
The functionally antagonistic POU family transcription factors Brn-3a and Brn-3b show opposite changes in expression during the growth arrest and differentiation of human neuroblastoma cells. Smith MD, Latchman DS International journal of cancer. Journal international du cancer. 1996 ; 67 (5) : 653-660. PMID 8782654
POU-domain factor expression in the trigeminal ganglion and implications for herpes virus regulation. Turner EE, Fedtsova N, Rosenfeld MG Neuroreport. 1996 ; 7 (18) : 2829-2832. PMID 9116190
Atlas Genet Cytogenet Oncol Haematol 2008; 4 611 Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Xiang M, Gan L, Zhou L, Klein WH, Nathans J Proceedings of the National Academy of Sciences of the United States of America. 1996 ; 93 (21) : 11950-11955. PMID 8876243
High expression of the POU factor Brn3a in aggressive neuroendocrine tumors. Leblond-Francillard M, Picon A, Bertagna X, de Keyzer Y The Journal of clinical endocrinology and metabolism. 1997 ; 82 (1) : 89-94. PMID 8989239
The Brn-3a transcription factor induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Smith MD, Dawson SJ, Latchman DS Molecular and cellular biology. 1997 ; 17 (1) : 345-354. PMID 8972215
Coordinate induction of the three neurofilament genes by the Brn-3a transcription factor. Smith MD, Morris PJ, Dawson SJ, Schwartz ML, Schlaepfer WW, Latchman DS The Journal of biological chemistry. 1997 ; 272 (34) : 21325-21333. PMID 9261145
Role of the Brn-3 family of POU-domain genes in the development of the auditory/vestibular, somatosensory, and visual systems. Xiang M, Gan L, Li D, Zhou L, Chen ZY, Wagner D, O'Malley BW Jr, Klein W, Nathans J Cold Spring Harbor symposia on quantitative biology. 1997 ; 62 : 325-336. PMID 9598366
The Brn-3a transcription factor. Latchman DS The international journal of biochemistry & cell biology. 1998 ; 30 (11) : 1153-1157. PMID 9839440
Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter. Gay RD, Dawson SJ, Murphy WJ, Russell SW, Latchman DS Biochimica et biophysica acta. 1998 ; 1443 (3) : 315-322. PMID 9878805
The HPV-activating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions. Ndisdang D, Morris PJ, Chapman C, Ho L, Singer A, Latchman DS The Journal of clinical investigation. 1998 ; 101 (8) : 1687-1692. PMID 9541499
The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression. Smith MD, Dawson SJ, Boxer LM, Latchman DS Nucleic acids research. 1998 ; 26 (18) : 4100-4107. PMID 9722627
NT-3 regulates expression of Brn3a but not Brn3b in developing mouse trigeminal sensory neurons. Wyatt S, Ensor L, Begbie J, Ernfors P, Reichardt LF, Latchman DS Brain research. Molecular brain research. 1998 ; 55 (2) : 254-264. PMID 9582431 p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 612 Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS The Journal of biological chemistry. 1999 ; 274 (21) : 15237-15244. PMID 10329733
POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression. Huang EJ, Zang K, Schmidt A, Saulys A, Xiang M, Reichardt LF Development (Cambridge, England). 1999 ; 126 (13) : 2869-2882. PMID 10357931
The Brn-3a transcription factor plays a critical role in regulating human papilloma virus gene expression and determining the growth characteristics of cervical cancer cells. Ndisang D, Budhram-Mahadeo V, Latchman DS The Journal of biological chemistry. 1999 ; 274 (40) : 28521-28527. PMID 10497216
Regulation of NGFI-A (Egr-1) gene expression by the POU domain transcription factor Brn-3a. Smith MD, Ensor EA, Stohl L, Wagner JA, Latchman DS Brain research. Molecular brain research. 1999 ; 74 (1-2) : 117-125. PMID 10640682
Autoregulatory sequences are revealed by complex stability screening of the mouse brn-3.0 locus. Trieu M, Rhee JM, Fedtsova N, Turner EE The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 ; 19 (15) : 6549-6558. PMID 10414983
Widespread elevated expression of the human papilloma virus (HPV)-activating cellular transcription factor Brn-3a in the cervix of women with CIN3 (cervical intraepithelial neoplasia stage 3). Ndisang D, Budhram-Mahadeo V, Singer A, Latchman DS Clinical science (London, England : 1979). 2000 ; 98 (5) : 601-602. PMID 10781392
The closely related POU family transcription factors Brn-3a and Brn-3b are expressed in distinct cell types in the testis. Budhram-Mahadeo V, Moore A, Morris PJ, Ward T, Weber B, Sassone-Corsi P, Latchman DS The international journal of biochemistry & cell biology. 2001 ; 33 (10) : 1027-1039. PMID 11470235
Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice. Eng SR, Gratwick K, Rhee JM, Fedtsova N, Gan L, Turner EE The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 ; 21 (2) : 541-549. PMID 11160433
The BRN-3A transcription factor protects sensory but not sympathetic neurons from programmed cell death/apoptosis. Ensor E, Smith MD, Latchman DS The Journal of biological chemistry. 2001 ; 276 (7) : 5204-5212. PMID 11053412
Signals from the ventral midline and isthmus regulate the development of Brn3.0-expressing neurons in the midbrain. Fedtsova N, Turner EE Mechanisms of development. 2001 ; 105 (1-2) : 129-144. PMID 11429288
Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding
Atlas Genet Cytogenet Oncol Haematol 2008; 4 613 of inner ear sensory neurons. Huang EJ, Liu W, Fritzsch B, Bianchi LM, Reichardt LF, Xiang M Development (Cambridge, England). 2001 ; 128 (13) : 2421-2432. PMID 11493560
The Brn-3a transcription factor plays a key role in regulating the growth of cervical cancer cells in vivo. Ndisang D, Budhram-Mahadeo V, Pedley B, Latchman DS Oncogene. 2001 ; 20 (35) : 4899-4903. PMID 11521202
Brn-3a activates the expression of Bcl-x(L) and promotes neuronal survival in vivo as well as in vitro. Smith MD, Melton LA, Ensor EA, Packham G, Anderson P, Kinloch RA, Latchman DS Molecular and cellular neurosciences. 2001 ; 17 (3) : 460-470. PMID 11273642
The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1). Budram-Mahadeo V, Morris PJ, Latchman DS Oncogene. 2002 ; 21 (39) : 6123-6131. PMID 12203124
The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells. Budhram-Mahadeo V, Morris P, Ndisang D, Irshad S, Lozano G, Pedley B, Latchman DS Neuroscience letters. 2002 ; 334 (1) : 1-4. PMID 12431761
Accessibility of phosphates in domain I of 23 S rRNA in the ribosomal 50 S subunit as detected by R(P) phosphorothioates. Maivali U, Pulk A, Loogvali EL, Remme J Biochimica et biophysica acta. 2002 ; 1579 (1) : 1-7. PMID 12401213
Effect of Brn-3a deficiency on nociceptors and low-threshold mechanoreceptors in the trigeminal ganglion. Ichikawa H, Mo Z, Xiang M, Sugimoto T Brain research. Molecular brain research. 2002 ; 104 (2) : 240-245. PMID 12225879
Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter. Perez-Sanchez C, Budhram-Mahadeo VS, Latchman DS Nucleic acids research. 2002 ; 30 (22) : 4872-4880. PMID 12433990
The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription. Thomas GR, Latchman DS Cancer biology & therapy. 2002 ; 1 (4) : 428-432. PMID 12432261
Brn3a regulation of TrkA/NGF receptor expression in developing sensory neurons. Ma L, Lei L, Eng SR, Turner E, Parada LF Development (Cambridge, England). 2003 ; 130 (15) : 3525-3534. PMID 12810599
Doppel expression is regulated by the Brn-3a and Brn-3b transcription factors.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 614 Calissano M, Ensor E, Brown DR, Latchman DS Neuroreport. 2004 ; 15 (3) : 483-486. PMID 15094508
Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Eng SR, Lanier J, Fedtsova N, Turner EE Development (Cambridge, England). 2004 ; 131 (16) : 3859-3870. PMID 15253936
Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a. Farooqui-Kabir SR, Budhram-Mahadeo V, Lewis H, Latchman DS, Marber MS, Heads RJ Cell death and differentiation. 2004 ; 11 (11) : 1242-1244. PMID 15272315
Distinct domains of Brn-3a regulate apoptosis and neurite outgrowth in vivo. Faulkes DJ, Ensor E, Le Rouzic E, Latchman DS Neuroreport. 2004 ; 15 (9) : 1421-1425. PMID 15194866
The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1. Gascoyne DM, Thomas GR, Latchman DS Oncogene. 2004 ; 23 (21) : 3830-3840. PMID 15021903
Coexpression of Brn-3a POU protein with p53 in a population of neuronal progenitor cells is associated with differentiation and protection against apoptosis. Hudson CD, Podesta J, Henderson D, Latchman DS, Budhram-Mahadeo V Journal of neuroscience research. 2004 ; 78 (6) : 803-814. PMID 15532030
EWS differentially activates transcription of the Brn-3a long and short isoform mRNAs from distinct promoters. Thomas GR, Faulkes DJ, Gascoyne D, Latchman DS Biochemical and biophysical research communications. 2004 ; 318 (4) : 1045-1051. PMID 15147979
Phosphorylation of the Brn-3a transcription factor is modulated during differentiation and regulates its functional activity. Calissano M, Faulkes D, Latchman DS Brain research. Molecular brain research. 2005 ; 141 (1) : 10-18. PMID 16126301
Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate. Hudson CD, Morris PJ, Latchman DS, Budhram-Mahadeo VS The Journal of biological chemistry. 2005 ; 280 (12) : 11851-11858. PMID 15598651
Brn-3a deficiency increases tyrosine hydroxylase-immunoreactive neurons in the dorsal root ganglion. Ichikawa H, Mo Z, Xiang M, Sugimoto T Brain research. 2005 ; 1036 (1-2) : 192-195. PMID 15725417
Brn-3a is required for the generation of proprioceptors in the mesencephalic trigeminal tract nucleus. Ichikawa H, Qiu F, Xiang M, Sugimoto T Brain research. 2005 ; 1053 (1-2) : 203-206. PMID 16040009
Atlas Genet Cytogenet Oncol Haematol 2008; 4 615
Effect of Brn-3a deficiency on primary nociceptors in the trigeminal ganglion. Ichikawa H, Schulz S, Hollt V, Mo Z, Xiang M, Sugimoto T Neuroscience research. 2005 ; 51 (4) : 445-451. PMID 15740807
Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90. Ripley BJ, Rahman MA, Isenberg DA, Latchman DS Arthritis and rheumatism. 2005 ; 52 (4) : 1171-1179. PMID 15818685
Brn-3a neuronal transcription factor functional expression in human prostate cancer. Diss JK, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MB, Latchman DS Prostate cancer and prostatic diseases. 2006 ; 9 (1) : 83-91. PMID 16276351
Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a. Ndisang D, Faulkes DJ, Gascoyne D, Lee SA, Ripley BJ, Sindos M, Singer A, Budhram-Mahadeo V, Cason J, Latchman DS Oncogene. 2006 ; 25 (1) : 51-60. PMID 16247485
Brn3a target gene recognition in embryonic sensory neurons. Lanier J, Quina LA, Eng SR, Cox E, Turner EE Developmental biology. 2007 ; 302 (2) : 703-716. PMID 17196582
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Contributor(s) Written 12-2007 Vishwanie Budhram-Mahadeo, David S Latchman Medical Molecular Biology Unit, Institute of Child Health, 30 Guilford St, London WC 1N1 EH, UK Citation This paper should be referenced as such : Budhram-Mahadeo V, Latchman DS . POU4F1 (POU class 4 homeobox 1). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/POU4F1ID44173ch13q31.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 616 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32))
Identity Other names DARPP-32 DARPP32 FLJ20940 t-DARPP HGNC PPP1R1B Location 17q12
Genomic localization of DARPP-32, with FISH using BAC clone CTD-2019C10 (Research Genetics) that contains DARPP-32, using fluorescent in situ hybridization (FISH) on a normal metaphase spread. Arrows indicate the green FITC hybridization signals. The ideogram of chromosome 17 together with the inverted DAPI banding and FISH hybridization signals on the two chromosome 17. The FISH signals localize to chromosome band 17q12-q21. DNA/RNA
