Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Volume 12, Number 5, Sep-Oct 2008 Previous Issue / Next Issue Genes XAF1 (XIAP associated factor-1) (17p13.2). Stéphanie Plenchette, Wai Gin Fong, Robert G Korneluk. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 668-673. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/XAF1ID44095ch17p13.html WWP1 (WW domain containing E3 ubiquitin protein ligase 1) (8q21.3). Ceshi Chen. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 674-680. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/WWP1ID42993ch8q21.html TSPAN1 (tetraspanin 1) (1p34.1). David Murray, Peter Doran. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 681-683. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TSPAN1ID44178ch1p34.html TCL1B (T-cell leukemia/lymphoma 1B) (14q32.13). Herbert Eradat, Michael A Teitell. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 684-686. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TCL1BID354ch14q32.html PVRL4 (poliovirus receptor-related 4) (1q23.3). Marc Lopez. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 687-690. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PVRL4ID44141ch1q23.html PTTG1IP (pituitary tumor-transforming 1 interacting protein) (21q22.3). Vicki Smith, Chris McCabe. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 691-694. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PTTG1IPID41944ch21q22.html PLAGL2 (Pleomorphic adenoma gene-like 2) (20q11.21). Abbas Abdollahi. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 695-700. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PLAGL2ID41738ch20q11.html PDCD6 (programmed cell death 6) (5p15.33). Martin W Berchtold. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 701-706. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PDCD6ID43402ch5p15.html P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) (12q24.31). Pablo Pelegrin, Annmarie Surprenant.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 I Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 707-712. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/P2RX7ID41623ch12q24.html NKX2-2 (NK2 homeobox 2) (20p11.22). Stephen L Lessnick, Leah A Owen. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 713-717. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/NKX22ID44177ch20p11.html MIB2 (mindbomb homolog 2 (Drosophila)) (1p36.33). Tamotsu Takeuchi. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 718-721. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/MIB2ID44179ch1p36.html KCNH1 (potassium voltage-gated channel, subfamily H (eag-related), member 1) (1q32.2). Luis A Pardo. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 722-727. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/KCNH1ID41048ch1q32.html IRF1 (interferon regulatory factor 1) (5q23.3). Patricia Palladinetti, Geoff Symonds, Alla Dolnikov. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 728-735. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/IRF1ID40990ch5q23.html EGLN1 (egl nine homolog 1 (C. elegans)) (1q42.2). Terhi Jokilehto, Panu M Jaakkola. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 736-740. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/EGLN1ID44140ch1q42.html CDC6 (cell division cycle 6 homolog (S. cerevisiae)) (17q21.3). Michael Zachariadis, Vassilis G Gorgoulis. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 741-748. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CDC6ID40014ch17q21.html AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)) (Xq12). Jason D'Antonio. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 749-755. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/ARID685chXq12.html Leukaemias t(4;17)(q12;q21) . Arjan Buijs, Marrie Bruin. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 756-758. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0417q12q21ID1470.html t(2;13)(p16;q12). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 759-760. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0213p16q12ID1212.html t(2;11)(q37;q23) in AML. Cecília Correia, Manuel R Teixeira. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 761-764. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0211q37q23ANLLID1457.html t(1;21)(q21;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 765. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0121q21q22ID1446.html t(1;21)(p35;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 766. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0121p35q22ID1447.html Solid Tumours
Atlas Genet Cytogenet Oncol Haematol 2008; 5 II Digestive organs: Liver: Combined hepatocellular and cholangiocarcinoma. Munechika Enjoji, Shinichi Aishima. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 767-771. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Tumors/HepatoCholangioCarcID5331.html Cancer Prone Diseases Holoprosencephaly-Diencephalic Hamartoblastoma (HDH). Marco Castori, Paola Grammatico. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 772-775. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Kprones/HoloDienHamartoID10142.html Congenital Myofibromatosis. Dina J Zand, Elaine H Zackai. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 776-778. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Kprones/CongMyofibromID10137.html Deep Insights Case Reports Translocation t(7;9)(q34;q32) found in pediatric T-cell Acute Lymphoblastic Leukemia. Jennifer JS Laffin, Randee J Blumer, Sara J Morrison-Delap, Elizabeth A Rauch, Eric B Johnson, Carol A Diamond, Kate J Thompson, Gordana Raca, Karen D Montgomery, Daniel F Kurtycz. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 779-780. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0709LaffinID100032.html Educational Items
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Atlas Genet Cytogenet Oncol Haematol 2008; 5 III Atlas of Genetics and Cytogenetics in Oncology and Haematology
XAF1 (XIAP associated factor-1)
Identity Other names HSXIAPAF1 BIRC4BP HGNC XAF1 Location 17p13.2 Location_base_pair Starts at 6599880 and ends at 6619688 bp from pter ( according to hg18- Mar_2006). Local_order Telomeric to TP53 gene (17p13.1) Note XAF1 not approved by the HUGO Gene Nomenclature Committee (HGNC). DNA/RNA
Schematic diagram of the XAF1 gene comprising 8 exons (in grey) and transcript variants. The sizes in base pairs (bp) of exons (above) and introns (below) are shown. (*) indicates the positions of the stop codons. Description The XAF1 gene exists as a single copy in the human genome; it contains 8 exons and was predicted to span over approximately 18 kb of the genomic DNA. Transcription Five isoforms of XAF1 cDNA have been identified and are expressed in a cell and tissue type specific-manner: The original XAF1, also called XAF1(A) (CDS: 906nt) The XAF1(B) isoform (CDS: 849nt); lacks exon 3 The XAF1(C) isoform (CDS: 495nt); contains exon 4b and a new stop codon The XAF1(D) isoform (CDS: 426nt); lacks exons 4b and 5 (new stop codon in exon 6) The XAF1(E) isoform (CDS: 369nt); lacks exons 3, 4b and 5 (new stop codon in exon 6) With Northern blot analysis, at least four distinct transcripts sizes have been identified in Homo sapiens (3.9 kb, 4.5 kb, 6.0 kb and 7.0 kb). How these mRNA species relate to isoform variants is not known. Pseudogene Not known Protein Description The full length XAF1 protein consists of 301 amino acids corresponding to a molecular weight of 33.411 kDa. The protein contains seven zinc fingers domains. The XAF1(B) isoform is predicted to lack the third N-terminal zinc finger of the previously described XAF1. The XAF1(C) is predicted to contain the first five amino-terminal zinc finger domains of the previously described XAF1 and also a unique 24 aa carboxy terminus.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 668 There is no evidence for XAF1 isoforms (C), (D) and (E) expression at the protein level. Expression Normal tissue: ubiquitous and differential expression in normal tissues; highest in heart and ovary and lowest in brain and testis at mRNA levels. The XAF1 protein also displays differential protein expression profile within normal cell or tissue development including placenta and motoneurons. Cancer: as opposed to normal cells, XAF1 is found either low or undetectable in tumor cell lines at both mRNA and protein levels. Expression varies also widely among different tumor cell lines. High levels of XAF1 protein were found in glioblastoma cells (SF-539) and ovarian cells (OVCAR-5). Detectable levels were found also in various gastric and colon cancer cell lines and also myeloma cells (U266). Localisation Nuclear and cytoplasmic distribution Function Tumor suppressor gene: loss of heterozygosity (LOH) found in 12 of 33 (36%) human primary colorectal carcinomas. The absence or reduced expression of XAF1 in cancer cell lines by genetic or epigenetic modifications have suggested a possible role in the suppression of development and/or progression of malignancy. IAP antagonist: XAF1 exerts a proapoptotic effect by directly interacting with BIRC4/XIAP and antagonizing its anticaspase activity. XAF1 enhances XIAP E3 ligase activity towards BIRC5/Survivin through a complex and mediates Survivin down- regulation. Interferon (IFN)-stimulated gene (ISG): XAF1 is an important mediator of IFN-induced sensitization to TNF-related apoptosis-inducing ligand (TRAIL) in cancer. Increasing expression of XAF1 sensitizes cells to apoptosis-induced by various stimuli including etoposide, 5-FU, TRAIL, anti-Fas Ab, TNF alpha , UV, H2O2, gamma- irradiation. Homology XAF1 shares high amino acid similarity with the zinc finger domains of FLN29 and TRAF6. Mutations Note Include genetic and epigenetic modification Epigenetics Aberrant promoter hypermethylation in the 5' proximal region (from +3nt to -234 nt) in a variety of gastric, colon, bladder, kidney and prostate cancer cell lines and tumors. Germinal Not known Somatic No somatic mutations in tumor cell lines examined. LOH described in colon tumors. Implicated in Entity Colorectal cancer, gastric cancer, urogenital cancer Oncogenesis XAF1 is proposed to be a tumor suppressor gene. Correlation of reduction in XAF1 expression with stage and grade within gastric and colorectal tumors demonstrating that the loss of XAF1 contributes to tumorigenesis. External links Nomenclature HGNC XAF1 30932 Entrez_Gene XAF1 54739 XIAP associated factor 1 Cards Atlas XAF1ID44095ch17p13 GeneCards XAF1 Ensembl XAF1 [Search_View] ENSG00000132530 [Gene_View] Genatlas XAF1 GeneLynx XAF1 eGenome XAF1 euGene 54739 Genomic and cartography XAF1 - 17p13.2 chr17:6599880-6619688 + 17p13.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl XAF1 - 17p13.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene XAF1
Atlas Genet Cytogenet Oncol Haematol 2008; 5 669 Gene and transcription Genbank AK056908 [ ENTREZ ] Genbank AK091799 [ ENTREZ ] Genbank AK290276 [ ENTREZ ] Genbank AK292710 [ ENTREZ ] Genbank AK292848 [ ENTREZ ] RefSeq NM_017523 [ SRS ] NM_017523 [ ENTREZ ] RefSeq NM_199139 [ SRS ] NM_199139 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq AC_000149 [ SRS ] AC_000149 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010718 [ SRS ] NT_010718 [ ENTREZ ] RefSeq NW_001838403 [ SRS ] NW_001838403 [ ENTREZ ] RefSeq NW_926584 [ SRS ] NW_926584 [ ENTREZ ] AceView XAF1 AceView - NCBI Unigene Hs.441975 [ SRS ] Hs.441975 [ NCBI ] HS441975 [ spliceNest ] Fast-db 2459 (alternative variants) Protein : pattern, domain, 3D structure Q6GPH4 [ SRS] Q6GPH4 [ EXPASY ] Q6GPH4 [ INTERPRO ] Q6GPH4 SwissProt [ UNIPROT ] Prosite PS50145 ZF_TRAF [ SRS ] PS50145 ZF_TRAF [ Expasy ] Interpro IPR001293 Znf_TRAF [ SRS ] IPR001293 Znf_TRAF [ EBI ] CluSTr Q6GPH4 Pfam PF02176 zf-TRAF [ SRS ] PF02176 zf-TRAF [ Sanger ] pfam02176 [ NCBI-CDD ] Blocks Q6GPH4 HPRD 06978 Protein Interaction databases DIP Q6GPH4 IntAct Q6GPH4 Polymorphism : SNP, mutations, diseases OMIM 606717 [ map ] GENECLINICS 606717 SNP NM_017523 [SNP-NCI] SNP NM_199139 [SNP-NCI] SNP XAF1 [GeneSNPs - Utah] XAF1] [HGBASE - SRS] HAPMAP XAF1 [HAPMAP] HGMD XAF1 General knowledge Family Browser XAF1 [UCSC Family Browser] SOURCE NM_017523 SOURCE NM_199139 SMD Hs.441975 SAGE Hs.441975 GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO mitochondrion [Amigo] mitochondrion GO apoptosis [Amigo] apoptosis GO zinc ion binding [Amigo] zinc ion binding GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle GO metal ion binding [Amigo] metal ion binding PubGene XAF1 TreeFam XAF1 CTD 54739 [Comparative ToxicoGenomics Database]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 670 Other databases Probes Probe XAF1 Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in Entrez Bibliography Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG Genomics. 2000 ; 70 (1) : 113-122. PMID 11087668
Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG Nature cell biology. 2001 ; 3 (2) : 128-133. PMID 11175744
Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S, Borden EC The Journal of biological chemistry. 2002 ; 277 (32) : 28504-28511. PMID 12029096
Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. Byun DS, Cho K, Ryu BK, Lee MG, Kang MJ, Kim HR, Chi SG Cancer research. 2003 ; 63 (21) : 7068-7075. PMID 14612497
Coexistence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Yang L, Cao Z, Yan H, Wood WC Cancer research. 2003 ; 63 (20) : 6815-6824. PMID 14583479
XAF1 expression is significantly reduced in human melanoma. Ng KC, Campos EI, Martinka M, Li G The Journal of investigative dermatology. 2004 ; 123 (6) : 1127-1134. PMID 15610524
Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between X-linked inhibitor of apoptosis proteins (XIAPs) and its inhibitor, XIAP-associated factor 1. Perrelet D, Perrin FE, Liston P, Korneluk RG, MacKenzie A, Ferrer-Alcon M, Kato AC The Journal of neuroscience. 2004 ; 24 (15) : 3777-3785. PMID 15084658
Low expression of XIAP-associated factor 1 in human colorectal cancers. Ma TL, Ni PH, Zhong J, Tan JH, Qiao MM, Jiang SH Chinese journal of digestive diseases. 2005 ; 6 (1) : 10-14. PMID 15667552
Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor. Fang X, Liu Z, Fan Y, Zheng C, Nilson S, Egevad L, Ekman P, Xu D International journal of cancer. 2006 ; 118 (10) : 2485-2489. PMID 16353137
Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Lee MG, Huh JS, Chung SK, Lee JH, Byun DS, Ryu BK, Kang MJ, Chae KS, Lee SJ, Lee CH, Kim JI,
Atlas Genet Cytogenet Oncol Haematol 2008; 5 671 Chang SG, Chi SG Oncogene. 2006 ; 25 (42) : 5807-5822. PMID 16909101
All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer. Wang J, Peng Y, Sun YW, He H, Zhu S, An X, Li M, Lin MC, Zou B, Xia HH, Jiang B, Chan AO, Yuen MF, Kung HF, Wong BC Gastroenterology. 2006 ; 130 (3) : 747-758. PMID 16530516
Xaf1 can cooperate with TNFalpha in the induction of apoptosis, independently of interaction with XIAP. Xia Y, Novak R, Lewis J, Duckett CS, Phillips AC Molecular and cellular biochemistry. 2006 ; 286 (1-2) : 67-76. PMID 16432762
Identification of a novel splice variant of X-linked inhibitor of apoptosis-associated factor 1. Yin W, Cheepala S, Clifford JL Biochemical and biophysical research communications. 2006 ; 339 (4) : 1148-1154. PMID 16343440
Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Zou B, Chim CS, Zeng H, Leung SY, Yang Y, Tu SP, Lin MC, Wang J, He H, Jiang SH, Sun YW, Yu LF, Yuen ST, Kung HF, Wong BC Gastroenterology. 2006 ; 131 (6) : 1835-1843. PMID 17087954
Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG The Journal of biological chemistry. 2007 ; 282 (36) : 26202-26209. PMID 17613533
Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses. Chung SK, Lee MG, Ryu BK, Lee JH, Han J, Byun DS, Chae KS, Lee KY, Jang JY, Kim HJ, Chi SG Gastroenterology. 2007 ; 132 (7) : 2459-2477. PMID 17570219
Gene expression and promoter methylation of the XIAP-associated Factor 1 in renal cell carcinomas: correlations with pathology and outcome. Kempkensteffen C, Hinz S, Schrader M, Christoph F, Magheli A, Krause H, Schostak M, Miller K, Weikert S Cancer letters. 2007 ; 254 (2) : 227-235. PMID 17449173
Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) - Pilot trial of a phase I/II study: study protocol. Rochet N, Jensen AD, Sterzing F, Munter MW, Eichbaum MH, Schneeweiss A, Sohn C, Debus J, Harms W BMC cancer. 2007 ; 7 : page 227. PMID 18093313
The role of XAF1 in cancer. Plenchette S, Cheung HH, Fong WG, LaCasse EC, Korneluk RG Current opinion in investigational drugs (London, England : 2000). 2007 ; 8 (6) : 469-476. PMID 17621877
Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via
Atlas Genet Cytogenet Oncol Haematol 2008; 5 672 caspase-independent apoptosis. Qi R, Gu J, Zhang Z, Yang K, Li B, Fan J, Wang C, He Z, Qiao L, Lin Z, Liu XY Cancer gene therapy. 2007 ; 14 (1) : 82-90. PMID 17008933
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Contributor(s) Written 01-2008 Stéphanie Plenchette, Wai Gin Fong, Robert G Korneluk Children's Hospital of Eastern Ontario, Apoptosis Research Centre, Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada Citation This paper should be referenced as such : Plenchette S, Fong WG, Korneluk RG . XAF1 (XIAP associated factor-1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/XAF1ID44095ch17p13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 673 Atlas of Genetics and Cytogenetics in Oncology and Haematology
WWP1 (WW domain containing E3 ubiquitin protein ligase 1)
Identity Other names AIP5 (Atropin-1-interacting protein 5) Tiul1 (TGIF-interacting ubiquitin ligase 1) HGNC WWP1 Location 8q21.3 Location_base_pair Starts at 87424110 and ends at 87549294 bp from pter ( according to hg18- Mar_2006). DNA/RNA
Boxes represent Exons. Description The WWP1 gene encompasses 26 exons which span approximatively 142 kb of DNA. BAC clone RPCI-459L5 contains the complete human WWP1 genome sequence. Transcription WWP1 mRNA is strongly or modestly expressed in human heart, muscle, placenta, kidney, liver, pancreas and testis (Mosser EA, 1998; Komuro A, 2004). The size of the WWP1 mRNA is about 4.2 Kb (Chen C, 2007). There are multiple splicing isoforms in the breast cancer cell line T47D (Flasza M, 2002). The open reading frame for the full length WWP1 gene is 2766 bp. The transcription is increased by TGFb (Chen C, 2007). Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 5 674
A: WWP1 protein B: Exogenous WWP1 expression in the 22Rv1 prostate cancer cell line was detected under a confocal microscopy. The endosomes are indicated by GFP-Rab5. C: Protein structure of WWP1 Description 922 amino acids; approximatively 110 kDa protein; The C2 domain at N-terminus is responsible for calcium-dependent phospholipid binding. The four WW domains in the middle are responsible for protein-protein interaction with PY motifs. The HECT domain at the C-terminus is responsible for the ubiquitin transfer. The Cystein 890 is the catalytic center. The underlined WWP1 substrates do not have a PY motif (PPXY). A smaller WWP1 protein isoform was detected in two prostate cancer cell lines PC-3 and LAPC-4 (Chen C, 2007). Protein structure: The HECT domain of WWP1 (see Figure 2C) (Verdecia MA, 2003). Expression The WWP1 protein is lowly expressed in normal prostate and breast but is frequently upregulated in prostate and breast cancers due to the gene amplification. Localisation Predominately on membrane structures in cytoplasm and occasionally in nucleus (see Figure 2B).