This schematic illustration shows the genomic structure of DARPP-32 and its transcriptional splice variant that encodes a truncated DARPP-32 protein (t-DARPP). The sequence length of the mRNA of DARPP-32 is 1,841 bp, including the untranslated 3' and 5' ends. The length of the transcriptional splice variant of DARPP-32 that encodes a truncated DARPP-32 protein (t-DARPP) is 1,502 bp. DARPP-32 and t-DARPP share an identical sequence from exon 2 to the 3' end. Each of them has seven exons. Each of DARPP-32 and t-DARPP transcripts has its own unique exon 1, where exon1 in DARPP-32 includes 548 bp whereas exon1 in t-DARPP consists of unique 207 bp that does not match with exon1 of DARPP-32. Description DARPP-32 gene is located at 17q12. Both full length DARPP-32 and its transcriptional splice variant (t-DARPP) consist of seven exons where only exon 1 is unique in each of the two transcripts. Transcription 2 alternative transcripts
Atlas Genet Cytogenet Oncol Haematol 2008; 4 617 Pseudogene Unknown Protein Description DARPP-32 encodes a protein of 204 amino acids (about 32 kD), whereas t-DARPP encodes a 168 amino acid protein (about 28 kD). DARPP-32 contains four phosphorylation sites at Thr34, Thr75, Ser102, and Ser137, whereas t-DARPP lacks the Thr34 phosphorylation site of DARPP-32. The schematic illustration, shown above, demonstrates the phosphorylation sites of DARPP-32 and t-DARPP shown in yellow color. Expression DARPP-32 protein is highly expressed in medium-sized spiny neurons of the neostriatum. DARPP-32 was characterized as a major target for dopamine and protein kinase A signaling. Modulation of DARPP-32 phosphorylation state provides a molecular mechanism for integrating signals through several neurotransmitters and steroid hormones that stimulate dopaminoceptic neurons in various regions of the brain. Activation of PKA or PKG leads to phosphorylation of DARPP-32 at Thr34 and subsequently converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). Cdk5 can also phosphorylate DARPP-32 at Thr75 and this converts DARPP-32 into a PKA inhibitor. Expression of t-DARPP in the brain was not reported. Protein and mRNA expression of both DARPP-32 and t-DARPP are expressed at varying levels in several types of normal epithelial tissues outside the brain. DARPP-32 and t-DARPP are over-expressed in carcinomas of the breast, prostate, colon, and stomach compared with normal tissue samples. The observation that DARPP-32 and t- DARPP are frequently over-expressed in common subtypes of human cancers suggests that these proteins may play a role in tumorigenesis. The expression of t- DARPP has been shown to increase the AKT kinase activity and regulate the levels of BCL2 in cancer cells. This effect is believed to mediate resistance to drug-induced apoptosis. Localisation Cytosolic Homology Unknown Mutations Note Unknown Implicated in Entity Dopaminergic disorders Disease DARPP-32 plays a key role in cognitive function, and multiple brain functions. DARPP-32 is a key mediator of the biochemical, electrophysiological, transcriptional, and behavioral effects of dopamine. In this respect, DARPP-32 plays a critical role in dopaminoceptive neurons in the neostriatum (and likely in other brain regions) in signal transduction pathways regulated by a variety of neurotransmitters, neuromodulators, and neuropeptides. Abnormal signaling through DARPP-32 has been implicated in several major neurologic and psychiatric disorders. DARPP-32 may be involved in the pathogenesis of schizophrenia and plays a role in mediating the actions of a broad range of drugs of abuse. Entity Cancers Oncogenesis Over-expression of DARPP-32 and t-DARPP are associated with gastric cancer, and confer a potent anti-apoptotic function in cancer cells through a p53-independent mechanism that involves preservation of mitochondrial membrane potential and increased Bcl2 expression levels. t-DARPP transcriptionally up-regulates Bcl2 by an Akt-dependent mechanism through activation of CREB/ATF-1 transcription factors in gastric cancer. DARPP-32 is frequently over-expressed in multiple human adenocarcinomas suggesting that DARPP-32 proteins may be important in tumorigenesis. Decreased expression of DARPP-32, however, in oral premalignant and malignant lesions was observed, and thereby suggested that DARPP-32 may be a tumor suppressor in this particular malignancy. In addition, phosphorylation of DARPP-32 at Thr34 or Thr75 appears to regulate breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. External links Nomenclature HGNC PPP1R1B 9287 Entrez_Gene PPP1R1B 84152 protein phosphatase 1, regulatory (inhibitor) subunit 1B
Atlas Genet Cytogenet Oncol Haematol 2008; 4 618 Cards Atlas PPP1R1BID44096ch17q12 GeneCards PPP1R1B Ensembl PPP1R1B [Search_View] ENSG00000131771 [Gene_View] Genatlas PPP1R1B GeneLynx PPP1R1B eGenome PPP1R1B euGene 84152 Genomic and cartography PPP1R1B - 17q12 chr17:35036705-35046403 + 17 [Description] (hg18- GoldenPath Mar_2006) Ensembl PPP1R1B - 17 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PPP1R1B Gene and transcription Genbank AF233349 [ ENTREZ ] Genbank AF435972 [ ENTREZ ] Genbank AF435973 [ ENTREZ ] Genbank AF435974 [ ENTREZ ] Genbank AF464196 [ ENTREZ ] RefSeq NM_032192 [ SRS ] NM_032192 [ ENTREZ ] RefSeq NM_181505 [ SRS ] NM_181505 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq AC_000149 [ SRS ] AC_000149 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010755 [ SRS ] NT_010755 [ ENTREZ ] RefSeq NW_001838435 [ SRS ] NW_001838435 [ ENTREZ ] RefSeq NW_926828 [ SRS ] NW_926828 [ ENTREZ ] AceView PPP1R1B AceView - NCBI Unigene Hs.286192 [ SRS ] Hs.286192 [ NCBI ] HS286192 [ spliceNest ] Fast-db 9542 (alternative variants) Protein : pattern, domain, 3D structure Q9NNW1 [ SRS] Q9NNW1 [ EXPASY ] Q9NNW1 [ INTERPRO ] Q9NNW1 SwissProt [ UNIPROT ] Interpro IPR015670 DARP-32 [ SRS ] IPR015670 DARP-32 [ EBI ] Interpro IPR008466 PPI_1DARPP-32 [ SRS ] IPR008466 PPI_1DARPP-32 [ EBI ] CluSTr Q9NNW1 Blocks Q9NNW1 HPRD 05097 Protein Interaction databases DIP Q9NNW1 IntAct Q9NNW1 Polymorphism : SNP, mutations, diseases OMIM 604399 [ map ] GENECLINICS 604399 SNP PPP1R1B [dbSNP-NCBI] SNP NM_032192 [SNP-NCI] SNP NM_181505 [SNP-NCI] SNP PPP1R1B [GeneSNPs - Utah] PPP1R1B] [HGBASE - SRS] HAPMAP PPP1R1B [HAPMAP] COSMIC PPP1R1B [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PPP1R1B General knowledge
Atlas Genet Cytogenet Oncol Haematol 2008; 4 619 Family Browser PPP1R1B [UCSC Family Browser] SOURCE NM_032192 SOURCE NM_181505 SMD Hs.286192 SAGE Hs.286192 GO protein kinase inhibitor activity [Amigo] protein kinase inhibitor activity GO protein phosphatase inhibitor activity [Amigo] protein phosphatase inhibitor activity GO cytoplasm [Amigo] cytoplasm GO signal transduction [Amigo] signal transduction BIOCARTA Regulation of ck1/cdk5 by type 1 glutamate receptors [Genes] BIOCARTA FOSB gene expression and drug abuse [Genes] PubGene PPP1R1B TreeFam PPP1R1B CTD 84152 [Comparative ToxicoGenomics Database] Other databases Probes Probe PPP1R1B Related clones (RZPD - Berlin) PubMed PubMed 40 Pubmed reference(s) in LocusLink Bibliography DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Hemmings HC Jr, Greengard P, Tung HY, Cohen P Nature. 1984 ; 310 (5977) : 503-505. PMID 6087160
Neuronal phosphoproteins. Mediators of signal transduction. Greengard P Molecular neurobiology. 1987 ; 1 (1-2) : 81-119. PMID 2908293
Studies of the physiological role of specific neuronal phosphoproteins. Greengard P, Browning MD Advances in second messenger and phosphoprotein research. 1988 ; 21 : 133-146. PMID 3137955
Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Halpain S, Girault JA, Greengard P Nature. 1990 ; 343 (6256) : 369-372. PMID 2153935
Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Halpain S, Girault JA, Greengard P Nature. 1990 ; 343 (6256) : 369-372. PMID 2153935
Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue. Brene S, Lindefors N, Ehrlich M, Taubes T, Horiuchi A, Kopp J, Hall H, Sedvall G, Greengard P, Persson H The Journal of neuroscience : the official journal of the Society for Neuroscience. 1994 ; 14 (3 Pt 1) : 985-998. PMID 8120638
Bidirectional regulation of DARPP-32 phosphorylation by dopamine. Nishi A, Snyder GL, Greengard P The Journal of neuroscience : the official journal of the Society for Neuroscience. 1997 ; 17 (21) : 8147-8155. PMID 9334390
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DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P Science (New York, N.Y.). 1998 ; 281 (5378) : 838-842. PMID 9694658
The DARPP-32/protein phosphatase-1 cascade: a model for signal integration. Greengard P, Nairn AC, Girault JA, Ouimet CC, Snyder GL, Fisone G, Allen PB, Fienberg A, Nishi A Brain research. Brain research reviews. 1998 ; 26 (2-3) : 274-284. PMID 9651542
Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P Nature. 1999 ; 402 (6762) : 669-671. PMID 10604473
Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Greengard P, Allen PB, Nairn AC Neuron. 1999 ; 23 (3) : 435-447. PMID 10433257
Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro. Mayerhofer A, Hemmings HC Jr, Snyder GL, Greengard P, Boddien S, Berg U, Brucker C The Journal of clinical endocrinology and metabolism. 1999 ; 84 (1) : 257-264. PMID 9920093
Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Mani SK, Fienberg AA, O'Callaghan JP, Snyder GL, Allen PB, Dash PK, Moore AN, Mitchell AJ, Bibb J, Greengard P, O'Malley BW Science (New York, N.Y.). 2000 ; 287 (5455) : 1053-1056. PMID 10669419
Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. El-Rifai W, Smith MF Jr, Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF Jr, Powell SM Cancer research. 2002 ; 62 (14) : 4061-4064. PMID 12124342
Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Lindskog M, Svenningsson P, Pozzi L, Kim Y, Fienberg AA, Bibb JA, Fredholm BB, Nairn AC, Greengard P, Fisone G Nature. 2002 ; 418 (6899) : 774-778. PMID 12181566
Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate- regulated phosphoprotein in common adenocarcinomas. Beckler A, Moskaluk CA, Zaika A, Hampton GM, Powell SM, Frierson HF Jr, El-Rifai W Cancer. 2003 ; 98 (7) : 1547-1551. PMID 14508844
The role of DARPP-32 in the actions of drugs of abuse. Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, Greengard P Neuropharmacology. 2004 ; 47 Suppl 1 : 14-23. PMID 15464122
Atlas Genet Cytogenet Oncol Haematol 2008; 4 621 Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Belkhiri A, Zaika A, Pidkovka N, Knuutila S, Moskaluk C, El-Rifai W Cancer research. 2005 ; 65 (15) : 6583-6592. PMID 16061638
DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation. Garcia-Jimenez C, Zaballos MA, Santisteban P Molecular endocrinology (Baltimore, Md.). 2005 ; 19 (12) : 3060-3072. PMID 16020482
Overexpression of DARPP-32 in colorectal adenocarcinoma. Wang MS, Pan Y, Liu N, Guo C, Hong L, Fan D International journal of clinical practice. 2005 ; 59 (1) : 58-61. PMID 15707466
Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR The Journal of clinical investigation. 2007 ; 117 (3) : 672-682. PMID 17290303 t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W Cancer research. 2008 ; 68 (2) : 395-403. PMID 18199533
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Contributor(s) Written 12-2007 Wael El-Rifai, Abbes Belkhiri Department of Surgery, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee Citation This paper should be referenced as such : El-Rifai W, Belkhiri A . PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PPP1R1BID44096ch17q12.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 622 Atlas of Genetics and Cytogenetics in Oncology and Haematology
RMRP (RNA component of mitochondrial RNA processing endoribonuclease)
Identity Other names CHH RMRPR HGNC RMRP Location 9p21-p12
Figure 1: Cartoon of the RMRP genomic gene structure. The RMRP gene is an intronless gene that is 267 bp long (violet). The promoter region contains a SP1 binding site (blue), an octamer (red), a proximal sequence element (PSE) (green) and a TATA box (yellow). DNA/RNA Note RMRP is the RNA component of the RNase MRP protein complex. It functions as a RNA and is not translated into a protein.