Atlas Genet Cytogenet Oncol Haematol 2008; 5 675 Function WWP1 is an E3 ubiquitin ligase. WWP1 negatively regulates the transforming growth factor-beta (TGF-b) signaling by targeting its molecular components, including TGF-beta receptor 1 (TbR1) (Komuro A, 2004), Smad2 (Seo SR, 2004), and Smad4 (Moren A, 2005) for ubiquitin mediated degradation. In addition, WWP1 has been reported to target the epithelial Na+ channel (ENaC) (Malbert-Colas L, 2003), Notch (Shaye DD, 2005), Runx2 (Jones DC, 2006; Shen R, 2006), KLF2 (Zhang X, 2004), and KLF5 (Chen C, 2005) for ubiquitin-mediated proteolysis. Recently, WWP1 has been demonstrated to inhibit p53 activity through exporting p53 from the nucleus after ubiquitination (Laine A, 2007). Overall, WWP1 may play a pro- survival role in several tumor types including breast (Chen C, 2007) and prostate (Chen C, 2007). WWP1 has also shown to promote virus budding (Martin-Serrano J, 2005; Heidecker G, 2007). Homology WWP1 belongs to the C2-WW-HECT E3 family which contains 8 other members (Chen C, 2007). The WWP1 gene is highly-conserved among species (from human to c. elegant). Mutations Somatic The WWP1 gene is rarely mutated in human prostate cancer (Chen C, 2007). Two sequence alterations were detected in prostate cancer xenografts. One was 2393A-->T (Glu798Val) in CWR91 and the other was 721A-->T (Thr241Ser) in LuCaP35. Additionally, some mutations in the HECT domain decrease the E3 ligase activity (Verdecia MA, 2003). Implicated in Entity Prostate cancer Disease The WWP1 gene is amplified in 31-44% prostate cancer cell lines/xenografts/tumors. Consistently, the WWP1 mRNA and protein is up-regulated in these samples compared to immortalized prostate epithelial cell lines. WWP1 knock-down increases the TGFb- induced CDK inhibitor p15 expression and decreases PC-3 prostate cancer cell growth in vitro. These results suggest that WWP1 may be an oncogene in prostate cancer. Entity Breast cancer Disease The WWP1 gene is amplified in 41-51% breast cancer cell lines/tumors. Consistently, the WWP1 mRNA and protein is up-regulated in breast cancer cells compared to immortalized breast epithelial cell lines. WWP1 knock-down induces growth arrest and apoptosis in MCF7 and HCC1500 breast cancer cell lines. Forced expression of WWP1 promotes MCF10A and 184B5 immortalized breast epithelial cell proliferation in an E3 ligase independent manner.
WWP1 protein expression in normal breast epithelial cells and breast cancer cells by immunohistochemical staining. External links Nomenclature HGNC WWP1 17004 Entrez_Gene WWP1 11059 WW domain containing E3 ubiquitin protein ligase 1 Cards Atlas WWP1ID42993ch8q21 GeneCards WWP1
Atlas Genet Cytogenet Oncol Haematol 2008; 5 676 Ensembl WWP1 [Search_View] ENSG00000123124 [Gene_View] Genatlas WWP1 GeneLynx WWP1 eGenome WWP1 euGene 11059 Genomic and cartography WWP1 - 8q21.3 chr8:87424110-87549294 + 8q21 [Description] (hg18- GoldenPath Mar_2006) Ensembl WWP1 - 8q21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene WWP1 Gene and transcription Genbank AK292800 [ ENTREZ ] Genbank AK310683 [ ENTREZ ] Genbank AL050082 [ ENTREZ ] Genbank AL136739 [ ENTREZ ] Genbank AW137654 [ ENTREZ ] RefSeq NM_007013 [ SRS ] NM_007013 [ ENTREZ ] RefSeq AC_000051 [ SRS ] AC_000051 [ ENTREZ ] RefSeq AC_000140 [ SRS ] AC_000140 [ ENTREZ ] RefSeq NC_000008 [ SRS ] NC_000008 [ ENTREZ ] RefSeq NT_008046 [ SRS ] NT_008046 [ ENTREZ ] RefSeq NW_001839136 [ SRS ] NW_001839136 [ ENTREZ ] RefSeq NW_923984 [ SRS ] NW_923984 [ ENTREZ ] AceView WWP1 AceView - NCBI Unigene Hs.655189 [ SRS ] Hs.655189 [ NCBI ] HS655189 [ spliceNest ] Fast-db 6456 (alternative variants) Protein : pattern, domain, 3D structure Q5YLC1 [ SRS] Q5YLC1 [ EXPASY ] Q5YLC1 [ INTERPRO ] Q5YLC1 SwissProt [ UNIPROT ] Prosite PS50004 C2 [ SRS ] PS50004 C2 [ Expasy ] Prosite PS50237 HECT [ SRS ] PS50237 HECT [ Expasy ] Prosite PS01159 WW_DOMAIN_1 [ SRS ] PS01159 WW_DOMAIN_1 [ Expasy ] Prosite PS50020 WW_DOMAIN_2 [ SRS ] PS50020 WW_DOMAIN_2 [ Expasy ] Interpro IPR000008 C2_Ca-dep [ SRS ] IPR000008 C2_Ca-dep [ EBI ] Interpro IPR000569 HECT [ SRS ] IPR000569 HECT [ EBI ] Interpro IPR002349 WW [ SRS ] IPR002349 WW [ EBI ] Interpro IPR001202 WW_Rsp5_WWP [ SRS ] IPR001202 WW_Rsp5_WWP [ EBI ] CluSTr Q5YLC1 Pfam PF00168 C2 [ SRS ] PF00168 C2 [ Sanger ] pfam00168 [ NCBI-CDD ] Pfam PF00632 HECT [ SRS ] PF00632 HECT [ Sanger ] pfam00632 [ NCBI-CDD ] Pfam PF00397 WW [ SRS ] PF00397 WW [ Sanger ] pfam00397 [ NCBI-CDD ] Smart SM00239 C2 [EMBL] Smart SM00119 HECTc [EMBL] Smart SM00456 WW [EMBL] Blocks Q5YLC1 HPRD 03811 Protein Interaction databases DIP Q5YLC1 IntAct Q5YLC1 Polymorphism : SNP, mutations, diseases OMIM 602307 [ map ] GENECLINICS 602307
Atlas Genet Cytogenet Oncol Haematol 2008; 5 677 SNP WWP1 [dbSNP-NCBI] SNP NM_007013 [SNP-NCI] SNP WWP1 [GeneSNPs - Utah] WWP1] [HGBASE - SRS] HAPMAP WWP1 [HAPMAP] COSMIC WWP1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD WWP1 General knowledge Family Browser WWP1 [UCSC Family Browser] SOURCE NM_007013 SMD Hs.655189 SAGE Hs.655189 GO ubiquitin ligase complex [Amigo] ubiquitin ligase complex GO ubiquitin-protein ligase activity [Amigo] ubiquitin-protein ligase activity GO protein binding [Amigo] protein binding GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO protein modification process [Amigo] protein modification process GO signal transduction [Amigo] signal transduction GO central nervous system development [Amigo] central nervous system development GO negative regulation of transcription [Amigo] negative regulation of transcription GO protein ubiquitination [Amigo] protein ubiquitination GO ligase activity [Amigo] ligase activity interspecies interaction between organisms [Amigo] interspecies interaction between GO organisms GO entry of virus into host cell [Amigo] entry of virus into host cell KEGG Ubiquitin mediated proteolysis KEGG Dentatorubropallidoluysian atrophy (DRPLA) PubGene WWP1 TreeFam WWP1 CTD 11059 [Comparative ToxicoGenomics Database] Other databases Probes Probe WWP1 Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in Entrez Bibliography Physical and functional interactions between the transactivation domain of the hematopoietic transcription factor NF-E2 and WW domains. Mosser EA, Kasanov JD, Forsberg EC, Kay BK, Ney PA, Bresnick EH Biochemistry. 1998 ; 37 (39) : 13686-13695. PMID 9753456
Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. Flasza M, Gorman P, Roylance R, Canfield AE, Baron M Biochemical and biophysical research communications. 2002 ; 290 (1) : 431-437. PMID 11779188
Differential expression and localisation of WWP1, a Nedd4-like protein, in epithelia. Malbert-Colas L, Fay M, Cluzeaud F, Blot-Chabaud M, Farman N, Dhermy D, Lecomte MC Pflugers Archiv : European journal of physiology. 2003 ; 447 (1) : 35-43. PMID 12908109
Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME, Hunter T, Noel JP Molecular cell. 2003 ; 11 (1) : 249-259.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 678 PMID 12535537
Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain- containing protein 1 (WWP1). Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K Oncogene. 2004 ; 23 (41) : 6914-6923. PMID 15221015
The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. Seo SR, Lallemand F, Ferrand N, Pessah M, L'Hoste S, Camonis J, Atfi A The EMBO journal. 2004 ; 23 (19) : 3780-3792. PMID 15359284
WWP1-dependent ubiquitination and degradation of the lung Kruppel-like factor, KLF2. Zhang X, Srinivasan SV, Lingrel JB Biochemical and biophysical research communications. 2004 ; 316 (1) : 139-148. PMID 15003522
Human Kruppel-like factor 5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells. Chen C, Sun X, Guo P, Dong XY, Sethi P, Cheng X, Zhou J, Ling J, Simons JW, Lingrel JB, Dong JT The Journal of biological chemistry. 2005 ; 280 (50) : 41553-41561. PMID 16223724
HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway. Martin-Serrano J, Eastman SW, Chung W, Bieniasz PD The Journal of cell biology. 2005 ; 168 (1) : 89-101. PMID 15623582
Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. Moren A, Imamura T, Miyazono K, Heldin CH, Moustakas A The Journal of biological chemistry. 2005 ; 280 (23) : 22115-22123. PMID 15817471
LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans. Shaye DD, Greenwald I Development. 2005 ; 132 (22) : 5081-5092. PMID 16236769
Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Jones DC, Wein MN, Oukka M, Hofstaetter JG, Glimcher MJ, Glimcher LH Science. 2006 ; 312 (5777) : 1223-1227. PMID 16728642
Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O'keefe RJ, Chen D The Journal of biological chemistry. 2006 ; 281 (6) : 3569-3576. PMID 16299379
The Nedd4-like family of E3 ubiquitin ligases and cancer. Chen C, Matesic LE Cancer metastasis reviews. 2007 ; 26 (3-4) : 587-604. PMID 17726579
Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Chen C, Sun X, Guo P, Dong XY, Sethi P, Zhou W, Zhou Z, Petros J, Frierson HF Jr, Vessella RL, Atfi A, Dong JT
Atlas Genet Cytogenet Oncol Haematol 2008; 5 679 Oncogene. 2007 ; 26 (16) : 2386-2394. PMID 17016436
The amplified WWP1 gene is a potential molecular target in breast cancer. Chen C, Zhou Z, Ross JS, Zhou W, Dong JT International journal of cancer. 2007 ; 121 (1) : 80-87. PMID 17330240
The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T- cell leukemia virus type 1. Heidecker G, Lloyd PA, Soheilian F, Nagashima K, Derse D Journal of virology. 2007 ; 81 (18) : 9769-9777. PMID 17609263
Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Laine A, Ronai Z Oncogene. 2007 ; 26 (10) : 1477-1483. PMID 16924229
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Contributor(s) Written 01-2008 Ceshi Chen The Center for Cell Biology and Cancer Research Albany Medical College MS355/350, Mail code 165, 47 New Scotland Ave. Albany, NY 12208, USA Citation This paper should be referenced as such : Chen C . WWP1 (WW domain containing E3 ubiquitin protein ligase 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/WWP1ID42993ch8q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 680 Atlas of Genetics and Cytogenetics in Oncology and Haematology
TSPAN1 (tetraspanin 1)
Identity Other names 9030418M05Rik NET-1 RP11-322N21.1 TSPAN-1 HGNC TSPAN1 Location 1p34.1 Location_base_pair Starts at 46418799 and ends at 46424217 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description The TSPAN1 gene is located on chromosome 1 in a 5419 bp sequence (46418799..46424217). The gene contains 10 exons. Transcription mRNA: 1297 nucleotides in length. Protein Description 241 amino acids, 26.2 kDa Protein. The 241 amino acid sequence is: 1 mqcfsfiktm milfnllifl cgaallavgi wvsidgasfl kifgplsssa mqfvnvgyfl; 61 iaagvvvfal gflgcygakt eskcalvtff filllifiae vaaavvalvy ttmaehfltl; 121 lvvpaikkdy gsqedftqvw nttmkglkcc gftnytdfed spyfkensaf ppfccndnvt; 181 ntanetctkq kahdqkvegc fnqllydirt navtvggvaa gigglelaam ivsmylycnl; 241 q Expression Widely expressed. Localisation Plasma Membrane Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. These are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. Homology Holomogy with Pan troglodytes (100%); Canis lupus familiaris (89%); Mus musculus (82%), Rattus norvegicus (82%), Gallus gallus (70%). Mutations Note TSPAN1 is subject to the following misense mutations : Source ID rs2234266 rs2234267 rs2234268 rs1047216 Wild type A C G A nucleotide Wild type M S V K amino acid Variant G T A G nucleotide Variant V F M E amino acid Amino Acid 0 37 86 188 Position Implicated in Entity Cervical Cancer Disease Cervical cancer is a malignant carcinoma or the cervix, typically composed of squamous cells. Most studies have found that human papillomavirus (HPV) infection is
Atlas Genet Cytogenet Oncol Haematol 2008; 5 681 responsible for virtually all cases of cervical cancer. Prognosis Prognosis depends on the stage of the cancer. The 5 year survival rate with treatment is 80 to 90% in patients with stage I disease and 50 to 65% in patients with stage II disease. 25 to 35% of women with stage III cancer and 15% or fewer of those with stage IV cancer are alive after 5 years. Prognosis drops dramatically with tumour metastasis. Thirty-five percent of patients with invasive cervical cancer have persistent or recurrent disease after treatment. Entity Hepatocellular Carcinoma Disease Hepatocellular Carcinoma (HCC) is a malignancy of the liver. Most cases of HCC are secondary to either a hepatitis B or C infection or cirrhosis. Prognosis The prognosis of HCC is dependent on many factors, including tumour size, tumour staging, the involvement of liver vessels, the presence of extrahepatic metastases and the vascularisation of the tumor. External links Nomenclature HGNC TSPAN1 20657 Entrez_Gene TSPAN1 10103 tetraspanin 1 Cards Atlas TSPAN1ID44178ch1p34 GeneCards TSPAN1 Ensembl TSPAN1 [Search_View] ENSG00000117472 [Gene_View] Genatlas TSPAN1 GeneLynx TSPAN1 eGenome TSPAN1 euGene 10103 Genomic and cartography TSPAN1 - 1p34.1 chr1:46418799-46424217 + 1p33 [Description] (hg18- GoldenPath Mar_2006) Ensembl TSPAN1 - 1p33 [CytoView] NCBI Mapview HomoloGene TSPAN1 Gene and transcription Genbank AF054838 [ ENTREZ ] Genbank AF065388 [ ENTREZ ] Genbank AF133425 [ ENTREZ ] Genbank AK313774 [ ENTREZ ] Genbank BC000695 [ ENTREZ ] RefSeq NM_005727 [ SRS ] NM_005727 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_032977 [ SRS ] NT_032977 [ ENTREZ ] RefSeq NW_001838578 [ SRS ] NW_001838578 [ ENTREZ ] RefSeq NW_921351 [ SRS ] NW_921351 [ ENTREZ ] AceView TSPAN1 AceView - NCBI Unigene Hs.38972 [ SRS ] Hs.38972 [ NCBI ] HS38972 [ spliceNest ] Fast-db 15814 (alternative variants) Protein : pattern, domain, 3D structure O60635 [ SRS] O60635 [ EXPASY ] O60635 [ INTERPRO ] O60635 [ UNIPROT SwissProt ] Prosite PS00421 TM4_1 [ SRS ] PS00421 TM4_1 [ Expasy ] Interpro IPR000301 Transmem_4 [ SRS ] IPR000301 Transmem_4 [ EBI ] CluSTr O60635 PF00335 Tetraspannin [ SRS ] PF00335 Tetraspannin [ Sanger ] pfam00335 Pfam [ NCBI-CDD ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 682 Blocks O60635 HPRD 18232 Protein Interaction databases DIP O60635 IntAct O60635 Polymorphism : SNP, mutations, diseases SNP TSPAN1 [dbSNP-NCBI] SNP NM_005727 [SNP-NCI] SNP TSPAN1 [GeneSNPs - Utah] TSPAN1] [HGBASE - SRS] HAPMAP TSPAN1 [HAPMAP] HGMD TSPAN1 General knowledge Family TSPAN1 [UCSC Family Browser] Browser SOURCE NM_005727 SMD Hs.38972 SAGE Hs.38972 GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane PubGene TSPAN1 TreeFam TSPAN1 CTD 10103 [Comparative ToxicoGenomics Database] Other databases Probes Probe TSPAN1 Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in Entrez Bibliography Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas. Wollscheid V, Kuhne-Heid R, Stein I, Jansen L, Kollner S, Schneider A, Durst M International journal of cancer. 2002 ; 99 (6) : 771-775. PMID 12115476