Figure 2: Expression pattern of the Rmrp gene. A: in situ hybridization of an E15.5 mouse embryo B: adult human Multiple tissue Northern Blot. Rmrp is ubiquitously expressed in human and mouse. H: hypertrophic chondrocytes. Transcription The RMRP gene is transcribed by the DNA dependent RNA polymerase III. The gene contains typical sequence elements of a RNA Pol III type 3 promoter. The core
Atlas Genet Cytogenet Oncol Haematol 2008; 4 623 sequence elements such as the PSE element and a TATA box can be found upstream of the transcription initiation site of the RMRP gene. In addition, transcription factor binding sites like a SP1 binding element and an octamer (recruits the transcription factor Oct-1) sequence could serve as distal sequence elements (DSE) to enhance the transcription of RMRP similar to the DSE element of the human U6 snRNA gene. Expression RMRP is strongly and ubiquitously expressed in mouse embryos (as an example an E15.5 mouse embryo is shown). In bone Rmrp is more strongly expressed in hypertrophic chondrocytes and pericondrium than in the zone of proliferating chondrocytes. There is also very strong expression in the epiphysis. In humans RMRP shows also a very strong expression in adult tissues. A little weaker expression is observed in skeletal muscle when compared to the GAPDH hybridization control. In Xenopus laevis oocytes RMRP is stronger expressed in developmental stages with a higher content of mitochondria. Function RMRP has been mostly studied in yeast and multiple functions have been attributed to this ribonucleoprotein complex, called RNase MRP. The yeast orthologues gene is called nme1. Firstly, it plays a role in mitochondrial DNA replication. It cleaves the RNA primer of RNA/DNA hybrid. This hybrid formation initiates the mitochondrial DNA replication. It is also involved in the RNA primer formation. Secondly, RMRP is involved in the progression of the cell cycle at the end of mitosis. Some nme1 mutants arrest in the late cycle of mitosis. These mutants present morphologically as large budded cells with dumbbell-shaped nuclei, and also exhibit extended spindles. This cell cycle arrest might be due to an increased level of CLB2. In wild type yeast strains the 5'UTR of CLB2 is cleaved by the RNase MRP complex. This causes a rapid degradation of the CLB2 mRNA, which leads to a cell cycle progression. Thirdly, RMRP also plays a role in the ribosomal RNA processing. In yeast, it cleaves pre- ribosomal RNA at the A3 site thus helps the maturation of the short and active form of the 5.8S rRNA. Homology RNase P is also a ribonucleoprotein endoribonuclease that is mainly involved in tRNA precursor maturation. RNase P and RNase MRP have eight proteins in common. The protein RPR2p is unique to the RNase P complex. In yeast two RNase MRP specific proteins have been identified; snm1 and rmp1. The loss of function of snm1 leads to a defect in the chromosome segregation during mitosis. But the exact mechanism is not understood yet. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 4 624
Figure 3: Cartoon of the ribosomal RNA processing. If Rnase MRP cleaves the 27SA2 rRNA at the A3 site, this leads to the formation of the short form of the 5.8S rRNA (5.8SS). In a second, less effective alternative pathway, the 27SA2 rRNA is directly cleaved at the B1L site that leads at the end to the formation of the long form of the 5.8S rRNA (5.8SL). Mutations Note So far 93 different mutations have been identified in CHH patients. These include 24 promoter mutations that are either duplications, triplications or insertions that occur exclusively between the TATA box and the transcription start site. The size of the promoter mutations varies between 6 and 24 bp. In vitro studies have shown that these promoter mutations decrease the level of the RMRP transcript but do not abolish the RNA transcription completely. 69 different mutations in the 267 bp long transcript have been found up to now. 57 of these are single base pair substitutions spread out over the entire transcript. Also 11 small insertions, duplications and deletions have been found. The largest deletion identified so far involves the last 10 bp of the RMRP transcript. The mutations lead to a significant decrease of the RMRP RNA level in CHH, despite the nature of the mutation. These mutations might influence the secondary structure of the RNA, the binding of the proteins to the RNA or the RNA stability itself. The most frequently found mutation among CHH patients is a 70 A>G transition mutation with an ancient founder origin established in Finland and is the only mutation found in Amish CHH patients. Patients either carry two mutations in the RMRP transcript or are compound heterozygous for a promoter mutation and a transcript mutation. Interestingly, none of the patients exhibit two promoter mutations. In addition 11 polymorphisms and 17 rare sequence variants have been observed. This is very remarkable considering the small size of the RMRP gene. So far no complete deletion of the entire RMRP gene has been observed. This suggests that complete loss of RMRP function might be incompatible with life. This is also supported by the fact that the knock out of the yeast NME1 gene is lethal. Implicated in Entity Cartilage Hair Hypoplasia (CHH)
Atlas Genet Cytogenet Oncol Haematol 2008; 4 625 Prognosis The adult height ranges between 111 and 151 cm in males and between 104 and 137 cm in females. Around 20% of Cartilage Hair Hypoplasia patients exhibit recurrent to severe infections. These patients show evidence of immune deficiency in vivo and in vitro.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 626
Atlas Genet Cytogenet Oncol Haematol 2008; 4 627
Atlas Genet Cytogenet Oncol Haematol 2008; 4 628 Oncogenesis A predisposition to certain cancers primarily lymphomas has been reported. External links Nomenclature HGNC RMRP 10031 Entrez_Gene RMRP 6023 RNA component of mitochondrial RNA processing endoribonuclease Cards Atlas RMRPID44001ch9p21 GeneCards RMRP Ensembl RMRP [Search_View] ENSG00000107014 [Gene_View] Genatlas RMRP GeneLynx RMRP eGenome RMRP euGene 6023 Genomic and cartography GoldenPath RMRP - Ensembl RMRP - [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene RMRP Gene and transcription Genbank AA593275 [ ENTREZ ] RefSeq AC_000052 [ SRS ] AC_000052 [ ENTREZ ] RefSeq AC_000141 [ SRS ] AC_000141 [ ENTREZ ] RefSeq NC_000009 [ SRS ] NC_000009 [ ENTREZ ] RefSeq NT_008413 [ SRS ] NT_008413 [ ENTREZ ] RefSeq NW_001839149 [ SRS ] NW_001839149 [ ENTREZ ] RefSeq NW_924062 [ SRS ] NW_924062 [ ENTREZ ] AceView RMRP AceView - NCBI Unigene Hs.587502 [ SRS ] Hs.587502 [ NCBI ] HS587502 [ spliceNest ] Protein : pattern, domain, 3D structure Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 157660;250250;250460;607095 [ map ] GENECLINICS 157660;250250;250460;607095 SNP RMRP [dbSNP-NCBI] SNP RMRP [GeneSNPs - Utah] RMRP] [HGBASE - SRS] HAPMAP RMRP [HAPMAP] HGMD RMRP General knowledge Family Browser RMRP [UCSC Family Browser] SMD Hs.587502 SAGE Hs.587502 PubGene RMRP TreeFam RMRP CTD 6023 [Comparative ToxicoGenomics Database] Other databases Probes Probe RMRP Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. Chang DD, Clayton DA The EMBO journal. 1987 ; 6 (2) : 409-417.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 629 PMID 3582365
Characterization of human MRP/Th RNA and its nuclear gene: full length MRP/Th RNA is an active endoribonuclease when assembled as an RNP. Topper JN, Clayton DA Nucleic acids research. 1990 ; 18 (4) : 793-799. PMID 1690392
Yeast site-specific ribonucleoprotein endoribonuclease MRP contains an RNA component homologous to mammalian RNase MRP RNA and essential for cell viability. Schmitt ME, Clayton DA Genes & development. 1992 ; 6 (10) : 1975-1985. PMID 1398074
The RNA of RNase MRP is required for normal processing of ribosomal RNA. Chu S, Archer RH, Zengel JM, Lindahl L Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (2) : 659-663. PMID 8290578
Characterization of a unique protein component of yeast RNase MRP: an RNA-binding protein with a zinc-cluster domain. Schmitt ME, Clayton DA Genes & development. 1994 ; 8 (21) : 2617-2628. PMID 7958920
Accurate processing of a eukaryotic precursor ribosomal RNA by ribonuclease MRP in vitro. Lygerou Z, Allmang C, Tollervey D, Seraphin B Science (New York, N.Y.). 1996 ; 272 (5259) : 268-270. PMID 8602511
RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication. Lee DY, Clayton DA Genes & development. 1997 ; 11 (5) : 582-592. PMID 9119223
Mutational analysis of the RNA component of Saccharomyces cerevisiae RNase MRP reveals distinct nuclear phenotypes. Shadel GS, Buckenmeyer GA, Clayton DA, Schmitt ME Gene. 2000 ; 245 (1) : 175-184. PMID 10713458
Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage- hair hypoplasia. Ridanpaa M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Makitie O, Kaitila I, de la Chapelle A Cell. 2001 ; 104 (2) : 195-203. PMID 11207361
RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Bonafé L, Schmitt K, Eich G, Giedion A, Superti-Furga A Clinical genetics. 2002 ; 61 (2) : 146-151. PMID 11940090
The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis. Cai T, Aulds J, Gill T, Cerio M, Schmitt ME Genetics. 2002 ; 161 (3) : 1029-1042.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 630 PMID 12136008
Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP. Ridanpaa M, Sistonen P, Rockas S, Rimoin DL, Makitie O, Kaitila I European journal of human genetics : EJHG. 2002 ; 10 (7) : 439-447. PMID 12107819
Recruitment of RNA polymerase III to its target promoters. Schramm L, Hernandez N Genes & development. 2002 ; 16 (20) : 2593-2620. PMID 12381659
RMRP mutations in Japanese patients with cartilage-hair hypoplasia. Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Ohashi H, Nishimura G, Ikegawa S American journal of medical genetics. Part A. 2003 ; 123 (3) : 253-256. PMID 14608646
The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Ridanpaa M, Jain P, McKusick VA, Francomano CA, Kaitila I American journal of medical genetics. Part C, Seminars in medical genetics. 2003 ; 121 (1) : 81-83. PMID 12888988
RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation. Gill T, Cai T, Aulds J, Wierzbicki S, Schmitt ME Molecular and cellular biology. 2004 ; 24 (3) : 945-953. PMID 14729943
Mutual interactions between subunits of the human RNase MRP ribonucleoprotein complex. Welting TJ, van Venrooij WJ, Pruijn GJ Nucleic acids research. 2004 ; 32 (7) : 2138-2146. PMID 15096576
Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. Bonafe L, Dermitzakis ET, Unger S, Greenberg CR, Campos-Xavier BA, Zankl A, Ucla C, Antonarakis SE, Superti-Furga A, Reymond A PLoS genetics. 2005 ; 1 (4) : page e47. PMID 16244706
Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B Human molecular genetics. 2005 ; 14 (23) : 3723-3740. PMID 16254002
Severely incapacitating mutations in patients with extreme short stature identify RNA- processing endoribonuclease RMRP as an essential cell growth regulator. Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, Ruschendorf F, Sticht H, Spranger J, Muller D, Zweier C, Schmitt ME, Reis A, Rauch A American journal of human genetics. 2005 ; 77 (5) : 795-806. PMID 16252239
RMRP mutations in cartilage-hair hypoplasia. Hermanns P, Tran A, Munivez E, Carter S, Zabel B, Lee B, Leroy JG American journal of medical genetics. Part A. 2006 ; 140 (19) : 2121-2130. PMID 16838329
Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 631 Hirose Y, Nakashima E, Ohashi H, Mochizuki H, Bando Y, Ogata T, Adachi M, Toba E, Nishimura G, Ikegawa S Journal of human genetics. 2006 ; 51 (8) : 706-710. PMID 16832578
A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia. Munoz-Robles J, Allende LM, Clemente J, Calleja S, Varela P, Gonzalez L, de Pablos P, Paz E, Morales P Immunobiology. 2006 ; 211 (9) : 753-757. PMID 17015150
RNase MRP RNA and human genetic diseases. Martin AN, Li Y Cell research. 2007 ; 17 (3) : 219-226. PMID 17189938
Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A American journal of human genetics. 2007 ; 81 (3) : 519-529. PMID 17701897