Association of NET-1 gene expression with human hepatocellular carcinoma. Chen L, Wang Z, Zhan X, Li DC, Zhu YY, Zhu J International journal of surgical pathology. 2007 ; 15 (4) : 346-353. PMID 17913940
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Contributor(s) Written 01-2008 David Murray, Peter Doran UCD School of Medicine and Medical Sciences, UCD-Mater Clinical Research Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland Citation This paper should be referenced as such : Murray D, Doran P . TSPAN1 (tetraspanin 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TSPAN1ID44178ch1p34.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 683 Atlas of Genetics and Cytogenetics in Oncology and Haematology
TCL1B (T-cell leukemia/lymphoma 1B)
Identity Other names TML1 HGNC TCL1B Location 14q32.13 Location_base_pair Starts at 95222516 and ends at 95228720 bp from pter ( according to hg18- Mar_2006). Local_order centromere - TCL6 (TNG1 and TNG2) - TCL1B - TCL1A - telomere DNA/RNA Description 6.5 kb TCL1B cDNA. 4 exons (181, 171, 69, 697 bp); centromere - exons 1 to 4 - telomere orientation; only the first three exons are coding. Located 15-16 kb centromeric of TCL1A. Transcription TCL1B transcripts detected by RT-PCR or Northern blot in fetal tissues (liver, thymus, spleen, and kidney) and in testis, placenta, peripheral blood lymphocytes, kidney, tonsil, spleen, and bone marrow. Pseudogene Localized to 5q12-5q13, lacks an initiating ATG and introns and has a stop codon in the middle of the ORF. Protein Description 15 kDa, 128 amino acid protein; one domain with a beta-barrel topology. Expression Undefined Localisation Undefined Function Undefined in vivo but binds and coactivates AKT (protein kinase B) in vitro and in transfected cell lines. Homology 30% identical to TCL1A, 60% similar to TCL1A 36% identical to MTCP1, 63% similar to MTCP1 Implicated in Entity Expression in rare mature T cell leukemias carrying t(14;14)(q11;q32.1) causing a TCRalpha/delta-TCL1A/TCL1B translocation. Expression in some Burkitt lymphoma cell lines. Disease May be upregulated in T-cell prolymphocytic leukemia (T-PLL) with t(14;14)(q11;q32.1) and in Burkitt lymphoma Oncogenesis TCL1 over expression by chromosomal rearrangement is a critical oncogenetic mechanism in T-PLL; a role for TCL1B over expression in oncogenesis is not yet shown. External links Nomenclature HGNC TCL1B 11649 Entrez_Gene TCL1B 9623 T-cell leukemia/lymphoma 1B Cards Atlas TCL1BID354ch14q32 GeneCards TCL1B Ensembl TCL1B [Search_View] ENSG00000213231 [Gene_View] Genatlas TCL1B GeneLynx TCL1B eGenome TCL1B euGene 9623 Genomic and cartography TCL1B - 14q32.13 chr14:95222516-95228720 + 14q32.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl TCL1B - 14q32.1 [CytoView]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 684 NCBI Mapview OMIM Disease map [OMIM] HomoloGene TCL1B Gene and transcription Genbank AB018563 [ ENTREZ ] Genbank AF110466 [ ENTREZ ] Genbank AF137027 [ ENTREZ ] Genbank AK023714 [ ENTREZ ] Genbank BC041616 [ ENTREZ ] RefSeq NM_004918 [ SRS ] NM_004918 [ ENTREZ ] RefSeq NM_199206 [ SRS ] NM_199206 [ 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_001838115 [ SRS ] NW_001838115 [ ENTREZ ] RefSeq NW_925561 [ SRS ] NW_925561 [ ENTREZ ] AceView TCL1B AceView - NCBI Unigene Hs.632346 [ SRS ] Hs.632346 [ NCBI ] HS632346 [ spliceNest ] Fast-db 5433 (alternative variants) Protein : pattern, domain, 3D structure O95988 [ SRS] O95988 [ EXPASY ] O95988 [ INTERPRO ] O95988 SwissProt [ UNIPROT ] Interpro IPR004832 TCL1_MTCP1 [ SRS ] IPR004832 TCL1_MTCP1 [ EBI ] CluSTr O95988 PF01840 TCL1_MTCP1 [ SRS ] PF01840 TCL1_MTCP1 [ Sanger ] pfam01840 Pfam [ NCBI-CDD ] Prodom PD015575 TCL1_MTCP1[INRA-Toulouse] O95988 TCL1B_HUMAN [ Domain structure ] O95988 TCL1B_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks O95988 HPRD 04795 Protein Interaction databases DIP O95988 IntAct O95988 Polymorphism : SNP, mutations, diseases OMIM 603769 [ map ] GENECLINICS 603769 SNP TCL1B [dbSNP-NCBI] SNP NM_004918 [SNP-NCI] SNP NM_199206 [SNP-NCI] SNP TCL1B [GeneSNPs - Utah] TCL1B] [HGBASE - SRS] HAPMAP TCL1B [HAPMAP] HGMD TCL1B General knowledge Family Browser TCL1B [UCSC Family Browser] SOURCE NM_004918 SOURCE NM_199206 SMD Hs.632346 SAGE Hs.632346 PubGene TCL1B TreeFam TCL1B CTD 9623 [Comparative ToxicoGenomics Database] Other databases
Atlas Genet Cytogenet Oncol Haematol 2008; 5 685 Probes Probe TCL1B Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in Entrez Bibliography Abnormalities at 14q32.1 in T cell malignancies involve two oncogenes. Pekarsky Y, Hallas C, Isobe M, Russo G, Croce CM Proc Natl Acad Sci U S A. 1999 ; 96 (6) : 2949-2951. PMID 10077617
Identification of the TCL1/MTCP1-like 1 (TML1) gene from the region next to the TCL1 locus. Sugimoto J, Hatakeyama T, Narducci MG, Russo G, Isobe M Cancer research. 1999 ; 59 (10) : 2313-2317. PMID 10344735
The protooncogene TCL1 is an Akt kinase coactivator. Laine J, Kunstle G, Obata T, Sha M, Noguchi M Molecular cell. 2000 ; 6 (2) : 395-407. PMID 10983986
Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Pekarsky Y, Koval A, Hallas C, Bichi R, Tresini M, Malstrom S, Russo G, Tsichlis P, Croce CM Proc Natl Acad Sci U S A. 2000 ; 97 (7) : 3028-3033. PMID 10716693
Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family. Laine J, Kunstle G, Obata T, Noguchi M The Journal of biological chemistry. 2002 ; 277 (5) : 3743-3751. PMID 11707444
The TCL1 family of oncoproteins: co-activators of transformation. Teitell MA Nature reviews. Cancer. 2005 ; 5 (8) : 640-648. PMID 16056259
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Contributor(s) Written 01-2008 Herbert Eradat, Michael A Teitell Departments of Medicine (H.E.) and Pathology and Laboratory Medicine (M.A.T.), David Geffen School of Medicine at UCLA, 675 Charles Young Drive South, 4-762 MacDonald Research Laboratories, Los Angeles, CA 90095-1732, USA Citation This paper should be referenced as such : Eradat H, Teitell MA . TCL1B (T-cell leukemia/lymphoma 1B). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TCL1BID354ch14q32.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 686 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PVRL4 (poliovirus receptor-related 4)
Identity Other names LNIR PRR4 Nectin-4 HGNC PVRL4 Location 1q23.3 Location_base_pair Starts at 159308120 and ends at 159325966 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description The PVRL4 gene spans 17.85 kb, consists of 9 exons and 8 introns. Transcription The human Nectin-4 mRNA consists of 1458 or 1533 bases (alternative splice forms). Protein
Extracellular region of dimeric Nectin-4 is composed with three Ig domains of Ig V and IgC types. The last 4 aminoacids in the C-terminus region binds to the scaffold F-actin binding protein AF-6/afadin. Nectin-4 ectodomain is shedded from cell surface by the metalloprotease TACE/ ADAM-17. Description Nectin-4 protein is 510 aminoacid long. Molecular weight is 66 kDa. Expression Nectin-4 expression in mainly expressed during development. In mice Nectin-4 transcript are detected at day 11 d.p.c. In human Nectin-4 is not expressed in adult tissues. Localisation Nectin-4 is expressed at epithelial adherens junctions. In tumors Nectin-4 expression can be observed in the cytoplasm. Function Nectin-4 binds Nectin-1 through IgV domain interaction. Nectin-1 is involved in development. Nectin-4 increases tumor cell migration. Homology With other members of the family. Implicated in Entity Breast carcinoma of basal subtypes. Disease Nectin-4 is found in breast tumors and its expression correlates with the basal subtype. The soluble form is detected in sera of patients with metastatic breast carcinoma and is a marker of disease progression. Prognosis Adverse prognosis.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 687
Oncogenesis Related to tumor cell migration. External links Nomenclature HGNC PVRL4 19688 Entrez_Gene PVRL4 81607 poliovirus receptor-related 4 Cards Atlas PVRL4ID44141ch1q23 GeneCards PVRL4 Ensembl PVRL4 [Search_View] ENSG00000143217 [Gene_View] Genatlas PVRL4 GeneLynx PVRL4 eGenome PVRL4 euGene 81607 Genomic and cartography PVRL4 - 1q23.3 chr1:159308120-159325966 - 1q22-q23.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl PVRL4 - 1q22-q23.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PVRL4 Gene and transcription Genbank AF160477 [ ENTREZ ] Genbank AF218028 [ ENTREZ ] Genbank AF426163 [ ENTREZ ] Genbank AK027753 [ ENTREZ ] Genbank BC010423 [ ENTREZ ] RefSeq NM_030916 [ SRS ] NM_030916 [ ENTREZ ] 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_001838531 [ SRS ] NW_001838531 [ ENTREZ ] RefSeq NW_925683 [ SRS ] NW_925683 [ ENTREZ ] AceView PVRL4 AceView - NCBI Unigene Hs.492490 [ SRS ] Hs.492490 [ NCBI ] HS492490 [ spliceNest ] Fast-db 17478 (alternative variants) Protein : pattern, domain, 3D structure Q96NY8 [ SRS] Q96NY8 [ EXPASY ] Q96NY8 [ INTERPRO ] Q96NY8 SwissProt [ UNIPROT ] Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ] Interpro IPR013162 CD80_C2-set [ SRS ] IPR013162 CD80_C2-set [ EBI ] Interpro IPR013151 Ig [ SRS ] IPR013151 Ig [ EBI ] Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] Interpro IPR013783 Ig-like_fold [ SRS ] IPR013783 Ig-like_fold [ EBI ] Interpro IPR003599 Ig_sub [ SRS ] IPR003599 Ig_sub [ EBI ] Interpro IPR003598 Ig_sub2 [ SRS ] IPR003598 Ig_sub2 [ EBI ] Interpro IPR013106 Ig_V-set [ SRS ] IPR013106 Ig_V-set [ EBI ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 688 CluSTr Q96NY8 Pfam PF08205 C2-set_2 [ SRS ] PF08205 C2-set_2 [ Sanger ] pfam08205 [ NCBI-CDD ] Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ] Pfam PF07686 V-set [ SRS ] PF07686 V-set [ Sanger ] pfam07686 [ NCBI-CDD ] Smart SM00409 IG [EMBL] Smart SM00408 IGc2 [EMBL] Blocks Q96NY8 HPRD 17934 Protein Interaction databases DIP Q96NY8 IntAct Q96NY8 Polymorphism : SNP, mutations, diseases OMIM 609607 [ map ] GENECLINICS 609607 SNP PVRL4 [dbSNP-NCBI] SNP NM_030916 [SNP-NCI] SNP PVRL4 [GeneSNPs - Utah] PVRL4] [HGBASE - SRS] HAPMAP PVRL4 [HAPMAP] HGMD PVRL4 General knowledge Family Browser PVRL4 [UCSC Family Browser] SOURCE NM_030916 SMD Hs.492490 SAGE Hs.492490 GO protein binding [Amigo] protein binding GO extracellular region [Amigo] extracellular region GO plasma membrane [Amigo] plasma membrane GO cell adhesion [Amigo] cell adhesion GO integral to membrane [Amigo] integral to membrane GO cell junction [Amigo] cell junction KEGG Adherens junction PubGene PVRL4 TreeFam PVRL4 CTD 81607 [Comparative ToxicoGenomics Database] Other databases Probes Probe PVRL4 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in Entrez Bibliography Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. Reymond N, Fabre S, Lecocq E, Adelaide J, Dubreuil P, Lopez M The Journal of biological chemistry. 2001 ; 276 (46) : 43205-43215. PMID 11544254
Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C'-C-D beta-strands of the nectin1 V domain. Fabre S, Reymond N, Cocchi F, Menotti L, Dubreuil P, Campadelli-Fiume G, Lopez M The Journal of biological chemistry. 2002 ; 277 (30) : 27006-27013. PMID 12011057
Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor- alpha-converting enzyme (TACE)/ADAM-17. Fabre-Lafay S, Garrido-Urbani S, Reymond N, Gonçalves A, Dubreuil P, Lopez M
Atlas Genet Cytogenet Oncol Haematol 2008; 5 689 The Journal of biological chemistry. 2005 ; 280 (20) : 19543-19550. PMID 15784625
Nectin-4 is a new histological and serological tumor associated marker for breast cancer. Fabre-Lafay S, Monville F, Garrido-Urbani S, Berruyer-Pouyet C, Ginestier C, Reymond N, Finetti P, Sauvan R, Adélaide J, Geneix J, Lecocq E, Popovici C, Dubreuil P, Viens P, Gonçalves A, Charafe- Jauffret E, Jacquemier J, Birnbaum D, Lopez M BMC cancer. 2007 ; 7 : page 73. PMID 17474988
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Contributor(s) Written 01-2008 Marc Lopez Centre de Recherches en Cancérologie de Marseille, Inserm UMR599, 27 bvd Leiroure, 13009 Marseille, France Citation This paper should be referenced as such : Lopez M . PVRL4 (poliovirus receptor-related 4). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PVRL4ID44141ch1q23.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 690 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PTTG1IP (pituitary tumor-transforming 1 interacting protein)
Identity Other names C21orf1 C21orf3 PBF HGNC PTTG1IP Location 21q22.3 Location_base_pair Starts at 45093941 and ends at 45118169 bp from pter ( according to hg18- Mar_2006).
DNA/RNA
Description The PTTG1IP gene consists of 6 exons and spans 24.23 kb of genomic sequence on chromosome 21 (from position 45,093,941 bp to 45,118,169 bp in the reverse strand orientation). Transcription The mRNA transcribed from this gene is 2,736 nucleotides long. Pseudogene No pseudogene has been described. Protein
Description Identified through its interaction with pituitary tumor transforming 1 (PTTG), the PTTG1IP protein is 180 amino acids long with a molecular mass of approximately 25 kDa. A putative signal peptide exists at the N-terminus (1-32). A domain of unknown function common to plexins, semaphorins and integrins (PSI) is located between residues 39-92. Adjacent to this is a putative transmembrane domain (95-122). A bipartite
Atlas Genet Cytogenet Oncol Haematol 2008; 5 691 nuclear localisation signal (NLS) is located between amino acids 149 and 166. The C- terminal 30 amino acids of PTTG1IP contain the PTTG binding domain and a putative tyrosine-based sorting signal. Potential post-translational modifications include putative phosphorlyation sites for cAMP- and cGMP-dependent kinase, protein kinase C and casein kinase II and five glycosylation sites for N-linked and O-linked oligosaccharides. Expression PTTG1IP is widely expressed and has been identified in all tissues examined including spleen, thymus, prostate, testis, ovary, small intestine, colon, leukocytes, spinal cord, thyroid, pituitary, lymph node, trachea, adrenal gland and bone marrow. Localisation A tagged PTTG1IP protein was located predominantly in the nucleus with partial expression also in the cytoplasm. Mutation of the NLS shifted PTTG1IP expression to a perinuclear and cytoplasm location. Other reports suggest that PTTG1IP is located predominantly in the cytoplasm. Function PTTG expression is predominantly nuclear in the presence of PTTG1IP. However, in the absence of PTTG1IP or with the NLS mutant of PTTG1IP, PTTG is mainly cytoplasmic. Hence, PTTG1IP is thought to facilitate the translocation of PTTG into the nucleus. Itself upregulated by PTTG, PTTG1IP is required for the ability of PTTG to transactivate basic fibroblast growth factor (FGF2). PTTG1IP has a described role in repressing iodide uptake into thyroid cells via transcriptional regulation of the sodium iodide symporter. In MC3T3-El cells, PTTG1IP is regulated by the transcription factor Runx2, implying a role in osteoblast differentiation. Mutations Note PTTG1IP has been sequenced in a series of thyroid tumours, but no mutations were evident. No mutations have been reported to date in any other studies. Implicated in Entity Thyroid tumours Disease Overexpression is observed in thyroid tumours compared to normal thyroid tissue. Prognosis PTTG1IP overexpression was significantly associated with early thyroid tumour recurrence. PTTG1IP can repress the expression of the sodium iodide transporter (NIS) and inhibit iodide uptake in in vitro models of the thyroid. NIS mRNA expression was inhibited by PTTG1IP via the NIS upstream enhancer (NUE). A poorer prognosis in thyroid tumours with increased PTTG1IP expression might be inferred, therefore, as a significant reduction of iodide uptake would reduce the efficacy of ablative radioiodine therapy. Oncogenesis PTTG1IP transforms cells in vitro and is tumourigenic in vivo. Entity Pituitary tumours Disease PTTG1IP is overexpressed in pituitary tumours compared with normal pituitary tissue. External links Nomenclature HGNC PTTG1IP 13524 Entrez_Gene PTTG1IP 754 pituitary tumor-transforming 1 interacting protein Cards Atlas PTTG1IPID41944ch21q22 GeneCards PTTG1IP Ensembl PTTG1IP [Search_View] ENSG00000183255 [Gene_View] Genatlas PTTG1IP GeneLynx PTTG1IP eGenome PTTG1IP euGene 754 Genomic and cartography PTTG1IP - 21q22.3 chr21:45093941-45118169 - 21q22.3 [Description] (hg18- GoldenPath Mar_2006) Ensembl PTTG1IP - 21q22.3 [CytoView] NCBI Mapview
Atlas Genet Cytogenet Oncol Haematol 2008; 5 692 OMIM Disease map [OMIM] HomoloGene PTTG1IP Gene and transcription Genbank AF086503 [ ENTREZ ] Genbank AF149785 [ ENTREZ ] Genbank AK094882 [ ENTREZ ] Genbank AK095586 [ ENTREZ ] Genbank AK290139 [ ENTREZ ] RefSeq NM_004339 [ SRS ] NM_004339 [ ENTREZ ] RefSeq AC_000064 [ SRS ] AC_000064 [ ENTREZ ] RefSeq AC_000153 [ SRS ] AC_000153 [ ENTREZ ] RefSeq NC_000021 [ SRS ] NC_000021 [ ENTREZ ] RefSeq NT_011515 [ SRS ] NT_011515 [ ENTREZ ] RefSeq NW_001838716 [ SRS ] NW_001838716 [ ENTREZ ] RefSeq NW_927384 [ SRS ] NW_927384 [ ENTREZ ] AceView PTTG1IP AceView - NCBI Unigene Hs.474010 [ SRS ] Hs.474010 [ NCBI ] HS474010 [ spliceNest ] Fast-db 4169 (alternative variants) Protein : pattern, domain, 3D structure P53801 [ SRS] P53801 [ EXPASY ] P53801 [ INTERPRO ] P53801 SwissProt [ UNIPROT ] Interpro IPR003659 Plexin-like [ SRS ] IPR003659 Plexin-like [ EBI ] CluSTr P53801 Smart SM00423 PSI [EMBL] Blocks P53801 HPRD 04807 Protein Interaction databases DIP P53801 IntAct P53801 Polymorphism : SNP, mutations, diseases OMIM 603784 [ map ] GENECLINICS 603784 SNP PTTG1IP [dbSNP-NCBI] SNP NM_004339 [SNP-NCI] SNP PTTG1IP [GeneSNPs - Utah] PTTG1IP] [HGBASE - SRS] HAPMAP PTTG1IP [HAPMAP] HGMD PTTG1IP General knowledge Family Browser PTTG1IP [UCSC Family Browser] SOURCE NM_004339 SMD Hs.474010 SAGE Hs.474010 GO molecular_function [Amigo] molecular_function GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO protein import into nucleus [Amigo] protein import into nucleus GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane PubGene PTTG1IP TreeFam PTTG1IP CTD 754 [Comparative ToxicoGenomics Database] Other databases Probes
Atlas Genet Cytogenet Oncol Haematol 2008; 5 693 Probe PTTG1IP Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in Entrez Bibliography Cloning of a novel human putative type Ia integral membrane protein mapping to 21q22.3. Yaspo ML, Aaltonen J, Horelli-Kuitunen N, Peltonen L, Lehrach H Genomics. 1998 ; 49 (1) : 133-136. PMID 9570958
A novel binding factor facilitates nuclear translocation and transcriptional activation function of the pituitary tumor-transforming gene product. Chien W, Pei L The Journal of biological chemistry. 2000 ; 275 (25) : 19422-19427. PMID 10781616
Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. McCabe CJ, Khaira JS, Boelaert K, Heaney AP, Tannahill LA, Hussain S, Mitchell R, Olliff J, Sheppard MC, Franklyn JA, Gittoes NJ Clinical endocrinology. 2003 ; 58 (2) : 141-150. PMID 12580928
Identification of novel genes of the bone-specific transcription factor Runx2. Stock M, Schafer H, Fliegauf M, Otto F Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2004 ; 19 (6) : 959-972. PMID 15190888
Pituitary tumor transforming gene binding factor: a novel transforming gene in thyroid tumorigenesis. Stratford AL, Boelaert K, Tannahill LA, Kim DS, Warfield A, Eggo MC, Gittoes NJ, Young LS, Franklyn JA, McCabe CJ The Journal of clinical endocrinology and metabolism. 2005 ; 90 (7) : 4341-4349. PMID 15886233
PTTG and PBF repress the human sodium iodide symporter. Boelaert K, Smith VE, Stratford AL, Kogai T, Tannahill LA, Watkinson JC, Eggo MC, Franklyn JA, McCabe CJ Oncogene. 2007 ; 26 (30) : 4344-4356. PMID 17297475
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Contributor(s) Written 01-2008 Vicki Smith, Chris McCabe Division of Medical Sciences, 2nd Floor IBR, University of Birmingham, Edgbaston, Birmingham B12 5TT, UK Citation This paper should be referenced as such : Smith V, McCabe C . PTTG1IP (pituitary tumor-transforming 1 interacting protein). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PTTG1IPID41944ch21q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 694 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PLAGL2 (Pleomorphic adenoma gene-like 2)
Identity Other names FLJ23283 KIAA0198 HGNC PLAGL2 Location 20q11.21 Location_base_pair Starts at 30243968 and ends at 30259207 bp from pter ( according to hg18- Mar_2006). DNA/RNA
PLAGL2 exons and corresponding nucleotide numbers on each GenBank sequence database are shown in this table. Description PLAGL2 (PLAG-Like 2; a PLAG family member; GenBank accession number AF006005) was identified by homology searches of the database of expressed sequence tags (ESTs) and sequence similarity to zinc-finger region of the human PLAGL1/LOT1/ZAC1 and PLAG1 proteins. Protein
Description PLAGL2 protein consists of 496 amino acid residues, six C2H2-type zinc finger domains in its amino-terminal region (shown as brown in the figure), and a proline- and serine-rich carboxyl terminus (shown as blue). Expression Northern analysis showed that the PLAGL2 mRNA is expressed in fetal kidney, liver, lung, and brain but not in adult tissues. However, PCR analysis showed that PLAGL2 is ubiquitously expressed in almost all adult and fetal human tissues, except for the relatively low level of expression observed in fetal brain. Localisation Nuclear. Function PLAGL2 can bind and activate human insulin-like growth factor II (IGF II) gene promoter; therefore, the oncogenic capacity of PLAGL2 may be mediated by activating the IGF-II mitogenic pathway. However, PLAGL2, possibly by association with HIF-1, may also have apoptotic role since it can activate Nip3 promoter and induce transcription in Balb/c3T3 fibroblasts and Neuro2a neuroblastoma cells, leading to apoptosis. PLAGL2 mRNA can be induced upon iron deficiency or hypoxia in mouse macrophage cell line RAW264.7, mouse erythroleukemia (MEL) cells, and Balb/c3T3
Atlas Genet Cytogenet Oncol Haematol 2008; 5 695 cells. In addition, PLAGL2 can also transactivate the surfactant protein-C (SP-C), a protein whose expression occurs principally in type II pneumocytes located in the distal lung alveolae. Additional data suggest that repression of the transactivating capacity of PLAGL2 may be directly related to sumoylation. Also, PLAGL2 protein is acetylated and activated by p300 and deacetylated and repressed by HDAC7, involving the lysine residues as the acetylation target. Therefore, it appears that the activity of PLAGL2 is tightly modulated by both sumoylation and acetylation, which may have opposite effects on their transactivation. Tip60 can modulate PLAGL2 function through both acetylation and inhibition of sumoylation, resulting in an enhanced PLAGL2-mediated transactivation. PLAGL2 can bind and stabilize (by preventing proteasomal degradation) Pirh2 dimer, a p53 inducible E3 ligase involved in the ubiquitination of p53. PLAGL2 can also regulate NCF2 gene expression through binding to the tumor necrosis factor (TNF)-alpha-responsive region of the NCF2 promoter, thus regulating p67(phox) expression and NADPH oxidase activity. PLAGL2 was recently found to aid in the efficient uptake of chylomicrons by intestinal lacteal vessels. Homology Homologous to the human PLAG1 and PLAGL1 proteins. Mutations Note Mutation has not been reported in the PLAGL2 coding region. Implicated in Entity Carcinogenicity Note PLAGL2 is an oncoprotein involved in various malignancies including lipoblastomas, hepatoblastomas, and acute myeloid leukemia. PLAGL2 expression is increased in human cancers including acute myeloid leukemia (AML). The expression is increased in 20% of human AML samples. The PLAGL2 gene can independently cooperate with CBFB- MYH11 fusion gene in leukemogenesis. AML subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11, encoding CBFbeta-SMMHC fusion protein. This fusion protein inhibits the core-binding factor (CBF), resulting in a block of hematopoietic differentiation and induction of leukemia in the presence of additional mutations. Disease Cancer; lipoblastomas, hepatoblastomas, and acute myeloid leukemia. External links Nomenclature HGNC PLAGL2 9047 Entrez_Gene PLAGL2 5326 pleiomorphic adenoma gene-like 2 Cards Atlas PLAGL2ID41738ch20q11 GeneCards PLAGL2 Ensembl PLAGL2 [Search_View] ENSG00000126003 [Gene_View] Genatlas PLAGL2 GeneLynx PLAGL2 eGenome PLAGL2 euGene 5326 Genomic and cartography PLAGL2 - 20q11.21 chr20:30243968-30259207 - 20q11.21 [Description] (hg18- GoldenPath Mar_2006) Ensembl PLAGL2 - 20q11.21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PLAGL2 Gene and transcription Genbank AF006005 [ ENTREZ ] Genbank AK026951 [ ENTREZ ] Genbank AK292450 [ ENTREZ ] Genbank BC023655 [ ENTREZ ] Genbank D83784 [ ENTREZ ] RefSeq NM_002657 [ SRS ] NM_002657 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 696 RefSeq AC_000063 [ SRS ] AC_000063 [ ENTREZ ] RefSeq AC_000152 [ SRS ] AC_000152 [ ENTREZ ] RefSeq NC_000020 [ SRS ] NC_000020 [ ENTREZ ] RefSeq NT_028392 [ SRS ] NT_028392 [ ENTREZ ] RefSeq NW_001838664 [ SRS ] NW_001838664 [ ENTREZ ] RefSeq NW_927339 [ SRS ] NW_927339 [ ENTREZ ] AceView PLAGL2 AceView - NCBI Unigene Hs.154104 [ SRS ] Hs.154104 [ NCBI ] HS154104 [ spliceNest ] Fast-db 7793 (alternative variants) Protein : pattern, domain, 3D structure Q9UPG8 [ SRS] Q9UPG8 [ EXPASY ] Q9UPG8 [ INTERPRO ] Q9UPG8 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 Q9UPG8 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00355 ZnF_C2H2 [EMBL] Blocks Q9UPG8 HPRD 05333 Protein Interaction databases DIP Q9UPG8 IntAct Q9UPG8 Polymorphism : SNP, mutations, diseases OMIM 604866 [ map ] GENECLINICS 604866 SNP PLAGL2 [dbSNP-NCBI] SNP NM_002657 [SNP-NCI] SNP PLAGL2 [GeneSNPs - Utah] PLAGL2] [HGBASE - SRS] HAPMAP PLAGL2 [HAPMAP] COSMIC PLAGL2 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PLAGL2 General knowledge Family Browser PLAGL2 [UCSC Family Browser] SOURCE NM_002657 SMD Hs.154104 SAGE Hs.154104 GO transcription factor activity [Amigo] transcription factor activity GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO induction of apoptosis [Amigo] induction of apoptosis GO zinc ion binding [Amigo] zinc ion binding positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter GO metal ion binding [Amigo] metal ion binding PubGene PLAGL2