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Contributor(s) Written 12-2007 Pia Hermanns, Kerstin Reicherter, Brendan Lee Centre for Pediatrics and Adolescent Medicine, pediatric genetics section, Freiburg University Hospital, Germany (PH, KR) ; Howard Hughes Medical Institute (BL) ; Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA (BL) Citation This paper should be referenced as such : Hermanns P, Reicherter K, Lee B . RMRP (RNA component of mitochondrial RNA processing endoribonuclease). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RMRPID44001ch9p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 632 Atlas of Genetics and Cytogenetics in Oncology and Haematology
TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)
Identity Other names DCR3 (decoy receptor 3) DJ583P15.1.1 M68 TR6 (TNF receptor family member 6) HGNC TNFRSF6B Location 20q13.3 DNA/RNA
Description DNA sequence is located on chromosome 20. Transcription consists of 7 exons and 6 introns, spanning 3.6kb. A shorter transcription variance (M68E) has been identified, and is transcribed from 3 exons and 2 introns spanning 1.9kb as illustrated above. The difference occurs at the 5' untranslated region, but the two transcripts encode the same isoform. Mice do not have a gene orthologue to human TNFRSF6B. TNFRSF68B mRNA in Northen blot presents as a 1.2-knt band. Protein
A) Domains and Motifs. B) TNFRSF6B X-ray crystography Description TNFRSF6B protein is 300-amino acid long, and has a molecular weight of 35 kD. Although TNFRSF6B belongs to the TNFR superfamily, it lacks the transmembrane and cytosolic domains in its sequence, and is a secreted protein. It contains 4 TNFR cystein-rich regions, as illustrated above. TNFRSF6B can be easily cleaved between Arg218 and Ala219 in biological fluids and solutions. It has thus a very short (about 20 min) half-life in serum and in vivo. Mutation of arginine residue at position 218 to glutamine makes TNFRSF6B resistant to proteolysis, and significantly prolongs its half-life.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 633 TNFRSF6B can bind to the TNF family members FasL, LIGHT and TL1A. It does not bind to other known TNF family members. Human TNFRSF6B can bind to mouse FasL, LIGHT and TL1A. This allows human DcR3/TNFRSF6B to function in mouse models both in vitro and in vivo. The role of TNFRSF6B in apoptosis is obvious. FasL is a well-known molecule involved in apoptosis. LIGHT is a ligand for HVEM and LTbetaR, in addition to being a ligand for TNFRSF6B. LIGHT can induce apoptosis in cells expressing both HVEM and LTbetaR, or LTbetaR alone. TL1A, a member of the TNF family, can evoke apoptosis via its receptor, DR3. Consequently, the interaction of TNFRSF6B with FasL, LIGHT, and TL1A blocks apoptosis mediated by Fas, HVEM, LTbetaR and DR3. Expression Normal tissue and cells express low-level TNFRSF6B, and healthy individuals have near-background serum TNFRSF6B levels. About 60% of malignant tumors of various tissue origins overexpress TNFRSF6B, and these patients have elevated serum TNFRSF6B levels. Serum TNFRSF6B levels of tumor patients are positively correlated to the degree of tumor malignancy and status of metastasis. It is hypothesized that malignant tumor cells secrete TNFRSF6B as a way to achieve survival advantage by blocking multiple apoptosis pathways. Hepatocytes in liver cirrhosis have augmented TNFRSF6B expression and patients with liver cirrhosis have increased serum TNFRSF6B levels. TNFRSF6B expression is low in resting T cells but is augmented in activated T cells, which probably represents a fine-tuning mechanism to balance the need for clonal expansion and subsequent massive activation-induced T cell death. About 40% of systemic lupus erythematosus patients have elevated serum TNFRSF6B levels. TNFRSF6B expression in rheumatoid arthritis fibroblast-like synoviocytes is increased by TNF alpha Localisation TNFRSF6B is a secreted protein, and is thus detected in body fluids. However, it can also be detected in cytoplasm before it is secreted. Function As TNFRSF6B can block ligands from interacting with Fas, HVEM, LTbetaR, and DR3, all of which mediate apoptosis, it is thus can effectively inhibit apoptosis in many cell types. It is believed that many types of malignant tumors gain survival advantage by secreting TNFRSF6B which blocks tumor cell apoptosis. Syngeneic islets transplanted to diabetes recipients survive better in the presence of administered exogenous human TNFRSF6B, due to the blockage of FasL-, LIGHT- and TL1A-triggered islets apoptosis. Transgenic expression of human TNFRSF6B in NOD mouse islets reduces diabetes pathogenesis, again, due to anti-apoptotic effect of TNFRSF6B. The forward signaling from FasL to Fas, and from LIGHT to HVEM can provide costimulation signals to resting T cells. Blocking of these two signaling pathways reduces T cell responses to antigens. As LIGHT and FasL, although being ligands, are also transmembrane proteins, and are capable of reversely transducing costimulating signals into T cells, TNFRSF6B can also block such reverse signaling. The end result is that TNFRSF6B can reduce several costimulation pathways in T cells and inhibit T cell immune responses, such as cytokine secretion and proliferation in vitro, and cardiac allograft rejection in vivo in mouse models. When human TNFRSF6B is linked to a transmembrane domain and is expressed on the mouse tumor cell surface, it can effectively trigger T cell costimulation via LIGHT and FasL reverse signaling, and cause effective tumor vaccination in mouse models. When human TNFRSF6B is transgenically expressed in mice, it causes a systemic lupus erythrematosus-like syndrome. The expression of TNFRSF6B in bone marrow- derived cells is sufficient to induce this phenotype. Recombinant human TNFRSF6B ameliorates an autoimmune crescentic glomerulonephritis model in mice. TNFRSF6B can influence dendritic cells which in turn drive T cells to differentiate into Th2 cells. TNFRSF6B can inhibit actin polymerization of T cells upon mitogen stimulation, and repress T-cell pseudopodium formation, which is known to be important for cell-cell interaction. As a consequence, T-cell aggregation after activation is suppressed by either soluble or solid phase TNFRSF6B. Human T cells pretreated with soluble or solid-phase TNFRSF6B are compromised in migration in vitro and in vivo toward CXCL12. Mechanistically, a small GTPase Cdc42
Atlas Genet Cytogenet Oncol Haematol 2008; 4 634 fails to be activated after TNFRSF6B pretreatment of human T cells, and further downstream, p38 mitogen-activated protein kinase activation, actin polymerization, and pseudopodium formation are all down-regulated in the treated T cells. Phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide are impaired in TNFRSF6B-treated macrophages. Mutations Note Not reported yet. Implicated in Entity Malignant tumors Disease Oncogenesis TNFRSF6B is overexpressed in about 60% of various malignant tumors. Its anti- apoptotic effect provides the tumors a survival advantage, and its role in reducing T cell costimulation favors tumor evasion from the immune surveillance. No TNFRSF6B gene amplification in tumors has been identified. Diagnosis and prognosis TNFRSF6B in sera or tumor can be used as a parameter for tumor diagnosis and prognosis. The degree of tumor malignancy is correlated to TNFRSF6B levels. When a TNFRSF6B-expressing tumor is resected, serum TNFRSF6B levels will decrease to near-zero level. The re-arising of serum TNFRSF6B in such patients will indicate tumor reoccurrence. Therapeutics When TNFRSF6B is anchored on tumor cell surface, it can increase the antigenicity of the tumor, and such TNFRSF6B-expressing tumors can be used as tumor vaccine. Entity Systemic lupus erythematosus (SLE) Disease Pathogenesis About 50% of SLE patients have elevated serum TNFRSF6B levels, and the levels augment during SLE flare-up. In animal models, human TNFRSF6B overexpression in mouse cells of hematopoietic origin leads to a SLE-like syndrome, suggesting a pathogenic role of TNFRSF6B in SLE. Diagnosis Serum TNFRSF6B can be used as a diagnostic parameter for SLE and SLE disease activity. Therapeutics Due to the pathogenic effect of TNFRSF6B on SLE, it is speculated that neutralizing TNFRSF6B might have therapeutic effect on a subpopulation of SLE patients, who are serum TNFSF6B positive. Entity Islet primary nonfunction during islet transplantation Disease Therapeutics Due to the anti-apoptotic effect of TNFRSF6B, it can effectively protect islets from apoptosis during their isolation, transportation, and primary non-function after transplantation. External links Nomenclature HGNC TNFRSF6B 11921 Entrez_Gene TNFRSF6B 8771 tumor necrosis factor receptor superfamily, member 6b, decoy Cards Atlas TNFRSF6BID42628ch20q13 GeneCards TNFRSF6B Ensembl TNFRSF6B [Search_View] ENSG00000026036 [Gene_View] Genatlas TNFRSF6B GeneLynx TNFRSF6B eGenome TNFRSF6B euGene 8771 Genomic and cartography TNFRSF6B - 20q13.3 chr20:61798465-61800479 + 20q13.3 [Description] GoldenPath (hg18-Mar_2006)
Atlas Genet Cytogenet Oncol Haematol 2008; 4 635 Ensembl TNFRSF6B - 20q13.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene TNFRSF6B Gene and transcription Genbank AF104419 [ ENTREZ ] Genbank AF134240 [ ENTREZ ] Genbank AF217793 [ ENTREZ ] Genbank AF217794 [ ENTREZ ] Genbank AY358279 [ ENTREZ ] RefSeq NM_003823 [ SRS ] NM_003823 [ ENTREZ ] RefSeq NM_032945 [ SRS ] NM_032945 [ ENTREZ ] RefSeq AC_000063 [ SRS ] AC_000063 [ ENTREZ ] RefSeq AC_000152 [ SRS ] AC_000152 [ ENTREZ ] RefSeq NC_000020 [ SRS ] NC_000020 [ ENTREZ ] RefSeq NT_011333 [ SRS ] NT_011333 [ ENTREZ ] RefSeq NW_001838671 [ SRS ] NW_001838671 [ ENTREZ ] RefSeq NW_927339 [ SRS ] NW_927339 [ ENTREZ ] AceView TNFRSF6B AceView - NCBI Unigene Hs.434878 [ SRS ] Hs.434878 [ NCBI ] HS434878 [ spliceNest ] Fast-db 15232 (alternative variants) Protein : pattern, domain, 3D structure O95407 [ SRS] O95407 [ EXPASY ] O95407 [ INTERPRO ] O95407 SwissProt [ UNIPROT ] Prosite PS00652 TNFR_NGFR_1 [ SRS ] PS00652 TNFR_NGFR_1 [ Expasy ] Prosite PS50050 TNFR_NGFR_2 [ SRS ] PS50050 TNFR_NGFR_2 [ Expasy ] Interpro IPR001368 TNFR_c6 [ SRS ] IPR001368 TNFR_c6 [ EBI ] CluSTr O95407 PF00020 TNFR_c6 [ SRS ] PF00020 TNFR_c6 [ Sanger ] pfam00020 [ NCBI-CDD Pfam ] Smart SM00208 TNFR [EMBL] Blocks O95407 HPRD 04527 Protein Interaction databases DIP O95407 IntAct O95407 Polymorphism : SNP, mutations, diseases OMIM 603361 [ map ] GENECLINICS 603361 SNP TNFRSF6B [dbSNP-NCBI] SNP NM_003823 [SNP-NCI] SNP NM_032945 [SNP-NCI] SNP TNFRSF6B [GeneSNPs - Utah] TNFRSF6B] [HGBASE - SRS] HAPMAP TNFRSF6B [HAPMAP] COSMIC TNFRSF6B [Somatic mutation (COSMIC-CGP-Sanger)] HGMD TNFRSF6B General knowledge Family Browser TNFRSF6B [UCSC Family Browser] SOURCE NM_003823 SOURCE NM_032945 SMD Hs.434878 SAGE Hs.434878 GO nucleic acid binding [Amigo] nucleic acid binding GO receptor activity [Amigo] receptor activity
Atlas Genet Cytogenet Oncol Haematol 2008; 4 636 GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO extracellular region [Amigo] extracellular region GO soluble fraction [Amigo] soluble fraction nucleobase, nucleoside, nucleotide and nucleic acid metabolic process GO [Amigo] nucleobase, nucleoside, nucleotide and nucleic acid metabolic process GO apoptosis [Amigo] apoptosis GO anti-apoptosis [Amigo] anti-apoptosis GO ATP-dependent helicase activity [Amigo] ATP-dependent helicase activity hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides GO [Amigo] hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides KEGG Cytokine-cytokine receptor interaction PubGene TNFRSF6B TreeFam TNFRSF6B CTD 8771 [Comparative ToxicoGenomics Database] Other databases Probes Probe TNFRSF6B Related clones (RZPD - Berlin) PubMed PubMed 38 Pubmed reference(s) in LocusLink Bibliography Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A Nature. 1998 ; 396 (6712) : 699-703. PMID 9872321
A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS The Journal of biological chemistry. 1999 ; 274 (20) : 13733-13736. PMID 10318773
Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Bai C, Connolly B, Metzker ML, Hilliard CA, Liu X, Sandig V, Soderman A, Galloway SM, Liu Q, Austin CP, Caskey CT Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (3) : 1230-1235. PMID 10655513
Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. Ohshima K, Haraoka S, Sugihara M, Suzumiya J, Kawasaki C, Kanda M, Kikuchi M Cancer letters. 2000 ; 160 (1) : 89-97. PMID 11098089
Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Otsuki T, Tomokuni A, Sakaguchi H, Aikoh T, Matsuki T, Isozaki Y, Hyodoh F, Ueki H, Kusaka M, Kita S, Ueki A Clinical and experimental immunology. 2000 ; 119 (2) : 323-327. PMID 10632670
Ultraviolet light (UV) regulation of the TNF family decoy receptors DcR2 and DcR3 in human keratinocytes.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 637 Maeda T, Hao C, Tron VA Journal of cutaneous medicine and surgery. 2001 ; 5 (4) : 294-298. PMID 11907838
Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand- induced apoptosis and chemotaxis. Roth W, Isenmann S, Nakamura M, Platten M, Wick W, Kleihues P, Bahr M, Ohgaki H, Ashkenazi A, Weller M Cancer research. 2001 ; 61 (6) : 2759-2765. PMID 11289159
Modulation of T-cell responses to alloantigens by TR6/DcR3. Zhang J, Salcedo TW, Wan X, Ullrich S, Hu B, Gregorio T, Feng P, Qi S, Chen H, Cho YH, Li Y, Moore PA, Wu J The Journal of clinical investigation. 2001 ; 107 (11) : 1459-1468. PMID 11390428
Modulation of dendritic cell differentiation and maturation by decoy receptor 3. Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC, Chen L, Hsieh SL Journal of immunology (Baltimore, Md. : 1950). 2002 ; 168 (10) : 4846-4853. PMID 11994433
DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer. Mild G, Bachmann F, Boulay JL, Glatz K, Laffer U, Lowy A, Metzger U, Reuter J, Terracciano L, Herrmann R, Rochlitz C International journal of cancer. Journal international du cancer. 2002 ; 102 (3) : 254-257. PMID 12397645
The prognostic significance of overexpression of the decoy receptor for Fas ligand (DcR3) in patients with gastric carcinomas. Takahama Y, Yamada Y, Emoto K, Fujimoto H, Takayama T, Ueno M, Uchida H, Hirao S, Mizuno T, Nakajima Y Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2002 ; 5 (2) : 61-68. PMID 12111580
A TNF family member LIGHT transduces costimulatory signals into human T cells. Wan X, Zhang J, Luo H, Shi G, Kapnik E, Kim S, Kanakaraj P, Wu J Journal of immunology (Baltimore, Md. : 1950). 2002 ; 169 (12) : 6813-6821. PMID 12471113
Characterization of chicken TNFR superfamily decoy receptors, DcR3 and osteoprotegerin. Bridgham JT, Johnson AL Biochemical and biophysical research communications. 2003 ; 307 (4) : 956-961. PMID 12878204
Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo. Shi G, Wu Y, Zhang J, Wu J Journal of immunology (Baltimore, Md. : 1950). 2003 ; 171 (7) : 3407-3414. PMID 14500635
Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. Tsuji S, Hosotani R, Yonehara S, Masui T, Tulachan SS, Nakajima S, Kobayashi H, Koizumi M, Toyoda E, Ito D, Kami K, Mori T, Fujimoto K, Doi R, Imamura M International journal of cancer. Journal international du cancer. 2003 ; 106 (1) : 17-25. PMID 12794752
DcR3/TR6 modulates immune cell interactions.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 638 Wan X, Shi G, Semenuk M, Zhang J, Wu J Journal of cellular biochemistry. 2003 ; 89 (3) : 603-612. PMID 12761893
Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue. Wortinger MA, Foley JW, Larocque P, Witcher DR, Lahn M, Jakubowski JA, Glasebrook A, Song HY Immunology. 2003 ; 110 (2) : 225-233. PMID 14511236
Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3(R218Q)], in cynomolgus monkeys and mice. Wroblewski VJ, McCloud C, Davis K, Manetta J, Micanovic R, Witcher DR Drug metabolism and disposition: the biological fate of chemicals. 2003 ; 31 (4) : 502-507. PMID 12642478
Decoy receptor 3 (DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT. Wroblewski VJ, Witcher DR, Becker GW, Davis KA, Dou S, Micanovic R, Newton CM, Noblitt TW, Richardson JM, Song HY, Hale JE Biochemical pharmacology. 2003 ; 65 (4) : 657-667. PMID 12566095
DcR3/TR6 effectively prevents islet primary nonfunction after transplantation. Wu Y, Han B, Luo H, Roduit R, Salcedo TW, Moore PA, Zhang J, Wu J Diabetes. 2003 ; 52 (9) : 2279-2286. PMID 12941767
Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients. Wu Y, Han B, Sheng H, Lin M, Moore PA, Zhang J, Wu J International journal of cancer. Journal international du cancer. 2003 ; 105 (5) : 724-732. PMID 12740925
Modulation of macrophage differentiation and activation by decoy receptor 3. Chang YC, Hsu TL, Lin HH, Chio CC, Chiu AW, Chen NJ, Lin CH, Hsieh SL Journal of leukocyte biology. 2004 ; 75 (3) : 486-494. PMID 14657214
Quantification and detection of DcR3, a decoy receptor in TNFR family. Chen J, Zhang L, Kim S Journal of immunological methods. 2004 ; 285 (1) : 63-70. PMID 14871535
Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis. Gill RM, Hunt JS The American journal of pathology. 2004 ; 165 (1) : 309-317. PMID 15215185
Enhanced adhesion of monocytes via reverse signaling triggered by decoy receptor 3. Hsu MJ, Lin WW, Tsao WC, Chang YC, Hsu TL, Chiu AW, Chio CC, Hsieh SL Experimental cell research. 2004 ; 292 (2) : 241-251. PMID 14697332
Serum concentration of soluble decoy receptor 3 in glioma patients before and after surgery. Hwang SL, Lin CL, Cheng CY, Lin FA, Lieu AS, Howng SL, Lee KS The Kaohsiung journal of medical sciences. 2004 ; 20 (3) : 124-127. PMID 15124896
Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial
Atlas Genet Cytogenet Oncol Haematol 2008; 4 639 antigens in human monocytes and myeloid dendritic cells. Kim S, McAuliffe WJ, Zaritskaya LS, Moore PA, Zhang L, Nardelli B Infection and immunity. 2004 ; 72 (1) : 89-93. PMID 14688085
Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical- induced autoimmune destruction in nonobese diabetic mice. Sung HH, Juang JH, Lin YC, Kuo CH, Hung JT, Chen A, Chang DM, Chang SY, Hsieh SL, Sytwu HK The Journal of experimental medicine. 2004 ; 199 (8) : 1143-1151. PMID 15078896
Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A, a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action. Yang CR, Hsieh SL, Teng CM, Ho FM, Su WL, Lin WW Cancer research. 2004 ; 64 (3) : 1122-1129. PMID 14871847
Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells. Yang CR, Wang JH, Hsieh SL, Wang SM, Hsu TL, Lin WW Cell death and differentiation. 2004 ; 11 Suppl 1 : S97-107. PMID 15002040
Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3. Wu YY, Chang YC, Hsu TL, Hsieh SL, Lai MZ The Journal of biological chemistry. 2004 ; 279 (42) : 44211-44218. PMID 15475369
Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. Wu SF, Liu TM, Lin YC, Sytwu HK, Juan HF, Chen ST, Shen KL, Hsi SC, Hsieh SL Journal of leukocyte biology. 2004 ; 75 (2) : 293-306. PMID 14634066
Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Arakawa Y, Tachibana O, Hasegawa M, Miyamori T, Yamashita J, Hayashi Y Acta neuropathologica. 2005 ; 109 (3) : 294-298. PMID 15627206
Attenuation of Th1 response in decoy receptor 3 transgenic mice. Hsu TL, Wu YY, Chang YC, Yang CY, Lai MZ, Su WB, Hsieh SL Journal of immunology (Baltimore, Md. : 1950). 2005 ; 175 (8) : 5135-5145. PMID 16210617
Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Kim S, Fotiadu A, Kotoula V Clinical immunology (Orlando, Fla.). 2005 ; 115 (3) : 286-294. PMID 15893696
Overexpression of decoy receptor 3 in precancerous lesions and adenocarcinoma of the esophagus. Li H, Zhang L, Lou H, Ding I, Kim S, Wang L, Huang J, Di Sant'Agnese PA, Lei JY American journal of clinical pathology. 2005 ; 124 (2) : 282-287. PMID 16040301
Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. Shen HW, Gao SL, Wu YL, Peng SY World journal of gastroenterology : WJG. 2005 ; 11 (38) : 5926-5930.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 640 PMID 16273601
Tumor vaccine based on cell surface expression of DcR3/TR6. Shi G, Mao J, Yu G, Zhang J, Wu J Journal of immunology (Baltimore, Md. : 1950). 2005 ; 174 (8) : 4727-4735. PMID 15814697
Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. Yang CR, Hsieh SL, Ho FM, Lin WW Journal of immunology (Baltimore, Md. : 1950). 2005 ; 174 (3) : 1647-1656. PMID 15661928
The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion. Chang YC, Chan YH, Jackson DG, Hsieh SL Journal of immunology (Baltimore, Md. : 1950). 2006 ; 176 (1) : 173-180. PMID 16365408
Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells. Fayad R, Brand MI, Stone D, Keshavarzian A, Qiao L European journal of immunology. 2006 ; 36 (8) : 2215-2222. PMID 16856205
Alterations of Fas and Fas-related molecules in patients with silicosis. Otsuki T, Miura Y, Nishimura Y, Hyodoh F, Takata A, Kusaka M, Katsuyama H, Tomita M, Ueki A, Kishimoto T Experimental biology and medicine (Maywood, N.J.). 2006 ; 231 (5) : 522-533. PMID 16636300
Overexpression of human decoy receptor 3 in mice results in a systemic lupus erythematosus- like syndrome. Han B, Moore PA, Wu J, Luo H Arthritis and rheumatism. 2007 ; 56 (11) : 3748-3758. PMID 17968950
Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against Fas- induced apoptosis. Hayashi S, Miura Y, Nishiyama T, Mitani M, Tateishi K, Sakai Y, Hashiramoto A, Kurosaka M, Shiozawa S, Doita M Arthritis and rheumatism. 2007 ; 56 (4) : 1067-1075. PMID 17393415
Epstein-Barr virus transcription activator Rta upregulates decoy receptor 3 expression by binding to its promoter. Ho CH, Hsu CF, Fong PF, Tai SK, Hsieh SL, Chen CJ Journal of virology. 2007 ; 81 (9) : 4837-4847. PMID 17301127
Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice. Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A Journal of the American Society of Nephrology : JASN. 2007 ; 18 (9) : 2473-2485. PMID 17687076
Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW Gynecologic oncology. 2007 ; 106 (1) : 112-118. PMID 17490732
Atlas Genet Cytogenet Oncol Haematol 2008; 4 641
Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice. Tang CH, Hsu TL, Lin WW, Lai MZ, Yang RS, Hsieh SL, Fu WM The Journal of biological chemistry. 2007 ; 282 (4) : 2346-2354. PMID 17099218
Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3). You RI, Chang YC, Chen PM, Wang WS, Hsu TL, Yang CY, Lee CT, Hsieh SL Blood. 2008 ; 111 (3) : 1480-1488. PMID 18006694
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Contributor(s) Written 12-2007 Jiangping Wu, Bing Han CHUM Research Center, University of Montreal, Canada Citation This paper should be referenced as such : Wu J, Han B . TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/TNFRSF6BID42628ch20q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 642 Atlas of Genetics and Cytogenetics in Oncology and Haematology
TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10)
Identity Other names APO2L Apo-2L CD253 TL2 TRAIL TRAIL-PEN HGNC TNFSF10 Location 3q26 DNA/RNA
Organization of the human TRAIL gene. Description 5 exons; DNA size 17805 bp. Transcription CDS: 846 nt; Krieg A. et al. (BJC 2003) reported two splice variants in neoplastic and non-neoplastic cells. Pseudogene No known pseudogenes. Protein
Diagram 1. TRAIL receptor system. Diagram 2. Schematic representation of the structure of TRAIL protein. Note 281 AA, 32509 Da; TRAIL (TNF-Related Apoptosis-Inducing Ligand) was originally identified by two independent groups and characterized as a member of the TNF (Tumor Necrosis Factor) family of death-inducing ligands. TRAIL can bind to five different receptors found on a variety of cell types: four membrane-bound and one soluble receptor. Two of these membrane receptors, TRAIL-R1/death receptor 4 (DR4) and TRAIL-R2/death