Atlas Genet Cytogenet Oncol Haematol 2008; 5 697 TreeFam PLAGL2 CTD 5326 [Comparative ToxicoGenomics Database] Other databases Probes Probe PLAGL2 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in Entrez Bibliography Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells. Abdollahi A, Godwin AK, Miller PD, Getts LA, Schultz DC, Taguchi T, Testa JR, Hamilton TC Cancer research. 1997 ; 57 (10) : 2029-2034. PMID 9158001
Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors. Abdollahi A, Roberts D, Godwin AK, Schultz DC, Sonoda G, Testa JR, Hamilton TC Oncogene. 1997 ; 14 (16) : 1973-1979. PMID 9150364
Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain. Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L The EMBO journal. 1997 ; 16 (10) : 2814-2825. PMID 9184226
Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJ The Journal of biological chemistry. 1998 ; 273 (36) : 23026-23032. PMID 9722527
PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Voz ML, Agten NS, Van de Ven WJ, Kas K Cancer research. 2000 ; 60 (1) : 106-113. PMID 10646861
Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines. Furukawa T, Adachi Y, Fujisawa J, Kambe T, Yamaguchi-Iwai Y, Sasaki R, Kuwahara J, Ikehara S, Tokunaga R, Taketani S Oncogene. 2001 ; 20 (34) : 4718-4727. PMID 11498794
The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities. Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML Cancer research. 2002 ; 62 (5) : 1510-1517. PMID 11888928
A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis. Mizutani A, Furukawa T, Adachi Y, Ikehara S, Taketani S The Journal of biological chemistry. 2002 ; 277 (18) : 15851-15858. PMID 11832486
Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Castilla LH, Perrat P, Martinez NJ, Landrette SF, Keys R, Oikemus S, Flanegan J, Heilman S, Garrett
Atlas Genet Cytogenet Oncol Haematol 2008; 5 698 L, Dutra A, Anderson S, Pihan GA, Wolff L, Liu PP Proc Natl Acad Sci U S A. 2004 ; 101 (14) : 4924-4929. PMID 15044690
Repression of the Transactivating Capacity of the Oncoprotein PLAG1 by SUMOylation. Van Dyck F, Delvaux EL, Van de Ven WJ, Chavez MV The Journal of biological chemistry. 2004 ; 279 (34) : 36121-36131. PMID 15208321
Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb- MYH11. Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ, Delwel R, Castilla LH Blood. 2005 ; 105 (7) : 2900-2907. PMID 15585652
Pleiomorphic adenoma gene-like-2, a zinc finger protein, transactivates the surfactant protein- C promoter. Yang MC, Weissler JC, Terada LS, Deng F, Yang YS American journal of respiratory cell and molecular biology. 2005 ; 32 (1) : 35-43. PMID 15361364
Sumoylation and acetylation play opposite roles in the transactivation of PLAG1 and PLAGL2. Zheng G, Yang YC The Journal of biological chemistry. 2005 ; 280 (49) : 40773-40781. PMID 16207715
Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Kuo YH, Landrette SF, Heilman SA, Perrat PN, Garrett L, Liu PP, Le Beau MM, Kogan SC, Castilla LH Cancer cell. 2006 ; 9 (1) : 57-68. PMID 16413472
Cloning and embryonic expression of zebrafish PLAG genes. Pendeville H, Peers B, Kas K, Voz ML Gene expression patterns : GEP. 2006 ; 6 (3) : 267-276. PMID 16378757
LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions. Abdollahi A Journal of cellular physiology. 2007 ; 210 (1) : 16-25. PMID 17063461
Binding of pleomorphic adenoma gene-like 2 to the tumor necrosis factor (TNF)-alpha- responsive region of the NCF2 promoter regulates p67(phox) expression and NADPH oxidase activity. Ammons MC, Siemsen DW, Nelson-Overton LK, Quinn MT, Gauss KA The Journal of biological chemistry. 2007 ; 282 (24) : 17941-17952. PMID 17462995
PLAGL2 translocation and SP-C promoter activity--a cellular response of lung cells to hypoxia. Guo Y, Yang MC, Weissler JC, Yang YS Biochemical and biophysical research communications. 2007 ; 360 (3) : 659-665. PMID 17618602
Tip60 modulates PLAGL2-mediated transactivation by acetylation. Ning J, Zheng G, Yang YC Journal of cellular biochemistry. 2008 ; 103 (3) : 730-739. PMID 17551969
Atlas Genet Cytogenet Oncol Haematol 2008; 5 699 Loss of the PlagL2 transcription factor affects lacteal uptake of chylomicrons. Van Dyck F, Braem CV, Chen Z, Declercq J, Deckers R, Kim BM, Ito S, Wu MK, Cohen DE, Dewerchin M, Derua R, Waelkens E, Fiette L, Roebroek A, Schuit F, Van de Ven WJ, Shivdasani RA Cell metabolism. 2007 ; 6 (5) : 406-413. PMID 17983586
PLAG1, the prototype of the PLAG gene family: versatility in tumour development (review). Van Dyck F, Declercq J, Braem CV, Van de Ven WJ International journal of oncology. 2007 ; 30 (4) : 765-774. PMID 17332914
PLAGL2 controls the stability of Pirh2, an E3 ubiquitin ligase for p53. Zheng G, Ning J, Yang YC Biochemical and biophysical research communications. 2007 ; 364 (2) : 344-350. PMID 17950244
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Contributor(s) Written 01-2008 Abbas Abdollahi Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, BioLife Sciences Building, Suite 446, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA Citation This paper should be referenced as such : Abdollahi A . PLAGL2 (Pleomorphic adenoma gene-like 2). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PLAGL2ID41738ch20q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 700 Atlas of Genetics and Cytogenetics in Oncology and Haematology
PDCD6 (programmed cell death 6)
Identity Other names ALG-2 MGC111017 MGC119050 MGC9123 PEF1B HGNC PDCD6 Location 5p15.33 Location_base_pair Starts at 324736 and ends at 368089 bp from pter ( according to hg18-Mar_2006). DNA/RNA
Map of the PDCD gene at 5pt-15.2, black boxes indicate exons, red boxes indicate untranslated exons. Description The PDCD6 gene contains 43351 bp. The coding sequence extends from 324738 nt to 368089 nt and contains 6 exons. The initiation codon is located at position 101 in exon 1. Exon 3 sequence is identical with AHRR (HGNC symbol Synonyms: AHH, AHHR, KIAA1234) position 357291-357336 at the same locus. Transcription is in a telomere to centromere direction. There is one alternative splice site (validated by ESTs and RNAse protection analysis) at the 5' of exon 4 creating a 6 bp shorter exon corresponding of a protein lacking GF121/122. Pseudogene Q7Z6L2_HUMAN, lOC728613, p15.33, NC-000005.8, 1650672 - 1705673 in a centromere to telomere direction. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 5 701
Protein structure: 3-dimensional structure of the PDCD6 dimer: EF1, EF3, EF5 are the functional calcium binding domains (blue). In green are the calcium ions, in yellow is the N-terminal peptide modeled on the protein, in cyan and red are G121 and F122 missing in the known splice form. Description 191 amino acids, 21.7 kDa, member of the penta EF hand protein family. Expression Ubiquitously expressed, higher abundance in some tumor tissues. Localisation Cytoplasmic, nuclear and unidentified structures in the cytoplasm. Function PDCD6 (product of the apoptosis-linked gene 2) is a calcium binding protein with 5 EF hand motifs originally identified as a proapoptotic protein in a genetic screen. A knock out mouse with deleted PDCD6 gene showed no obvious phenotype. Newer results indicate that inhibition of PDCD6 expression reduces cellular viability. Several target proteins, which interact with PDCD6 in a calcium dependent fashion have been found. Most prominent are AIP1/Alix, an adaptor protein involved in apoptosis, endocytosis, adhesion and cytokinesis as well as TSG101, a tumor suppressor gene product, which is a component of the ESRT-1 (endosomal sorting complex required for transport I) and Sec31A, a component of the COPII, ER to Golgi transport vesicles. As all these proteins are linked to intracellular trafficking PDCD6 may connect calcium signaling to trafficking processes through these target proteins or yet to be identified novel PDCD6 targets and thereby regulates cell viability. As a commercial anti PDCD6 antibody, which turned out to be directed against the cochaperone protein p23 and not against PDCD6 was used to confirm interaction of PDCD6 with target proteins some of the early reports on PDCD6 have to be treated with caution. Homology PEF (Penta EF-hand) family proteins sorcin, grancalcin, calpain light and heavy chain, peflin. Mutations Note not known Implicated in Entity Various cancers Note PDCD6 has been reported to be downregulated in atherosclerotic plaques as shown by Western array anaysis. However, it was found later that the cochaperone p23 and not PDCD6 was downregulated due to the use of a nonspecific antibody. Oncogenesis PDCD6 downregulation has been implicated in ocular melanoma, possibly giving cancer cells a growth advantage. PDCD6 has been shown to be significantly upregulated in rat hepatomas and human small lung cancer as well as in non small lung cancer cells analyzed in specimens of
Atlas Genet Cytogenet Oncol Haematol 2008; 5 702 263 patients. In a tissue microarray analysis with ca 8000 samples of normal and tumor tissues strong PDCD6 signals were detected in urothelium (benign), adeno dysplasia, thymoma and neuroendocrine tumors with over 35 % of the samples to give a moderate or strong staining. Brenner, carcinoid and cribriform tumors gave the strongest signals. In normal tissues cells of the urothelium of the kidney and urinary bladder, islet cells of the pancreas, columnar ductal cells of the seminal vesicle, tall columnar cells of the epididymus and ciliated as well as secretory cells of the fallopian tube were stained for PDCD6 with strongest intensity but below the one found in strongly staining tumor cells. PDCD6 downregulation with siRNA inhibited growth of HeLa cells. PDCD6 might therefore play a role as a cellular viability factor. However, no correlation between PDCD6 staining intensity and survival of patients with lung cancer, colon cancer or breast cancer was found. External links Nomenclature HGNC PDCD6 8765 Entrez_Gene PDCD6 10016 programmed cell death 6 Cards Atlas PDCD6ID43402ch5p15 GeneCards PDCD6 Ensembl PDCD6 [Search_View] ENSG00000063438 [Gene_View] Genatlas PDCD6 GeneLynx PDCD6 eGenome PDCD6 euGene 10016 Genomic and cartography PDCD6 - 5p15.33 chr5:324736-368089 + 5p15.33 [Description] (hg18- GoldenPath Mar_2006) Ensembl PDCD6 - 5p15.33 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PDCD6 Gene and transcription Genbank AF035606 [ ENTREZ ] Genbank AK001917 [ ENTREZ ] Genbank AK128087 [ ENTREZ ] Genbank AK223366 [ ENTREZ ] Genbank AK308872 [ ENTREZ ] RefSeq NM_013232 [ SRS ] NM_013232 [ ENTREZ ] RefSeq AC_000048 [ SRS ] AC_000048 [ ENTREZ ] RefSeq AC_000137 [ SRS ] AC_000137 [ ENTREZ ] RefSeq NC_000005 [ SRS ] NC_000005 [ ENTREZ ] RefSeq NT_006576 [ SRS ] NT_006576 [ ENTREZ ] RefSeq NW_001838923 [ SRS ] NW_001838923 [ ENTREZ ] RefSeq NW_922496 [ SRS ] NW_922496 [ ENTREZ ] AceView PDCD6 AceView - NCBI Unigene Hs.50823 [ SRS ] Hs.50823 [ NCBI ] HS50823 [ spliceNest ] Fast-db 709 (alternative variants) Protein : pattern, domain, 3D structure O75340 [ SRS] O75340 [ EXPASY ] O75340 [ INTERPRO ] O75340 SwissProt [ UNIPROT ] Prosite PS00018 EF_HAND_1 [ SRS ] PS00018 EF_HAND_1 [ Expasy ] Prosite PS50222 EF_HAND_2 [ SRS ] PS50222 EF_HAND_2 [ Expasy ] Interpro IPR011992 EF-Hand_type [ SRS ] IPR011992 EF-Hand_type [ EBI ] Interpro IPR002048 EF_hand_Ca_bd [ SRS ] IPR002048 EF_hand_Ca_bd [ EBI ] CluSTr O75340
Atlas Genet Cytogenet Oncol Haematol 2008; 5 703 Pfam PF00036 efhand [ SRS ] PF00036 efhand [ Sanger ] pfam00036 [ NCBI-CDD ] Smart SM00054 EFh [EMBL] Prodom PD000012 EF-hand[INRA-Toulouse] O75340 PDCD6_HUMAN [ Domain structure ] O75340 PDCD6_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks O75340 HPRD 03035 Protein Interaction databases DIP O75340 IntAct O75340 Polymorphism : SNP, mutations, diseases OMIM 601057 [ map ] GENECLINICS 601057 SNP PDCD6 [dbSNP-NCBI] SNP NM_013232 [SNP-NCI] SNP PDCD6 [GeneSNPs - Utah] PDCD6] [HGBASE - SRS] HAPMAP PDCD6 [HAPMAP] COSMIC PDCD6 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD PDCD6 General knowledge Family Browser PDCD6 [UCSC Family Browser] SOURCE NM_013232 SMD Hs.50823 SAGE Hs.50823 GO calcium ion binding [Amigo] calcium ion binding GO nucleus [Amigo] nucleus GO endoplasmic reticulum [Amigo] endoplasmic reticulum GO endoplasmic reticulum membrane [Amigo] endoplasmic reticulum membrane GO apoptosis [Amigo] apoptosis induction of apoptosis by extracellular signals [Amigo] induction of apoptosis by GO extracellular signals GO membrane [Amigo] membrane GO nuclear membrane [Amigo] nuclear membrane GO calcium-dependent protein binding [Amigo] calcium-dependent protein binding GO response to calcium ion [Amigo] response to calcium ion PubGene PDCD6 TreeFam PDCD6 CTD 10016 [Comparative ToxicoGenomics Database] Other databases Probes Probe PDCD6 Related clones (RZPD - Berlin) PubMed PubMed 33 Pubmed reference(s) in Entrez Bibliography Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Vito P, Lacana E, D'Adamio L Science. 1996 ; 271 (5248) : 521-525. PMID 8560270
Calcium-induced exposure of a hydrophobic surface of mouse ALG-2, which is a member of the penta-EF-hand protein family. Maki M, Yamaguchi K, Kitaura Y, Satoh H, Hitomi K Journal of biochemistry. 1998 ; 124 (6) : 1170-1177. PMID 9832622
Atlas Genet Cytogenet Oncol Haematol 2008; 5 704 Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis- linked-gene 2 (ALG-2) protein. Missotten M, Nichols A, Rieger K, Sadoul R Cell death and differentiation. 1999 ; 6 (2) : 124-129. PMID 10200558
Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction. Vito P, Pellegrini L, Guiet C, D'Adamio L The Journal of biological chemistry. 1999 ; 274 (3) : 1533-1540. PMID 9880530
Two forms of the apoptosis-linked protein ALG-2 with different Ca(2+) affinities and target recognition. Tarabykina S, Moller AL, Durussel I, Cox J, Berchtold MW The Journal of biological chemistry. 2000 ; 275 (14) : 10514-10518. PMID 10744743
Structure of apoptosis-linked protein ALG-2: insights into Ca2+-induced changes in penta-EF- hand proteins. Jia J, Tarabykina S, Hansen C, Berchtold M, Cygler M Structure (London, England : 1993). 2001 ; 9 (4) : 267-275. PMID 11525164
Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner. Kitaura Y, Matsumoto S, Satoh H, Hitomi K, Maki M The Journal of biological chemistry. 2001 ; 276 (17) : 14053-14058. PMID 11278427
Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function. Jang IK, Hu R, Lacana E, D'Adamio L, Gu H Molecular and cellular biology. 2002 ; 22 (12) : 4094-4100. PMID 12024023
Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins. Maki M, Kitaura Y, Satoh H, Ohkouchi S, Shibata H Biochimica et biophysica acta. 2002 ; 1600 (1-2) : 51-60. PMID 12445459
Up-regulation of ALG-2 in hepatomas and lung cancer tissue. la Cour JM, Mollerup J, Winding P, Tarabykina S, Sehested M, Berchtold MW The American journal of pathology. 2003 ; 163 (1) : 81-89. PMID 12819013
Properties of the co-chaperone protein p23 erroneously attributed to ALG-2 (apoptosis-linked gene 2). Mollerup J, Krogh TN, Nielsen PF, Berchtold MW FEBS letters. 2003 ; 555 (3) : 478-482. PMID 14675759
Cytosolic prostaglandin E2 synthase/p23 but not apoptosis-linked gene 2 is downregulated in human atherosclerotic plaques. Martinet W, Schrijvers DM, De Meyer GR, Herman AG, Kockx MM Cardiovascular research. 2004 ; 61 (2) : 360-361. PMID 14736553
ALG-2, a multifunctional calcium binding protein? Tarabykina S, Mollerup J, Winding P, Berchtold MW Frontiers in bioscience. 2004 ; 9 : 1817-1832.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 705 PMID 14977589
Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma. Subramanian L, Crabb JW, Cox J, Durussel I, Walker TM, van Ginkel PR, Bhattacharya S, Dellaria JM, Palczewski K, Polans AS Biochemistry. 2004 ; 43 (35) : 11175-11186. PMID 15366927
The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B. Katoh K, Suzuki H, Terasawa Y, Mizuno T, Yasuda J, Shibata H, Maki M The Biochemical journal. 2005 ; 391 (Pt 3) : 677-685. PMID 16004603
Do Alix and ALG-2 really control endosomes for better or for worse? Sadoul R Biology of the cell. 2006 ; 98 (1) : 69-77. PMID 1635 4163
The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A. Yamasaki A, Tani K, Yamamoto A, Kitamura N, Komada M Molecular biology of the cell. 2006 ; 17 (11) : 4876-4887. PMID 16957052
ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+- dependent manner. Shibata H, Suzuki H, Yoshida H, Maki M Biochemical and biophysical research communications. 2007 ; 353 (3) : 756-763. PMID 17196169
ALG-2 oscillates in subcellular localization, unitemporally with calcium oscillations. la Cour JM, Mollerup J, Berchtold MW Biochemical and biophysical research communications. 2007 ; 353 (4) : 1063-1067. PMID 17214967
The apoptosis linked gene ALG-2 is dysregulated in tumors of various origin and contributes to cancer cell viability. La Cour JM, Hoj BR, Mollerup J, Simon R, Sauter G, Berchtold MW Molecular Oncology (. 2008.
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Contributor(s) Written 01-2008 Martin W Berchtold Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark Citation This paper should be referenced as such : Berchtold MW . PDCD6 (programmed cell death 6). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PDCD6ID43402ch5p15.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 706 Atlas of Genetics and Cytogenetics in Oncology and Haematology
P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7)
Identity Other names MGC20089 P2X7 P2Z HGNC P2RX7 Location 12q24.31 Location_base_pair Starts at 120055061 and ends at 120108241 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description The P2RX7 gene is comprised of 13 coding exons. Transcription The full length transcript is 3135 bp long and 10 alternative splicing isoforms have been identified. Pseudogene Not known. Protein Description The protein has 595 residues amino acids and compromises a 69 kDa calculated molecular weight. However, N-glycosylation in the extracellular loop increases the size of the P2X7 receptor to about 75-85 KDa; the protein is composed successively (from the N- to the C-terminus) by: 25 amino acid intracellular N-terminus 21 amino acid first transmembrane domain 288 amino acid extracellular loop 21 amino acid second transmembrane domain 240 amino acid intracellular C-terminal region Expression In a wide variety of tissues including heart, liver, pancreas, thymus, skeletal muscle and brain, although in brain the expression is mainly restricted to microglia. It also has relevant expression and function in immune cells (mainly in antigen presenting cells, such as monocytes, macrophages and dendritic cells). Localisation Mainly is found in the plasma membrane, however it also can be found in intracellular membrane compartments while trafficking to the plasma membrane. Function Acts as a ligand gated ion channel, sensing high concentration of extracellular ATP. Responsible for ATP-dependent activation and release of proinflammatory cytokines of the interleukin-1 family, mainly interleukin-1beta, interleukin-18 and interleukin-1alpha, playing a pivotal role in inflammatory responses. Prolonged stimulation of the P2X7 receptor can lead to plasma membrane bleb formation, opening of pannexin-1 dependent membrane pores and eventual cell death. Homology With other P2X receptors, with the higher homology with P2RX4. Excluding the unique C-terminal domain, homology is 39-49% with other P2X receptors. Mutations Germinal The human P2X7 receptor gene is highly polymorphic and more then 260 SNP have been described, only four loss-of-function and one gain-of-function SNP have been described to date: Loss of protein function: 946 G to A (Arg-307 to Gln) 1068 G to A (Ala-348 to Thr) 1513 A to C (Glu-496 to Ala) 1729 T to A (Ile-568 to Asp) Gain of protein function: 489 C to T (His-155 to Tyr) Somatic Not known in human. Implicated in
Atlas Genet Cytogenet Oncol Haematol 2008; 5 707 Entity Extrapulmonary tuberculosis Note The P2RX7 1513C allele has been strongly associated with extrapulmonary tuberculosis. The allele was associated with a reduced killing of Mycobacterium tuberculosis by macrophages. Entity Chronic lymphoid leukemia (CLL) Note The 1513C allele of P2RX7 has been associated with the clinical course of patients affected by chronic lymphocytic leukemia (CLL). There is a possible role for the P2X7 receptor in the susceptibility to familial CLL or, alternately, the 1513C allele may be in linkage disequilibrium with a nearby susceptibility gene. Entity Various cancers, including breast cancer, prostate cancer, papillary thyroid cancer and neuroblastoma. Note P2X7 receptor is overexpressed in a variety of cancers (see above). A detailed understanding of the mechanistic contribution mediated by P2RX7 has yet to be established. However, there is substantial evidence that the P2X7 receptor may mediate cell survival and growth by increasing the efficiency of oxidative phosphorylation and total intracellular ATP stores. Finally it has been proposed that the P2X7 receptor may be a candidate marker of papillary thyroid cancer. External links Nomenclature HGNC P2RX7 8537 Entrez_Gene P2RX7 5027 purinergic receptor P2X, ligand-gated ion channel, 7 Cards Atlas P2RX7ID41623ch12q24 GeneCards P2RX7 Ensembl P2RX7 [Search_View] ENSG00000089041 [Gene_View] Genatlas P2RX7 GeneLynx P2RX7 eGenome P2RX7 euGene 5027 Genomic and cartography P2RX7 - 12q24.31 chr12:120055061-120108241 + 12q24 [Description] (hg18- GoldenPath Mar_2006) Ensembl P2RX7 - 12q24 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene P2RX7 Gene and transcription Genbank AB209709 [ ENTREZ ] Genbank AK090866 [ ENTREZ ] Genbank AK225163 [ ENTREZ ] Genbank AK290405 [ ENTREZ ] Genbank AY847298 [ ENTREZ ] RefSeq NM_002562 [ SRS ] NM_002562 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq AC_000144 [ SRS ] AC_000144 [ ENTREZ ] 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 P2RX7 AceView - NCBI Unigene Hs.507102 [ SRS ] Hs.507102 [ NCBI ] HS507102 [ spliceNest ] Fast-db 14226 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q0IJ51 [ SRS] Q0IJ51 [ EXPASY ] Q0IJ51 [ INTERPRO ] Q0IJ51 [ UNIPROT ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 708 Prosite PS01212 P2X_RECEPTOR [ SRS ] PS01212 P2X_RECEPTOR [ Expasy ] Interpro IPR003050 P2X7_purnocptor [ SRS ] IPR003050 P2X7_purnocptor [ EBI ] Interpro IPR001429 P2X_purnocptor [ SRS ] IPR001429 P2X_purnocptor [ EBI ] CluSTr Q0IJ51 PF00864 P2X_receptor [ SRS ] PF00864 P2X_receptor [ Sanger ] pfam00864 Pfam [ NCBI-CDD ] Blocks Q0IJ51 HPRD 03977 Protein Interaction databases DIP Q0IJ51 IntAct Q0IJ51 Polymorphism : SNP, mutations, diseases OMIM 151400;602566 [ map ] GENECLINICS 151400;602566 SNP P2RX7 [dbSNP-NCBI] SNP NM_002562 [SNP-NCI] SNP P2RX7 [GeneSNPs - Utah] P2RX7] [HGBASE - SRS] HAPMAP P2RX7 [HAPMAP] COSMIC P2RX7 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD P2RX7 General knowledge Family Browser P2RX7 [UCSC Family Browser] SOURCE NM_002562 SMD Hs.507102 SAGE Hs.507102 GO lipopolysaccharide binding [Amigo] lipopolysaccharide binding GO purinergic nucleotide receptor activity [Amigo] purinergic nucleotide receptor activity GO regulation of sodium ion transport [Amigo] regulation of sodium ion transport GO receptor activity [Amigo] receptor activity GO ATP-gated cation channel activity [Amigo] ATP-gated cation channel activity GO receptor binding [Amigo] receptor binding GO ion channel activity [Amigo] ion channel activity GO ATP binding [Amigo] ATP binding GO cytoplasm [Amigo] cytoplasm GO plasma membrane [Amigo] plasma membrane GO integral to plasma membrane [Amigo] integral to plasma membrane GO ion transport [Amigo] ion transport cell surface receptor linked signal transduction [Amigo] cell surface receptor linked GO signal transduction positive regulation of calcium ion transport into cytosol [Amigo] positive regulation of GO calcium ion transport into cytosol GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO sensory perception of pain [Amigo] sensory perception of pain positive regulation of bone mineralization [Amigo] positive regulation of bone GO mineralization GO bleb [Amigo] bleb GO response to ATP [Amigo] response to ATP GO protein homodimerization activity [Amigo] protein homodimerization activity GO regulation of apoptosis [Amigo] regulation of apoptosis negative regulation of MAPKKK cascade [Amigo] negative regulation of MAPKKK GO cascade GO negative regulation of bone resorption [Amigo] negative regulation of bone resorption GO positive regulation of cytolysis [Amigo] positive regulation of cytolysis
Atlas Genet Cytogenet Oncol Haematol 2008; 5 709 GO pore complex biogenesis [Amigo] pore complex biogenesis GO protein heterodimerization activity [Amigo] protein heterodimerization activity positive regulation of interleukin-1 beta secretion [Amigo] positive regulation of GO interleukin-1 beta secretion positive regulation of cytoskeleton organization and biogenesis [Amigo] positive GO regulation of cytoskeleton organization and biogenesis regulation of killing of cells of another organism [Amigo] regulation of killing of cells of GO another organism GO membrane depolarization [Amigo] membrane depolarization KEGG Calcium signaling pathway KEGG Neuroactive ligand-receptor interaction PubGene P2RX7 TreeFam P2RX7 CTD 5027 [Comparative ToxicoGenomics Database] Other databases Probes Probe P2RX7 Related clones (RZPD - Berlin) PubMed PubMed 89 Pubmed reference(s) in Entrez Bibliography The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Surprenant A, Rassendren F, Kawashima E, North RA, Buell G Science. 1996 ; 272 (5262) : 735-738. PMID 8614837