Atlas Genet Cytogenet Oncol Haematol 2008; 4 643 receptor 5 (DR5), act as agonistic receptors, containing a cytoplasmic death domain through which TRAIL can transmit an apoptotic signal. The other two membrane receptors, TRAIL-R3/decoy receptor 1 (DcR1) and TRAIL-R4/decoy receptor 2 (DcR2), can also bind TRAIL, but act as antagonistic/regulatory receptors, lacking the death domain. In addition to these four transmembrane receptors, a fifth soluble antagonistic receptor, osteoprotegerin (OPG), has been identified (Diagram 1). Description The extra-cellular domain of the membrane-bound TRAIL forms a bell shaped homo-trimer, much like other ligands of the TNF family. However, there is a unique insertion loop of about 16-20 amino acids in soluble TRAIL near its amino-terminal end (Diagram 2). Unlike other members of the TNF superfamily, TRAIL carries a zinc ion at the trimer interface, coordinated by the single unpaired cysteine residue (Cys 230) of each monomer (Diagram 2). This zinc ion is essential for structural integrity of TRAIL, and substituting the Cys 230 with alanine or serine strongly affects the capacity of TRAIL to induce apoptosis. Three molecules of TRAIL assemble with three molecules of the transmembrane receptor as a hexameric complex (3:3). Expression Membrane-bound TRAIL is expressed on the surface of activated immune cells, such as natural killer (NK) cells, T cells, macrophages and dendritic cells, whereas soluble TRAIL is present in the sera of normal individuals as well as of patients affected by neoplastic disorders. Soluble TRAIL is also released in the culture supernatant of activated peripheral blood mononuclear cells (PBMC) in response to interferon induction, so that it apparently seems to function as an immune effector molecule, mediating antitumor cytotoxicity and immune regulation. Importantly, this biological role of TRAIL is consistent with its tumor selective properties, since it implies that normal tissues are constitutively protected from circulating immune cells bearing TRAIL. Besides, a significant level of TRAIL transcript has been detected in many human tissues including thymus, spleen, PBMC, prostate, ovary, small intestine, colon and placenta, but not in the brain and it is expressed constitutively in some cell lines. Localisation TRAIL is a type II membrane protein of about 33-35 kD, which can be cleaved from the cell surface by the aspartic proteinase cathepsin E to form a soluble ligand of about 21 kD that retains biological activity. Function The best-characterized biological activity of TRAIL is to induce apoptotic cell death in a variety of neoplastic cells. Both full-length membrane expressed TRAIL and soluble TRAIL can rapidly induce apoptosis in a wide variety of human cancer cell lines and primary tumors (including hematological malignancies), showing minimal or absent cytotoxicity on normal cells, both in vitro and in vivo; thus TRAIL was identified as a potential tumor- specific cancer therapeutic. The wide expression of TRAIL and TRAIL-Rs in many normal tissues suggests that the physiological role of TRAIL is more complex than the simply induction of apoptosis in cancer cells. In this respect, several studies have demonstrated that the TRAIL-TRAIL receptors system elicit a physiological role in normal hematopoiesis (for example an anti-differentiative effect on erythroid maturation and a pro-maturative effect during megakaryocytopoiesis and in vascular physiology, promoting the survival, migration and proliferation of endothelial cells). It has also been demonstrated that TRAIL significantly counteracts the adhesion of peripheral blood derived monocytes and granulocytes to endothelial cells without inducing apoptosis in response to inflammatory cytokines in vitro, suggesting an anti-inflammatory activity of TRAIL. All these data are reviewed in Secchiero and Zauli, 2008.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 644 Homology GENE IDENTITY (%) SPECIES SYMBOL PROTEIN DNA HOMO SAPIENS TNFSF10 VS. PAN TNFSF10 98.9 99.3 TROGLODYTES VS. MUS TNFSF10 67.0 75.0 MUSCULUS VS. RATTUS TNFSF10 70.3 74.3 NORVEGICUS VS. GALLUS TNFSF10 59.3 64.2 GALLUS VS. DANIO RERIO TNFSF10L2 46.2 54.1 The homology of TRAIL with the other proteins of TNF family is reported below: GENE IDENTITY (%) SPECIES SYMBOL PROTEIN HOMO SAPIENS TNFSF10 HOMO SAPIENS TNF 23 HOMO SAPIENS RANKL 24 HOMO SAPIENS FASL 27 HOMO SAPIENS CD40L 23 HOMO SAPIENS CD137L NOT SIGNIFICANT HOMO SAPIENS OX40L NOT SIGNIFICANT HOMO SAPIENS CD27L NOT SIGNIFICANT HOMO SAPIENS CD30L NOT SIGNIFICANT HOMO SAPIENS LTA 22 HOMO SAPIENS LTB 21 HOMO SAPIENS APO3L NOT SIGNIFICANT HOMO SAPIENS APRIL NOT SIGNIFICANT HOMO SAPIENS TNFSF13B NOT SIGNIFICANT HOMO SAPIENS TNFSF14 25 HOMO SAPIENS TNFSF15 34 HOMO SAPIENS TNFSF18 NOT SIGNIFICANT Mutations
6 esonic variations. For details see: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=8743 Implicated in Entity Myelodysplastic Syndromes (MDS). Note The myelodysplastic syndromes comprise a heterogeneous group of clonal disorders, usually characterized by a normal or hypercellular marrow with dysplastic features leading to peripheral blood cytopenias and a variable incidence of transformation into acute myeloid leukemia (AML). Ineffective erythropoiesis is a common feature of MDS. One mechanism invoked to explain the apparent discrepancy between cellular marrow and peripheral blood cytopenias in patients with MDS is apoptosis, which occurs with increased frequency in MDS marrow. Disease The decrease of mature erythrocytes, the major clinical feature of MDS, has been attributed to the increased expression and release at the bone marrow level of TRAIL, that selectively inhibits erythroid development by specifically targeting immature erythroblasts, impairing erythropoiesis and contributing to the degree of anemia.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 645 Entity B-Chronic Lymphocytic Leukemia (B-CLL) Note B-CLL represents a quintessential example of human malignancies that are caused primarily by defects in apoptosis or programmed cell death. During the early stages of disease, mature B lymphocytes that constitute most B-CLL are largely quiescent G(0) phase cells, which accumulate not because they are dividing more rapidly than normal cells but because they survive longer than their normal counterparts due to defects in the apoptotic pathways. These noncycling CD5+/CD19+ B lymphocytes accumulate in the peripheral blood, marrow, spleen, and lymph nodes. Defects in apoptotic pathways contribute also to chemoresistance, rendering tumor cells less sensitive to the cytotoxic actions of currently available anticancer drugs, and can also promote resistance to cellular immune responses. Disease In order to elucidate the expression of TRAIL and its biological potential function in B- CLL, it has been examined the expression of TRAIL in B-CLL PBMC in comparison with PBMC obtained from healthy blood donors as well as the susceptibility of B-CLL cells to soluble recombinant TRAIL and the potential effects of endogenous membrane- bound TRAIL on autologous B-CLL cell survival. It has been shown that TRAIL is overexpressed in B-CLL PBMC in comparison with normal B cells, but B-CLL cells are resistant to TRAIL-mediated apoptosis. Taken together, these findings suggest that an aberrant expression of TRAIL might contribute to the pathogenesis of B-CLL. External links Nomenclature HGNC TNFSF10 11925 Entrez_Gene TNFSF10 8743 tumor necrosis factor (ligand) superfamily, member 10 Cards Atlas TNFSF10ID42632ch3q26 GeneCards TNFSF10 Ensembl TNFSF10 [Search_View] ENSG00000121858 [Gene_View] Genatlas TNFSF10 GeneLynx TNFSF10 eGenome TNFSF10 euGene 8743 Genomic and cartography TNFSF10 - 3q26 chr3:173706158-173723963 - 3q26 [Description] (hg18- GoldenPath Mar_2006) Ensembl TNFSF10 - 3q26 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene TNFSF10 Gene and transcription Genbank AK296085 [ ENTREZ ] Genbank AK312742 [ ENTREZ ] Genbank BC009795 [ ENTREZ ] Genbank BC020220 [ ENTREZ ] Genbank BC032722 [ ENTREZ ] RefSeq NM_003810 [ SRS ] NM_003810 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq AC_000135 [ SRS ] AC_000135 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_005612 [ SRS ] NT_005612 [ ENTREZ ] RefSeq NW_001838884 [ SRS ] NW_001838884 [ ENTREZ ] RefSeq NW_921807 [ SRS ] NW_921807 [ ENTREZ ] AceView TNFSF10 AceView - NCBI Unigene Hs.478275 [ SRS ] Hs.478275 [ NCBI ] HS478275 [ spliceNest ] Fast-db 14775 (alternative variants) Protein : pattern, domain, 3D structure
Atlas Genet Cytogenet Oncol Haematol 2008; 4 646 P50591 [ SRS] P50591 [ EXPASY ] P50591 [ INTERPRO ] P50591 SwissProt [ UNIPROT ] Prosite PS00251 TNF_1 [ SRS ] PS00251 TNF_1 [ Expasy ] Prosite PS50049 TNF_2 [ SRS ] PS50049 TNF_2 [ Expasy ] Interpro IPR017355 TNF10_TNF11 [ SRS ] IPR017355 TNF10_TNF11 [ EBI ] Interpro IPR006052 TNF_family [ SRS ] IPR006052 TNF_family [ EBI ] IPR008983 Tumour_necrosis_fac-like [ SRS ] IPR008983 Tumour_necrosis_fac-like Interpro [ EBI ] CluSTr P50591 Pfam PF00229 TNF [ SRS ] PF00229 TNF [ Sanger ] pfam00229 [ NCBI-CDD ] Smart SM00207 TNF [EMBL] Prodom PD002012 TNF_subf[INRA-Toulouse] P50591 TNF10_HUMAN [ Domain structure ] P50591 TNF10_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P50591 PDB 1D0G [ SRS ] 1D0G [ PdbSum ], 1D0G [ IMB ] 1D0G [ RSDB ] PDB 1D2Q [ SRS ] 1D2Q [ PdbSum ], 1D2Q [ IMB ] 1D2Q [ RSDB ] PDB 1D4V [ SRS ] 1D4V [ PdbSum ], 1D4V [ IMB ] 1D4V [ RSDB ] PDB 1DG6 [ SRS ] 1DG6 [ PdbSum ], 1DG6 [ IMB ] 1DG6 [ RSDB ] PDB 1DU3 [ SRS ] 1DU3 [ PdbSum ], 1DU3 [ IMB ] 1DU3 [ RSDB ] HPRD 04670 Protein Interaction databases DIP P50591 IntAct P50591 Polymorphism : SNP, mutations, diseases OMIM 603598 [ map ] GENECLINICS 603598 SNP TNFSF10 [dbSNP-NCBI] SNP NM_003810 [SNP-NCI] SNP TNFSF10 [GeneSNPs - Utah] TNFSF10] [HGBASE - SRS] HAPMAP TNFSF10 [HAPMAP] COSMIC TNFSF10 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD TNFSF10 General knowledge Family Browser TNFSF10 [UCSC Family Browser] SOURCE NM_003810 SMD Hs.478275 SAGE Hs.478275 GO cytokine activity [Amigo] cytokine activity GO tumor necrosis factor receptor binding [Amigo] tumor necrosis factor receptor binding GO extracellular region [Amigo] extracellular region GO extracellular space [Amigo] extracellular space GO soluble fraction [Amigo] soluble fraction GO integral to plasma membrane [Amigo] integral to plasma membrane GO apoptosis [Amigo] apoptosis GO induction of apoptosis [Amigo] induction of apoptosis GO immune response [Amigo] immune response GO signal transduction [Amigo] signal transduction GO cell-cell signaling [Amigo] cell-cell signaling GO zinc ion binding [Amigo] zinc ion binding activation of pro-apoptotic gene products [Amigo] activation of pro-apoptotic gene GO products GO membrane [Amigo] membrane GO positive regulation of I-kappaB kinase/NF-kappaB cascade [Amigo] positive regulation
Atlas Genet Cytogenet Oncol Haematol 2008; 4 647 of I-kappaB kinase/NF-kappaB cascade GO metal ion binding [Amigo] metal ion binding BIOCARTA Induction of apoptosis through DR3 and DR4/5 Death Receptors [Genes] KEGG Cytokine-cytokine receptor interaction KEGG Apoptosis KEGG Natural killer cell mediated cytotoxicity PubGene TNFSF10 TreeFam TNFSF10 CTD 8743 [Comparative ToxicoGenomics Database] Other databases Probes Probe TNFSF10 Related clones (RZPD - Berlin) PubMed PubMed 286 Pubmed reference(s) in LocusLink Bibliography Identification and characterization of a new member of the TNF family that induces apoptosis. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA Immunity. 1995 ; 3 (6) : 673-682. PMID 8777713
Apoptosis in bone marrow of myelodysplastic syndrome patients. Bogdanovic AD, Jankovic GM, Colovic MD, Trpinac DP, Bumbasirevic VZ Blood. 1996 ; 87 (7) : page 3064. PMID 8639933
Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily. Gruss HJ International journal of clinical & laboratory research. 1996 ; 26 (3) : 143-159. PMID 8905447
Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A The Journal of biological chemistry. 1996 ; 271 (22) : 12687-12690. PMID 8663110
Death receptors: signaling and modulation. Ashkenazi A, Dixit VM Science (New York, N.Y.). 1998 ; 281 (5381) : 1305-1308. PMID 9721089
Myelodysplasia. Heaney ML, Golde DW The New England journal of medicine. 1999 ; 340 (21) : 1649-1660. PMID 10341278
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM Molecular cell. 1999 ; 4 (4) : 563-571. PMID 10549288
A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Hymowitz SG, O'Connell MP, Ultsch MH, Hurst A, Totpal K, Ashkenazi A, de Vos AM, Kelley RF Biochemistry. 2000 ; 39 (4) : 633-640. PMID 10651627
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Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Reed JC, Kitada S, Kim Y, Byrd J Seminars in oncology. 2002 ; 29 (1 Suppl 2) : 10-24. PMID 11842384
TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis- inducing ligand (TRAIL) without apoptotic potential. Krieg A, Krieg T, Wenzel M, Schmitt M, Ramp U, Fang B, Gabbert HE, Gerharz CD, Mahotka C British journal of cancer. 2003 ; 88 (6) : 918-927. PMID 12644830
TRAIL regulates normal erythroid maturation through an ERK-dependent pathway. Secchiero P, Melloni E, Heikinheimo M, Mannisto S, Di Pietro R, Iacone A, Zauli G Blood. 2004 ; 103 (2) : 517-522. PMID 12969966
Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes. Campioni D, Secchiero P, Corallini F, Melloni E, Capitani S, Lanza F, Zauli G The American journal of pathology. 2005 ; 166 (2) : 557-563. PMID 15681838
Functional expression of TRAIL and TRAIL-R2 during human megakaryocytic development. Melloni E, Secchiero P, Celeghini C, Campioni D, Grill V, Guidotti L, Zauli G Journal of cellular physiology. 2005 ; 204 (3) : 975-982. PMID 15828026
TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release. Secchiero P, Corallini F, di Iasio MG, Gonelli A, Barbarotto E, Zauli G Blood. 2005 ; 105 (9) : 3413-3419. PMID 15644410
Aberrant expression of TRAIL in B chronic lymphocytic leukemia (B-CLL) cells. Secchiero P, Tiribelli M, Barbarotto E, Celeghini C, Michelutti A, Masolini P, Fanin R, Zauli G Journal of cellular physiology. 2005 ; 205 (2) : 246-252. PMID 15887227
The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelial cell biology. Zauli G, Secchiero P Cytokine & growth factor reviews. 2006 ; 17 (4) : 245-257. PMID 16750931
Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K Cancer research. 2007 ; 67 (22) : 10869-10878. PMID 18006832
Targeting death-inducing receptors in cancer therapy. Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ Oncogene. 2007 ; 26 (25) : 3745-3757. PMID 17530027
TRAIL and osteoprotegerin: a role in endothelial physiopathology? Corallini F, Rimondi E, Secchiero P Frontiers in bioscience : a journal and virtual library. 2008 ; 13 : 135-147.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 649 PMID 17981533
Tumor-necrosis-factor-related apoptosis-inducing ligand and the regulation of hematopoiesis. Secchiero P, Zauli G Current opinion in hematology. 2008 ; 15 (1) : 42-48. PMID 18043245
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Contributor(s) Written 12-2007 Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani Department of Morfology and Embriology, Human Anatomy Section, Ferrara University, Italy Citation This paper should be referenced as such : di Iasio MG, Melloni E, Secchiero P, Capitani S . TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/TNFSF10ID42632ch3q26.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 650 Atlas of Genetics and Cytogenetics in Oncology and Haematology dic(1;15)(p11;p11)
Identity
dic(1;15)(p11;p11) G- banding - Courtesy Catherine Roche-Lestienne, Olivier Theisen, Jean-Luc Lai. Clinics and Pathology Disease Myeloid malignancies Phenotype / Myloproliferative diseases (MPD) in 3 of 10 available cases (polycytemia vera (PV) in cell stem origin all 3 cases), myelodysplastic syndromes (MDS) in 6 cases (mainly refractory anaemia (RA): 5 cases; RARS in one case), acute myeloid leukaemia (AML) of M7 type in one case. Epidemiology At least 10 cases; balanced sex ratio (5M/5F); median age was 47 yrs (range 15-81)
Atlas Genet Cytogenet Oncol Haematol 2008; 4 651
Kaplan-Meier on 10 cases of dic(1;15) from the literature; survivals (in months) were: 4, 14, 23+, 24+, 27, 40+, 93+, 96, 235. Prognosis About 60% of cases were still alive 2 to 8 yrs after diagnosis (see figure1), but with a too short follow up of a too small cohort, no real conclusions can be drawn. It is likely that the prognosis depend more on the haematological diagnosis (AML versus MDS, vs MPD). Cytogenetics Cytogenetics presents as-15, + dic(1;15) in most, if not all, cases. It therefore results in trisomy 1q.; Morphological sole anomaly in about half cases, accompanied with del(5q) twice, +8 once, del(20q) once. Genes involved and Proteins Note Genes involved are unknown; the translocation breakpoints are likely to be in heterochromatic regions External links Other dic(1;15)(p11;p11) 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. Case Report Dic(1;15)(p11;p11) as a non-random abnormality in atypical MPD Case Report Dic(1;15)(p11;p11) as a non-random abnormality in Polycytemia Vera Case Report Dic(1;15)(p11;p11) as a non-random abnormality in Myelodysplasic syndrome Bibliography Cytogenetic studies in polycythemia vera. Wurster-Hill D, Whang-Peng J, McIntyre OR, Hsu LY, Hirschhorn K, Modan B, Pisciotta AV, Pierre R, Balcerzak SP, Murphy S, Weinfeld A Seminars in hematology. 1976 ; 13 (1) : 13-32. PMID 1251221
An identical translocation between chromosome 1 and 15 in two patients with myelodysplastic syndromes. Mecucci C, Tricot G, Boogaerts M, Van den Berghe H British journal of haematology. 1986 ; 62 (3) : 439-445. PMID 3954964
Trisomy 1q in polycythemia vera and its relation to disease transition. Swolin B, Weinfeld A, Westin J American journal of hematology. 1986 ; 22 (2) : 155-167. PMID 3706291
A dysmorphic child with myelodysplasia characterized by a duplication of 1q and multiple duplications of 3q. Mascarello JT, Osborn C, Kadota RP
Atlas Genet Cytogenet Oncol Haematol 2008; 4 652 Cancer genetics and cytogenetics. 1989 ; 38 (1) : 9-12. PMID 2713819
Cytogenetic analysis of 54 cases of myelodysplastic syndrome. Jotterand-Bellomo M, Parlier V, Schmidt PM, Beris P Cancer genetics and cytogenetics. 1990 ; 46 (2) : 157-172. PMID 2340487
Dicentric (1;15) in myeloid disorders. Michaux L, Dierlamm J, Mecucci C, Meeus P, Ameye G, Libouton JM, Verhoef G, Ferrant A, Louwagie A, Verellen-Dumoulin C, Van Den Berghe H Cancer genetics and cytogenetics. 1996 ; 88 (1) : 86-89. PMID 8630988
Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Dastugue N, Lafage-Pochitaloff M, Pages MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Leonard C, Bilhou-Nabera C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Perot C, Taviaux S, Fenneteaux O, Duchayne E, Groupe Francais d'Hematologie Cellulaire, Berger R Blood. 2002 ; 100 (2) : 618-626. PMID 12091356
Contributor(s) Written 08-2007 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 . dic(1;15)(p11;p11). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/dic0115p11p11ID1159.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 653 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(2;19)(p11;p13)
Clinics and Pathology Disease Acute myeloid leukaemia (AML) Phenotype / One de novo AML (M2 type), and a therapy related AML (t-AML) cell stem origin Epidemiology The de novo AML was a 11 year old girl; the t-AML case was a 58 year old female patient who had been treated for ovary carcinoma with melphalan 1.5 yrs before. Prognosis No complete remission (CR) in the de novo case; CR was obtained but a relapse occurred and the patient died 3 months after diagnosis in the therapy related case. Cytogenetics Cytogenetics Sole anomaly in the de novo AML case; complex karyotype in the t-AML case, with -5 Morphological and other abnormalities Genes involved and Proteins Note Genes involved are unknown. External links Other t(2;19)(p11;p13) Mitelman database (CGAP - NCBI) database Other t(2;19)(p11;p13) CancerChromosomes (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 Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine. Larson RA, Wernli M, Le Beau MM, Daly KM, Pape LH, Rowley JD, Vardiman JW Blood. 1988 ; 72 (4) : 1333-1339. PMID 3167210
Translocation t(2;19)(p11;p12-p13) in childhood with acute myeloid leukemia. Quilichini B, Zattara H, Cas E, BastideAlliez LA, Blachere A, Curtillet C, Fossat C, Michel G Atlas Genet Cytogenet Oncol Haematol. 2003 ; 7 (numero 1) : 137-140.
Contributor(s) Written 08-2007 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(2;19)(p11;p13). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0219p11p13ID1288.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 654 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;18)(q26;q11)
Clinics and Pathology Disease Myelodysplastic syndrome Epidemiology Only one case to date, a 73 year old female patient Prognosis No data Cytogenetics Cytogenetics There was also a del(5q) 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 t(3;18)(q26;q11) Mitelman database (CGAP - NCBI) database Other t(3;18)(q26;q11) CancerChromosomes (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 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 (4) : 349-356. PMID 16342172
The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R Gene. 2007 ; 396 (2) : 346-357. PMID 17507183
Contributor(s) Written 08-2007 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;18)(q26;q11). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0318q26q11ID1283.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 655 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;4)(p21;q34)
Identity
t(3;4)(p21;q34) G-banding Clinics and Pathology Disease Myeloid lineage, found in 1 myelodysplastic syndrome (MDS) and 1 Acute Myeloid Leukemia (AML) Phenotype / MDS-RA and M1 AML by FAB criteria, a primitive myeloid progenitor is likely to be cell stem origin involved Etiology No known prior exposure Epidemiology Only 2 cases to date, a 69 yr old female and a 31 yr old male, sex ratio 1M/1F Clinics Elevated WBC (68x109/l), 93% blasts in blood, lymphadenopaty, hepatosplenomegaly, high LDH in AML patient Cytology Positive for CD 34, HLDR, CD33, CD68, MPO in AML Treatment Chemotherapy followed by bone marrow transplantation in AML Evolution After the first cycle of therapy, persistent bone marrow infiltration with 11% blasts Prognosis Survival 6 month in MDS, 15 month+ in AML Cytogenetics Cytogenetics May be misinterpreted as t(3;5) in suboptimal preparations Morphological Cytogenetics FISH analysis is recommended to exclude the more frequent t(3;5) Molecular
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FISH with WCP 3 and 4 and LSI BCL6 and 5q EGR1 probes. Probes WCP 3 and 4 probes, locus specific BCl6 and 5q probes Additional t(3;4)(p21;q34) is part of a complex karyotype in MDS case associated with del(20q), anomalies sole abnormality in AML case Genes involved and Proteins Note 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). Frequent deletion or allelic loss of band 3p21 is common in solid tumors, indicating the presence of tumor suppressor genes on this chromosome arm. The association among structural chromosome 3 aberrations and fragile sites on 3p may indicate the importance of previous mutagen exposure in the etiology of these diseases. Although several cancer-related genes have been located to 3p21, no gene has yet been identified to be related with hematological malignancies. One of the candidate genes may be the AF3p21 gene, a novel fusion partner of the MLL gene described in a patient who had developed therapy-related leukemia with t(3;11)(p21;q23). AF3p21 encodes a protein localized exclusively in the cell nucleus, suggesting the possibility that AF3p21 protein plays a role in signal transduction in the nucleus. External links Other t(3;4)(p21;q34) Mitelman database (CGAP - NCBI) database Other t(3;4)(p21;q34) CancerChromosomes (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. Case Report t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient 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 Cytogenetics and cell genetics. 1996 ; 74 (4) : 295-299. PMID 8976389
Novel SH3 protein encoded by the AF3p21 gene is fused to the mixed lineage leukemia protein in a therapy-related leukemia with t(3;11) (p21;q23). Sano K, Hayakawa A, Piao JH, Kosaka Y, Nakamura H Blood. 2000 ; 95 (3) : 1066-1068.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 657 PMID 10648423
Genomic organization, tissue expression, and cellular localization of AF3p21, a fusion partner of MLL in therapy-related leukemia. Hayakawa A, Matsuda Y, Daibata M, Nakamura H, Sano K Genes, chromosomes & cancer. 2001 ; 30 (4) : 364-374. PMID 11241789
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 Cancer genetics and cytogenetics. 2006 ; 171 (1) : 9-16. PMID 17074585 t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient Zamecnikova A Atlas Genet Cytogenet Oncol Haematol..