The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. Rassendren F, Buell GN, Virginio C, Collo G, North RA, Surprenant A The Journal of biological chemistry. 1997 ; 272 (9) : 5482-5486. PMID 9038151
A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou S, Barden JA, Wiley JS The Journal of biological chemistry. 2001 ; 276 (14) : 11135-11142. PMID 11150303
P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR Blood. 2002 ; 99 (2) : 706-708. PMID 11781259
Molecular physiology of P2X receptors. North RA Physiological reviews. 2002 ; 82 (4) : 1013-1067. PMID 12270951
An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. Wiley JS, Dao-Ung LP, Li C, Shemon AN, Gu BJ, Smart ML, Fuller SJ, Barden JA, Petrou S, Sluyter R The Journal of biological chemistry. 2003 ; 278 (19) : 17108-17113. PMID 12586825
Association of the 1513C polymorphism in the P2X7 gene with familial forms of chronic lymphocytic leukaemia. Dao-Ung LP, Fuller SJ, Sluyter R, SkarRatt KK, Thunberg U, Tobin G, Byth K, Ban M, Rosenquist R, Stewart GJ, Wiley JS British journal of haematology. 2004 ; 125 (6) : 815-817. PMID 15180873
Atlas Genet Cytogenet Oncol Haematol 2008; 5 710
An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor. Gu BJ, Sluyter R, Skarratt KK, Shemon AN, Dao-Ung LP, Fuller SJ, Barden JA, Clarke AL, Petrou S, Wiley JS The Journal of biological chemistry. 2004 ; 279 (30) : 31287-31295. PMID 15123679
Differentiation between cancerous and normal hyperplastic lobules in breast lesions. Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird A, Barden JA Breast cancer research and treatment. 2004 ; 83 (1) : 1-10. PMID 14997049
Differentiation between cancerous and normal hyperplastic lobules in breast lesions. Slater M, Danieletto S, Pooley M, Cheng Teh L, Gidley-Baird A, Barden JA Breast cancer research and treatment. 2004 ; 83 (1) : 1-10. PMID 14997049
Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F Molecular biology of the cell. 2005 ; 16 (7) : 3260-3272. PMID 15901833
A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. Cabrini G, Falzoni S, Forchap SL, Pellegatti P, Balboni A, Agostini P, Cuneo A, Castoldi G, Baricordi OR, Di Virgilio F Journal of immunology (Baltimore, Md. : 1950). 2005 ; 175 (1) : 82-89. PMID 15972634
Identification and characterization of splice variants of the human P2X7 ATP channel. Cheewatrakoolpong B, Gilchrest H, Anthes JC, Greenfeder S Biochemical and biophysical research communications. 2005 ; 332 (1) : 17-27. PMID 15896293
A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. Feng YH, Li X, Wang L, Zhou L, Gorodeski GI The Journal of biological chemistry. 2006 ; 281 (25) : 17228-17237. PMID 16624800
The P2X7 receptor: a key player in IL-1 processing and release. Ferrari D, Pizzirani C, Adinolfi E, Lemoli RM, Curti A, Idzko M, Panther E, Di Virgilio F Journal of immunology. 2006 ; 176 (7) : 3877-3883. PMID 16547218
Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. Pelegrin P, Surprenant A The EMBO journal. 2006 ; 25 (21) : 5071-5082. PMID 17036048
The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P- dependent mechanism. Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V Cancer research. 2006 ; 66 (2) : 907-914. PMID 16424024
Atlas Genet Cytogenet Oncol Haematol 2008; 5 711 A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB, Wiley JS, Britton WJ American journal of respiratory and critical care medicine. 2007 ; 175 (4) : 360-366. PMID 17095747
Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease? Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG, Dardano A, Faviana P, Madec S, Di Virgilio F, Monzani F Endocrinology. 2008 ; 149 (1) : 389-396. PMID 17947359
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Contributor(s) Written 01-2008 Pablo Pelegrin, Annmarie Surprenant Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK Citation This paper should be referenced as such : Pelegrin P, Surprenant A . P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/P2RX7ID41623ch12q24.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 712 Atlas of Genetics and Cytogenetics in Oncology and Haematology
NKX2-2 (NK2 homeobox 2)
Identity Other names NKX2.2 NKX2B HGNC NKX2-2 Location 20p11.22 Location_base_pair Starts at 21439652 and ends at 21442664 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description Start- 21,439,648 base pairs from p arm terminus; End- 21,442,699 base pairs from p arm terminus; Size- 3,051 bases; Orientation- minus strand Protein
Schematic of NKX2-2 functional domains. The positions of the transcriptional repressor domain (TN), the homeodomain (HD), the NK2-specific domain (SD), and the transcriptional activation domain (TAD) are shown. Description 273 amino acids; 30133 Da. NKX2-2 is a member of the NK2 family of homeobox transcription factors. It has known roles in the development of the CNS as well as pancreatic beta cell differentiation. In the CNS NKX2-2 is known to be activated by SHH signaling which is important for its initial role in ventral patterning. NKX2-2 expression has additionally been shown to be critical for the differentiation of oligodendrocytes, and in fact necessary for this process to occur. In both instances, NKX2-2 mediated transcripitional repression is both necessary and sufficient for these processes to occur. Regulation of NKX2-2 expression in the pancreas is less well understood. NKX2-2 knock-out mice die soon after birth from diabetic complications as a result of a lack of fully differentiated pancreatic beta cells. While NKX2-2 mediated transcriptional repression has been demonstrated to be necessary and sufficient for its role in ß-cell differentiation, it remains unclear whether NKX2-2 mediated transcriptional activation is important for NKX2-2 function in adult ß-cells. Expression V3 neural progenitors; oligodendrocyte precursor cells; precursor and adult pancreatic beta cells. Localisation Nuclear Function NKX2-2 is a transcription factor Homology NKX2-2 shares homology with other members of the NK2 family of transcription factors most notably in the TN transcriptional repression, DNA binding homeodomain, and specific domain regions. Implicated in Entity Ewing's sarcoma Prognosis Roughly 50% survival at 5 years for Ewing's sarcoma. Cytogenetics Ewing's sarcoma cells harbor the characteristic translocation t(11;22)(q24;q12) in roughly 90% of cases. Hybrid/Mutated t(11;22)(q24;q12) fuses the 5' region of the EWSR1 gene on chromosome 22 with the Gene 3' portion of the FLI-1 gene on chromosome 11. Abnormal The translocation fusion product is termed EWS/FLI. Protein
Atlas Genet Cytogenet Oncol Haematol 2008; 5 713
Schematic diagram of wild-type EWS, wild-type FLI, and the EWS/FLI fusion transcripts. Oncogenesis NKX2-2 is up-regulated in Ewing's sarcoma by the EWS/FLI translocation protein product. NKX2.2 expression is necessary for the oncogenic phenotype of Ewing's sarcoma cells. External links Nomenclature HGNC NKX2-2 7835 Entrez_Gene NKX2-2 4821 NK2 homeobox 2 Cards Atlas NKX22ID44177ch20p11 GeneCards NKX2-2 Ensembl NKX2-2 [Search_View] ENSG00000125820 [Gene_View] Genatlas NKX2-2 GeneLynx NKX2-2 eGenome NKX2-2 euGene 4821 Genomic and cartography NKX2-2 - 20p11.22 chr20:21439652-21442664 - 20p11.22 [Description] (hg18- GoldenPath Mar_2006) Ensembl NKX2-2 - 20p11.22 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene NKX2-2 Gene and transcription Genbank BC075092 [ ENTREZ ] Genbank BC075093 [ ENTREZ ] Genbank BM314196 [ ENTREZ ] Genbank BQ632044 [ ENTREZ ] Genbank CA772329 [ ENTREZ ] RefSeq NM_002509 [ SRS ] NM_002509 [ ENTREZ ] RefSeq AC_000063 [ SRS ] AC_000063 [ ENTREZ ] RefSeq AC_000152 [ SRS ] AC_000152 [ ENTREZ ] RefSeq NC_000020 [ SRS ] NC_000020 [ ENTREZ ] RefSeq NT_011387 [ SRS ] NT_011387 [ ENTREZ ] RefSeq NW_001838652 [ SRS ] NW_001838652 [ ENTREZ ] RefSeq NW_927317 [ SRS ] NW_927317 [ ENTREZ ] AceView NKX2-2 AceView - NCBI Unigene Hs.516922 [ SRS ] Hs.516922 [ NCBI ] HS516922 [ spliceNest ] Fast-db 6733 (alternative variants) Protein : pattern, domain, 3D structure O95096 [ SRS] O95096 [ EXPASY ] O95096 [ INTERPRO ] O95096 SwissProt [ UNIPROT ] Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ] Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 714 Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ] Interpro IPR012287 Homeodomain-rel [ SRS ] IPR012287 Homeodomain-rel [ EBI ] CluSTr O95096 PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger ] pfam00046 [ NCBI- Pfam CDD ] Smart SM00389 HOX [EMBL] Prodom PD000010 Homeobox[INRA-Toulouse] O95096 NKX22_HUMAN [ Domain structure ] O95096 NKX22_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks O95096 HPRD 05213 Protein Interaction databases DIP O95096 IntAct O95096 Polymorphism : SNP, mutations, diseases OMIM 604612 [ map ] GENECLINICS 604612 SNP NKX2-2 [dbSNP-NCBI] SNP NM_002509 [SNP-NCI] SNP NKX2-2 [GeneSNPs - Utah] NKX2-2] [HGBASE - SRS] HAPMAP NKX2-2 [HAPMAP] HGMD NKX2-2 General knowledge Family Browser NKX2-2 [UCSC Family Browser] SOURCE NM_002509 SMD Hs.516922 SAGE Hs.516922 GO transcription factor activity [Amigo] transcription factor activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO multicellular organismal development [Amigo] multicellular organismal development GO nervous system development [Amigo] nervous system development GO brain development [Amigo] brain development GO oligodendrocyte development [Amigo] oligodendrocyte development spinal cord oligodendrocyte cell differentiation [Amigo] spinal cord oligodendrocyte cell GO differentiation GO endocrine pancreas development [Amigo] endocrine pancreas development GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding positive regulation of cell differentiation [Amigo] positive regulation of cell GO differentiation positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter GO cell development [Amigo] cell development GO neuron fate specification [Amigo] neuron fate specification KEGG Maturity onset diabetes of the young PubGene NKX2-2 TreeFam NKX2-2 CTD 4821 [Comparative ToxicoGenomics Database] Other databases Probes Probe NKX2-2 Related clones (RZPD - Berlin) PubMed
Atlas Genet Cytogenet Oncol Haematol 2008; 5 715 PubMed 12 Pubmed reference(s) in Entrez Bibliography Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G Nature. 1992 ; 359 (6391) : 162-165. PMID 1522903
Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC, Delattre O, Zucman J, Thomas G, Denny CT Proc Natl Acad Sci U S A. 1993 ; 90 (12) : 5752-5756. PMID 8516324
Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Sussel L, Kalamaras J, Hartigan-O'Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS Development. 1998 ; 125 (12) : 2213-2221. PMID 9584121
Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Briscoe J, Sussel L, Serup P, Hartigan-O'Connor D, Jessell TM, Rubenstein JL, Ericson J Nature. 1999 ; 398 (6728) : 622-627. PMID 10217145
Intramolecular control of transcriptional activity by the NK2-specific domain in NK-2 homeodomain proteins. Watada H, Mirmira RG, Kalamaras J, German MS Proc Natl Acad Sci U S A. 2000 ; 97 (17) : 9443-9448. PMID 10944215
Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Muhr J, Andersson E, Persson M, Jessell TM, Ericson J Cell. 2001 ; 104 (6) : 861-873. PMID 11290324
Stage-specific expression of myelin basic protein in oligodendrocytes involves Nkx2.2- mediated repression that is relieved by the Sp1 transcription factor. Wei Q, Miskimins WK, Miskimins R The Journal of biological chemistry. 2005 ; 280 (16) : 16284-16294. PMID 15695521
Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma. Owen LA, Lessnick SL Cell cycle (Georgetown, Tex.). 2006 ; 5 (18) : 2049-2053. PMID 16969112
Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma. Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, Lessnick SL Cancer cell. 2006 ; 9 (5) : 405-416. PMID 16697960
Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 716 Doyle MJ, Loomis ZL, Sussel L Development. 2007 ; 134 (3) : 515-523. PMID 17202186
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Contributor(s) Written 01-2008 Stephen L Lessnick, Leah A Owen Department of Oncological Sciences, University of Utah School of Medicine, Center for Children, Huntsman Cancer Institute, and Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, Utah, USA Citation This paper should be referenced as such : Lessnick SL, Owen LA . NKX2-2 (NK2 homeobox 2). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/NKX22ID44177ch20p11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 717 Atlas of Genetics and Cytogenetics in Oncology and Haematology
MIB2 (mindbomb homolog 2 (Drosophila))
Identity Other names FLJ20648 FLJ39787 ZZANK1 ZZZ5 Skeletrophin novelzin HGNC MIB2 Location 1p36.33 Location_base_pair Starts at 1540747 and ends at 1555848 bp from pter ( according to hg18- Mar_2006). ATAD3A (ATPase family, AAA domain containing 3B), is more telomeric, CDC2L2 Local_order (cell division cycle 2-like 2) is more centromeric. Note Orientation: plus strand. DNA/RNA Note There are at least six alternative splicing forms.