Contributor(s) Written 08-2007 Adriana Zamecnikova Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait Citation This paper should be referenced as such : Zamecnikova A . t(3;4)(p21;q34). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0304p21q34ID1433.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 658 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(4;21)(q31;q22)
Clinics and Pathology Disease Acute myeloid leukaemia (AML) Epidemiology only one case to date, a 81 year old male patient with M1 AML Prognosis no data Genes involved and Proteins Gene Name SH3D19/Eve1 Location 4q31 Protein adaptor protein; may play a role in the positive regulation of the activity of ADAMs (A disintegrin and metalloproteases) Gene Name RUNX1 Location 21q22 Protein Transcription factor (activator) for various hematopoietic-specific genes, which experssion is limited to hematopoetic stem cells, and endothelial cells and mesenchymal cells in the embryo; core binding factor family member which forms heterodimers with CBFB; binds to the core site 5' PyGPyGGTPy 3' of promotors and enhancers Result of the chromosomal anomaly
Hybrid gene
Description 5' RUNX1 -3' SH3D19 External links Other t(4;21)(q31;q22) Mitelman database (CGAP - NCBI) database Other t(4;21)(q31;q22) CancerChromosomes (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 Gene expression of Sh3d19, a novel adaptor protein with five Src homology 3 domains, in anagen mouse hair follicles. Shimomura Y, Aoki N, Ito K, Ito M Journal of dermatological science. 2003 ; 31 (1) : 43-51. PMID 12615363
ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands. Tanaka M, Nanba D, Mori S, Shiba F, Ishiguro H, Yoshino K, Matsuura N, Higashiyama S The Journal of biological chemistry. 2004 ; 279 (40) : 41950-41959. PMID 15280379
Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia. Nguyen TT, Ma LN, Slovak ML, Bangs CD, Cherry AM, Arber DA Genes, chromosomes & cancer. 2006 ; 45 (10) : 918-932. PMID 16858696
Atlas Genet Cytogenet Oncol Haematol 2008; 4 659 Contributor(s) Written 08-2007 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(4;21)(q31;q22). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0421q31q22ID1448.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 660 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)
Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage
Marta Gallego, Mariela Coccé, Andrea Bernasconi, Maria Felice, Cristina Alonso, Myriam Guitter Clinics Age and sex : 2 year(s) old female patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : hepatomegaly (3cm from CRB) ; splenomegaly (3cm from CRB) ; enlarged lymph nodes (Mediastinal lymph nodes) ; no central nervous system involvement Blood WBC : 254,4 x 109/l; Hb : 6,8 g/dl; platelets : 86 x 109/l; Bone marrow : 89% ( of infiltration by L2 lymphoblasts) Cyto pathology classification Cytology : Ambiguous lineage acute leukemia Immunophenotype : Blast cells were positive for T linage antigens: CD2, CD7, cCD3; B linage antigens: CD19 and cCD79a and myeloid antigens: CD13 and CD33. A minor (10%) myeloid blast population was also detected among the leukemic cells expressing MPO and CD117. Other positive markers were CD45, CD34, HLA-DR whereas CD10 and TdT were negative. Rearranged Ig Tcr : - Pathology : - Electron microscopy : - Precise diagnosis : acute leukemia of ambiguous lineage Survival Date of diagnosis: 04-2006 Treatment : 12-ALLIC/BFM-PROTOCOL Complete remission was obtained Treatment related death : - Relapse : - Status : Alive 07-2007 Survival : 14 month(s) Karyotype Sample : Bone marrow ; culture time : 24 h ; banding : G banding Results : 46,XX,t(8;12)(q13;p13)[16]/46,XX[4]. Karyotype at relapse : - Other molecular cytogenetics technics : Fluorescence in situ hybridization (FISH) with painting probes (WCP 8, WCP 12)and LSI ES Dual Color Translocation Probes (TEL/AML1 and AML1/ETO) (Vysis, Inc.) Other molecular cytogenetics results : ish t(8;12)(q13;p13)(WCP8+,WCP12+,TEL +,ETO-;WCP8+,WCP12+,ETO+,TEL-). FISH analysis with TEL/AML1 probe revealed that the gene ETV6 is in the derivate 8 and it is not involved in the translocation. Other molecular studies technics : RT-PCR results : BCR-ABLp210, BCR-ABLp190, MLL-AF4, MLL-AF9, MLL-ENL, E2A-PBX1 and ETV6-RUNX1 were negative.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 661 Partial GTG banded karyotype showing t(8;12)(q13;p13).
FISH with painting probes for chromosomes 8 (green) y 12 (red).
Atlas Genet Cytogenet Oncol Haematol 2008; 4 662 FISH with TEL/AML1 and AML1/ETO probes. Comments To our knowledge four cases of t(8;12)(q13;p13) have been reported in the literature. Three of them were described in childhood acute leukemia. The fourth case was described during disease progression in acute myelomonocytic leukemia with t(11;19). It was suggested that t(8;12) might play an important role in the relapse and lead to a poor prognosis. Our patient presented a bad response to prednisone and was considered of high risk group. At present she remains in complete remission. Internal links Atlas Card t(8;12)(q13;p13) Bibliography Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Pui CH, Williams DL, Raimondi SC, Rivera GK, Look AT, Dodge RK, George SL, Behm FG, Crist WM, Murphy SB Blood. 1987 ; 70 (1) : 247-253. PMID 3474042
New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases. Schneider NR, Carroll AJ, Shuster JJ, Pullen DJ, Link MP, Borowitz MJ, Camitta BM, Katz JA, Amylon MD Blood. 2000 ; 96 (7) : 2543-2549. PMID 11001909
Translocation (8;12)(q13;p13) during disease progression in acute myelomonocytic leukemia with t(11;19)(q23;p13.1). Yamamoto K, Nagata K, Tsurukubo Y, Inagaki K, Ono R, Taki T, Hayashi Y, Hamaguchi H Cancer genetics and cytogenetics. 2002 ; 137 (1) : 64-67. PMID 12377416
Contributor(s) Written Marta Gallego, Mariela Coccé, Andrea Bernasconi, Maria Felice, Cristina 08-2007 Alonso, Myriam Guitter Citation This paper should be referenced as such : Gallego M, Coccé M, Bernasconi A, Felice M, Alonso C, Guitter M . Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage. Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0812GallegoID100029.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 4 663 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)
A case of Chronic Lymphocytic Leukemia (CLL) with a rare chromosome abnormality: t(1;14;6) (q21;q32;p21), a variant of t(6;14)(p21;q32).
Alka Dwivedi, Thomas Casey, Siddharth G Adhvaryu Clinics Age and sex : 57 year(s) old female patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : no hepatomegaly ; no splenomegaly ; no central nervous system involvement Blood WBC : 34.1; Absolute lymphocyte count = 28,244 x 109/L. The lymphocytes were small and mature in appearance. Rare (less than 1%) prolymphocytes were present. x 109/l; Hb : 13.2 g/dl; platelets : 187 x 109/l; Cyto pathology classification Cytology : Chronic lymphocytic leukemia/Small lymphocytic lymphoma. Immunophenotype : Bone marrow 05/09/07: CD5+, CD19+, CD20+(dim), CD22+(very dim), CD23+, CD38+, HLA-DR+, surface lambda+(dim), ZAP-70+, CD10-. Matutes score =4 of 5. Pathology : See bone marrow above. Electron microscopy : Not performed. Precise diagnosis : Chronic lymphocytic leukemia/Small lymphocytic lymphoma. Survival Date of diagnosis: 06-2005; Original diagnosis made by flow cytometric analysis of peripheral blood on 06/2005. First bone marrow with cytogenetic analysis performed on 05/2007. Treatment : None to date Complete remission : None Treatment related death : - Relapse : N/A Status : Alive 04-2007 Karyotype Sample : Bone marrow ; culture time : 24 h, , 48 and 72 hours ; banding : GTW (G-banding by Trypsin treatment followed by Wright stain). Results : 46,XX,t(8;10)(p21;q22)c[16]/46,idem,t(1;14;6)(q21;q32;p21),-6,-12,+1-2mar [4] Karyotype at relapse : N/A Other molecular cytogenetics technics : Fluorescence In Situ Hybridization (FISH) using Vysis LSI IGH break apart (Cat # 32-191019) on the mataphases, CLL I probe set (LSI ATM/p53) and CLL II probe sets (CEP 12/CEP13q14.3/CEP13q34 probes) (Cat # 32-191025) on interphase nuclei. Other molecular cytogenetics results : 2. FISH analysis (Fig. 4) of IGH break-apart probe on G-banded metaphases (Fig. 1) showed the complex translocation, t(1;14;6)(q21;q32;p21). The LSI IgH 3¹ flanking region (250 kb) is labeled with Spectrum Orange and LSI IgH V 5¹ region (900 kb) is labeled with Spectrum Green. A normal fusion signal is seen on chromosome 14. A translocation between 14q32 and 6p21 led to the IgH signal being split with der(14) retaining the IgH 3¹ flanking region (red) and translocation of 5¹ IgH V region (green) to der (6). Subsequent complex translocations involving chromosomes 1, 14 and 6 are evident by der(14) and der (1) harboring the 1q and 6p regions, respectively. Other molecular studies technics : FISH studies on metaphases using LSI IGH break apart probes. results : FISH analysis confirmed the t(1;14;6)(q21;q32;p21).
Atlas Genet Cytogenet Oncol Haematol 2008; 4 664 Other findings results : N/A
A representative metaphase showing t(1;14;6) (q21;q32;p21) and other anomalies.
A representative metaphase of PHA stimulated blood culture showing t(8;10) (p12;q22) as the constitutional abnormality.
Atlas Genet Cytogenet Oncol Haematol 2008; 4 665 3a: A representative FISH result showing a normal signal pattern of ATM and p53 loci (ATM loci labeled with Spectrum Green and p53 loci labeled with Spectrum Orange). 3b: A representative FISH result showing a deletion of 13 (q34) (CEP 12, 13 (q14.3) and 13 (q34) labeled with Spectrums Orange, Green and Aqua, respectively).
Atlas Genet Cytogenet Oncol Haematol 2008; 4 666 A representative FISH result confirming the variant t(1;14;6) (q21;q32;p21) using the IGH break apart probe (entire IGH variable region (900kb) labeled with Spectrum Green and IGH 3' flanking region (250 kb) labeled with Spectrum Orange). A normal fusion signal (yellow) is seen on chromosome 14. Abnormal signal pattern for this probe is seen on der (14) retaining the 3'IgH flanking region and translocation of 5'IGH V region to der (6). Comments CLL is primarily a B-cell disease represented with the following anomalies; +12, del(11q) and del(17p). Cases of CLL with 14q32 (IGH) rearrangements have been reported. We present here a unique case of CLL showing a variant CCND3:IGH rearrangement in the form of t(1;14;6)(q21;q32;p21). The loss of 6q (indicated by -6) has been reported in CLL. Exact significance of monosomy 12 is not known. Interphase FISH showed del(13)(q34) in 10% cells, the significance of which is not known (Fig 3). Metaphase FISH performed with the LSI IGH break apart probe confirmed the t(1;14;6) (Fig 4).This case does not show the common deletions ( 6q, 13q14.3, 11q22-23 or 17p13) or amplification (trisomy 12). Call for collaboration Siddharth G Adhvaryu, Ph.D., FACMG, Clinical and Molecular Cytogenetics Laboratory, Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas-78229, USA; Corresponding Author: Dr Siddharth G Adhvaryu; E mail: [email protected] . Internal links Atlas Card t(6;14)(p21;q32) A novel chromosomal translocation (6;14) (p22;q32) in a case of precursor B-cell Acute Case Report Lymphoblastic Leukemia Bibliography Genomic aberrations and survival in chronic lymphocytic leukemia. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P The New England journal of medicine. 2000 ; 343 (26) : 1910-1916. PMID 11136261
Chronic lymphocytic leukemia. Chiorazzi N, Rai KR, Ferrarini M The New England journal of medicine. 2005 ; 352 (8) : 804-815. PMID 15728813
Chronic Lymphocytic Leukemia (CLL). Reddy KS Atlas Genet Cytogenet Oncol Haematol.May (numero 2005).
A novel chromosomal translocation (6;14) (p22;q32) in a case of precursor B-cell Acute Lymphoblastic leukemia. Adhvaryu SG, Dwivedi A, Stoll P Atlas Genet Cytogenet Oncol Haematol..
Contributor(s) Written 08-2007 Alka Dwivedi, Thomas Casey, Siddharth G Adhvaryu Citation This paper should be referenced as such : Dwivedi A, Casey T, Adhvaryu SG . A case of Chronic Lymphocytic Leukemia (CLL) with a rare chromosome abnormality: t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32).. Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0614AdhvaryuID100033.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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