Genomic structure of Mib2/skeletrophin Description 20 Exons spanning 14kb on 1p36.33. Protein
Schematic illustrating of mib2/skeletrophin. Expression Human mib2/skeletrophin is strongly expressed in adult brain, heart and skeletal muscles. Localisation Cytoplasmic Function Ubiquitin ligase to cytoplasmic domain of Notch ligands and NMDA receptor GRIN2B/NR2B subunit. Putative positive regulation of I-kappaB kinase/NF-kappaB cascade. Homology The protein structure of mib2/skeletrophin is closely related to MIB1 (mind bomb-1 homolog). Implicated in Entity Malignant melanoma, vertical growth phase. Oncogenesis Putative suppressor factor against malignant melanoma invasion. In invasive malignant melanoma, Mib2/skeletrophin gene expression is down-regulated by various epigenetic events described below. The promoter region of Mib2/skeletrophin gene contains typical CpG islands, which is hypermethylated in invasive malignant melanoma. A zinc- finger transcriptional factor Snail, which is overexpressed in many melanoma cells, repressed the Mib2/skeletrophin promoter activity via an E-box-related element. An activator protein-2, which has a tumor suppressor-like role in melanoma, increased Mib2/skeletrophin expression. Entity Multiple myeloma, especially at advanced stage with osteolytic lesion. Oncogenesis Putative oncogenic factor for multiple myeloma thorough bone marrow microenvironments. In multiple myeloma, Mib2/skeletrophin and its substrates, Jagged-1 and Jagged-2, are both overexpressed in bone marrow microenvironments. Ligands-dependent Notch activation is occurred by direct cell-cell interaction between multiple myeloma cells and bone marrow stromal cells and contribute the myeloma
Atlas Genet Cytogenet Oncol Haematol 2008; 5 718 niche, which is known as microenvironment suitable for myelomagenesis. External links Nomenclature HGNC MIB2 30577 Entrez_Gene MIB2 142678 mindbomb homolog 2 (Drosophila) Cards Atlas MIB2ID44179ch1p36 GeneCards MIB2 Ensembl MIB2 [Search_View] ENSG00000197530 [Gene_View] Genatlas MIB2 GeneLynx MIB2 eGenome MIB2 euGene 142678 Genomic and cartography MIB2 - 1p36.33 chr1:1540747-1555848 + 1p36.33 [Description] (hg18- GoldenPath Mar_2006) Ensembl MIB2 - 1p36.33 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MIB2 Gene and transcription Genbank AB064367 [ ENTREZ ] Genbank AB074480 [ ENTREZ ] Genbank AB076691 [ ENTREZ ] Genbank AB076692 [ ENTREZ ] Genbank AB076693 [ ENTREZ ] RefSeq NM_080875 [ SRS ] NM_080875 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004350 [ SRS ] NT_004350 [ ENTREZ ] RefSeq NW_001838585 [ SRS ] NW_001838585 [ ENTREZ ] RefSeq NW_921350 [ SRS ] NW_921350 [ ENTREZ ] AceView MIB2 AceView - NCBI Unigene Hs.593430 [ SRS ] Hs.593430 [ NCBI ] HS593430 [ spliceNest ] Fast-db 489 (alternative variants) Protein : pattern, domain, 3D structure HPRD 15905 Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 611141 [ map ] GENECLINICS 611141 SNP MIB2 [dbSNP-NCBI] SNP NM_080875 [SNP-NCI] SNP MIB2 [GeneSNPs - Utah] MIB2] [HGBASE - SRS] HAPMAP MIB2 [HAPMAP] HGMD MIB2 General knowledge Family Browser MIB2 [UCSC Family Browser] SOURCE NM_080875 SMD Hs.593430 SAGE Hs.593430 GO actin binding [Amigo] actin binding
Atlas Genet Cytogenet Oncol Haematol 2008; 5 719 GO signal transducer activity [Amigo] signal transducer activity GO protein binding [Amigo] protein binding GO cytoplasm [Amigo] cytoplasm GO endosome [Amigo] endosome GO Notch signaling pathway [Amigo] Notch signaling pathway GO zinc ion binding [Amigo] zinc ion binding GO ligase activity [Amigo] ligase activity positive regulation of I-kappaB kinase/NF-kappaB cascade [Amigo] positive GO regulation of I-kappaB kinase/NF-kappaB cascade GO metal ion binding [Amigo] metal ion binding PubGene MIB2 TreeFam MIB2 CTD 142678 [Comparative ToxicoGenomics Database] Other databases Probes Probe MIB2 Related clones (RZPD - Berlin) PubMed PubMed 14 Pubmed reference(s) in Entrez Bibliography Down-regulation of a novel actin-binding molecule, skeletrophin, in malignant melanoma. Takeuchi T, Heng HH, Ye CJ, Liang SB, Iwata J, Sonobe H, Ohtsuki Y The American journal of pathology. 2003 ; 163 (4) : 1395-1404. PMID 14507647
Mind bomb-2 is an E3 ligase for Notch ligand. Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH, Kim CH, Kong YY The Journal of biological chemistry. 2005 ; 280 (23) : 22335-22342. PMID 15824097
Skeletrophin, a novel RING molecule controlled by the chromatin remodeling complex, is downregulated in malignant melanoma. Takeuchi T, Adachi Y, Ohtsuki Y DNA and cell biology. 2005 ; 24 (5) : 339-344. PMID 15869411
Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma. Takeuchi T, Adachi Y, Ohtsuki Y The American journal of pathology. 2005 ; 166 (6) : 1817-1826. PMID 15920166
A ubiquitin ligase, skeletrophin, is a negative regulator of melanoma invasion. Takeuchi T, Adachi Y, Sonobe H, Furihata M, Ohtsuki Y Oncogene. 2006 ; 25 (53) : 7059-7069. PMID 16715130
Mind bomb-2 is an E3 ligase that ubiquitinates the N-methyl-D-aspartate receptor NR2B subunit in a phosphorylation-dependent manner. Jurd R, Thornton C, Wang J, Luong K, Phamluong K, Kharazia V, Gibb SL, Ron D The Journal of biological chemistry. 2008 ; 283 (1) : 301-310. PMID 17962190
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Atlas Genet Cytogenet Oncol Haematol 2008; 5 720 Contributor(s) Written 01-2008 Tamotsu Takeuchi Department of Pathology, Kochi Medical School, Kohasu, Okou, Nankoku, Kochi 783 8505, Japan Citation This paper should be referenced as such : Takeuchi T . MIB2 (mindbomb homolog 2 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/MIB2ID44179ch1p36.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 721 Atlas of Genetics and Cytogenetics in Oncology and Haematology
KCNH1 (potassium voltage-gated channel, subfamily H (eag-related), member 1)
Identity Other names EAG EAG1 ether a go-go h-eag Kv10.1 MGC142269 HGNC KCNH1 Location 1q32.2 Location_base_pair Starts at 208918280 and ends at 209374080 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description 450 Kb, 11 exons. Transcription Main RNA species with 9Kb. An alternatively spliced variant with 81 additional bp. Protein Description Tetramer consisting of subunits with 969 aminoacids each. The protein contains a PAS domain at the N-terminus, "Channel" domain with typical features of K channels (six putatively transmembrane segments and a pore loop between fifth and sixth). Large C- terminal domain with cyclic-nucleotide-binding domain, calmodulin binding site, tetramerizing coiled-coil. The sequence has many potential posttranslational modification sites, but only glycosylation has been reported. Expression Abundant in many brain regions, virtually absent from extracranial tissues. Detected in gastric gland chief cells, pancreatic acini, spermatogenic cells, endocervix, secretory endometrium, reactive lymph nodes (germinal centre), mast cells, macrophages, anterior pituitary, adrenal gland. Localisation Plasma membrane. Abundant in intracellular pools both in neurons and tumor cells. Function Voltage-gated potassium channel. Homology Homologous to the "six-transmembrane, one pore" potassium channel superfamily. Implicated in Entity Sarcomas (71% positivity). Disease Fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, synovial sarcoma. Prognosis Indicative of worse outcome in liposarcoma. Entity Solid epithelial tumors (70% positivity). Disease Esophageal, gastric, colon, hepatocellular, gallbladder, pancreatic, renal cell, transitional, prostate, cervical, endometrial, breast and bronchus carcinoma ; cystadenocarcinoma of the ovary, thyroid papillary carcinoma, basalioma, spinalioma, malignant melanoma. External links Nomenclature HGNC KCNH1 6250 Entrez_Gene KCNH1 3756 potassium voltage-gated channel, subfamily H (eag-related), member 1 Cards Atlas KCNH1ID41048ch1q32 GeneCards KCNH1 Ensembl KCNH1 [Search_View] ENSG00000143473 [Gene_View] Genatlas KCNH1
Atlas Genet Cytogenet Oncol Haematol 2008; 5 722 GeneLynx KCNH1 eGenome KCNH1 euGene 3756 Genomic and cartography KCNH1 - 1q32.2 chr1:208918280-209374080 - 1q32.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl KCNH1 - 1q32.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene KCNH1 Gene and transcription Genbank AF078741 [ ENTREZ ] Genbank AF078742 [ ENTREZ ] Genbank AJ001366 [ ENTREZ ] Genbank BC113709 [ ENTREZ ] RefSeq NM_002238 [ SRS ] NM_002238 [ ENTREZ ] RefSeq NM_172362 [ SRS ] NM_172362 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_021877 [ SRS ] NT_021877 [ ENTREZ ] RefSeq NW_001838537 [ SRS ] NW_001838537 [ ENTREZ ] RefSeq NW_926794 [ SRS ] NW_926794 [ ENTREZ ] AceView KCNH1 AceView - NCBI Unigene Hs.662282 [ SRS ] Hs.662282 [ NCBI ] HS662282 [ spliceNest ] Fast-db 17804 (alternative variants) Protein : pattern, domain, 3D structure O95259 [ SRS] O95259 [ EXPASY ] O95259 [ INTERPRO ] O95259 SwissProt [ UNIPROT ] Prosite PS00888 CNMP_BINDING_1 [ SRS ] PS00888 CNMP_BINDING_1 [ Expasy ] Prosite PS00889 CNMP_BINDING_2 [ SRS ] PS00889 CNMP_BINDING_2 [ Expasy ] Prosite PS50042 CNMP_BINDING_3 [ SRS ] PS50042 CNMP_BINDING_3 [ Expasy ] Prosite PS50113 PAC [ SRS ] PS50113 PAC [ Expasy ] Prosite PS50112 PAS [ SRS ] PS50112 PAS [ Expasy ] Interpro IPR000595 cNMP_bd [ SRS ] IPR000595 cNMP_bd [ EBI ] Interpro IPR005821 Ion_trans [ SRS ] IPR005821 Ion_trans [ EBI ] Interpro IPR003949 K_chnl_volt-dep_EAG [ SRS ] IPR003949 K_chnl_volt-dep_EAG [ EBI ] IPR003938 K_chnl_volt-dep_EAG/ELK/ERG [ SRS ] IPR003938 K_chnl_volt- Interpro dep_EAG/ELK/ERG [ EBI ] Interpro IPR001610 PAC [ SRS ] IPR001610 PAC [ EBI ] Interpro IPR000014 PAS [ SRS ] IPR000014 PAS [ EBI ] Interpro IPR000700 PAS-assoc_C [ SRS ] IPR000700 PAS-assoc_C [ EBI ] Interpro IPR013655 PAS_3 [ SRS ] IPR013655 PAS_3 [ EBI ] Interpro IPR014710 RmlC-like_jellyroll [ SRS ] IPR014710 RmlC-like_jellyroll [ EBI ] CluSTr O95259 PF00027 cNMP_binding [ SRS ] PF00027 cNMP_binding [ Sanger ] pfam00027 Pfam [ NCBI-CDD ] PF00520 Ion_trans [ SRS ] PF00520 Ion_trans [ Sanger ] pfam00520 [ NCBI- Pfam CDD ] Pfam PF08447 PAS_3 [ SRS ] PF08447 PAS_3 [ Sanger ] pfam08447 [ NCBI-CDD ] Smart SM00100 cNMP [EMBL] Smart SM00086 PAC [EMBL] Smart SM00091 PAS [EMBL] Blocks O95259
Atlas Genet Cytogenet Oncol Haematol 2008; 5 723 HPRD 04492 Protein Interaction databases DIP O95259 IntAct O95259 Polymorphism : SNP, mutations, diseases OMIM 603305 [ map ] GENECLINICS 603305 SNP KCNH1 [dbSNP-NCBI]
SNP NM_002238 [SNP-NCI] SNP NM_172362 [SNP-NCI] SNP KCNH1 [GeneSNPs - Utah] KCNH1] [HGBASE - SRS] HAPMAP KCNH1 [HAPMAP] HGMD KCNH1 General knowledge Family Browser KCNH1 [UCSC Family Browser] SOURCE NM_002238 SOURCE NM_172362 SMD Hs.662282 SAGE Hs.662282 GO two-component sensor activity [Amigo] two-component sensor activity two-component signal transduction system (phosphorelay) [Amigo] two-component GO signal transduction system (phosphorelay) GO voltage-gated ion channel activity [Amigo] voltage-gated ion channel activity delayed rectifier potassium channel activity [Amigo] delayed rectifier potassium GO channel activity GO calmodulin binding [Amigo] calmodulin binding regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO ion transport [Amigo] ion transport GO potassium ion transport [Amigo] potassium ion transport GO myoblast fusion [Amigo] myoblast fusion voltage-gated potassium channel complex [Amigo] voltage-gated potassium channel GO complex GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO potassium ion binding [Amigo] potassium ion binding PubGene KCNH1 TreeFam KCNH1 CTD 3756 [Comparative ToxicoGenomics Database] Other databases Probes Probe KCNH1 Related clones (RZPD - Berlin) PubMed PubMed 20 Pubmed reference(s) in Entrez Bibliography A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Warmke J, Drysdale R, Ganetzky B Science. 1991 ; 252 (5012) : 1560-1562. PMID 1840699
Functional expression of a rat homologue of the voltage gated either à go-go potassium channel reveals differences in selectivity and activation kinetics between the Drosophila channel and its mammalian counterpart. Ludwig J, Terlau H, Wunder F, Bruggemann A, Pardo LA, Marquardt A, Stuhmer W, Pongs O
Atlas Genet Cytogenet Oncol Haematol 2008; 5 724 The EMBO journal. 1994 ; 13 (19) : 4451-4458. PMID 7925287
Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-à-go-go potassium channel. Ludwig J, Owen D, Pongs O The EMBO journal. 1997 ; 16 (21) : 6337-6345. PMID 9400421
An ether -à-go-go K+ current, Ih-eag, contributes to the hyperpolarization of human fusion- competent myoblasts. Bijlenga P, Occhiodoro T, Liu JH, Bader CR, Bernheim L, Fischer-Lougheed J The Journal of physiology. 1998 ; 512 ( Pt 2) : 317-323. PMID 9763622
Cloning of a human ether-à-go-go potassium channel expressed in myoblasts at the onset of fusion. Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J FEBS letters. 1998 ; 434 (1-2) : 177-182. PMID 9738473
Cell cycle-related changes in the conducting properties of r-eag K+ channels. Pardo LA, Bruggemann A, Camacho J, Stuhmer W The Journal of cell biology. 1998 ; 143 (3) : 767-775. PMID 9813096
Oncogenic potential of EAG K(+) channels. Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, Beckh S, Stuhmer W The EMBO journal. 1999 ; 18 (20) : 5540-5547. PMID 10523298
Inhibition of human ether à go-go potassium channels by Ca(2+)/calmodulin. Schonherr R, Lober K, Heinemann SH The EMBO journal. 2000 ; 19 (13) : 3263-3271. PMID 10880439
Physiology of EAG K+ channels. Bauer CK, Schwarz JR The Journal of membrane biology. 2001 ; 182 (1) : 1-15. PMID 11426295
Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether.a-gogo K+ channel. Ouadid-Ahidouch H, Le Bourhis X, Roudbaraki M, Toillon RA, Delcourt P, Prevarskaya N Receptors & channels. 2001 ; 7 (5) : 345-356. PMID 11697078
Effects of imipramine on ion channels and proliferation of IGR1 melanoma cells. Gavrilova-Ruch O, Schonherr K, Gessner G, Schonherr R, Klapperstuck T, Wohlrab W, Heinemann SH The Journal of membrane biology. 2002 ; 188 (2) : 137-149. PMID 12172639
C-terminal domains implicated in the functional surface expression of potassium channels. Jenke M, Sanchez A, Monje F, Stuhmer W, Weseloh RM, Pardo LA The EMBO journal. 2003 ; 22 (3) : 395-403. PMID 12554641
Ether a go-go potassium channels as human cervical cancer markers. Farias LM, Ocana DB, Diaz L, Larrea F, Avila-Chavez E, Cadena A, Hinojosa LM, Lara G, Villanueva
Atlas Genet Cytogenet Oncol Haematol 2008; 5 725 LA, Vargas C, Hernandez-Gallegos E, Camacho-Arroyo I, Duenas-Gonzalez A, Perez-Cardenas E, Pardo LA, Morales A, Taja-Chayeb L, Escamilla J, Sanchez-Pena C, Camacho J Cancer research. 2004 ; 64 (19) : 6996-7001. PMID 15466192
Expression of ether à go-go potassium channels in human gliomas. Patt S, Preussat K, Beetz C, Kraft R, Schrey M, Kalff R, Schonherr K, Heinemann SH Neuroscience letters. 2004 ; 368 (3) : 249-253. PMID 15364405
Glycosylation of Eag1 (Kv10.1) potassium channels: intracellular trafficking and functional consequences. Napp J, Monje F, Stuhmer W, Pardo LA The Journal of biological chemistry. 2005 ; 280 (33) : 29506-29512. PMID 15964838
Overexpression of Eag1 potassium channels in clinical tumours. Hemmerlein B, Weseloh RM, Mello de Queiroz F, Knotgen H, Sanchez A, Rubio ME, Martin S, Schliephacke T, Jenke M, Heinz-Joachim-Radzun, Stuhmer W, Pardo LA Molecular cancer. 2006 ; 5 : page 41. PMID 17022810
Ether à go-go potassium channel expression in soft tissue sarcoma patients. Mello de Queiroz F, Suarez-Kurtz G, Stuhmer W, Pardo LA Molecular cancer. 2006 ; 5 : page 42. PMID 17022811
Silencing the activity and proliferative properties of the human EagI Potassium Channel by RNA Interference. Weber C, Mello de Queiroz F, Downie BR, Suckow A, Stuhmer W, Pardo LA The Journal of biological chemistry. 2006 ; 281 (19) : 13030-13037. PMID 16537547
Inhibition of human ether à go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. Ziechner U, Schonherr R, Born AK, Gavrilova-Ruch O, Glaser RW, Malesevic M, Kullertz G, Heinemann SH The FEBS journal. 2006 ; 273 (5) : 1074-1086. PMID 16478480
Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines. Ding XW, Yan JJ, An P, Lu P, Luo HS World journal of gastroenterology : WJG. 2007 ; 13 (8) : 1257-1261. PMID 17451210
Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Gomez-Varela D, Zwick-Wallasch E, Knotgen H, Sanchez A, Hettmann T, Ossipov D, Weseloh R, Contreras-Jurado C, Rothe M, Stuhmer W, Pardo LA Cancer research. 2007 ; 67 (15) : 7343-7349. PMID 17671204
Voltage-gated K+ channels support proliferation of colonic carcinoma cells. Spitzner M, Ousingsawat J, Scheidt K, Kunzelmann K, Schreiber R The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2007 ; 21 (1) : 35-44. PMID 17135369
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Contributor(s) Written 01-2008 Luis A Pardo Max-Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany Citation This paper should be referenced as such : Pardo LA . KCNH1 (potassium voltage-gated channel, subfamily H (eag-related), member 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/KCNH1ID41048ch1q32.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 727 Atlas of Genetics and Cytogenetics in Oncology and Haematology
IRF1 (interferon regulatory factor 1)
Identity Other names IRF-1 MAR HGNC IRF1 Location 5q23.3 Location_base_pair Starts at 131846684 and ends at 131854326 bp from pter ( according to hg18- Mar_2006). Note Interferon regulatory factor 1 belongs to a family of transcription factors described for their role in regulating type I and type II interferons. Specifically, IRF1 has been identified as an activator of interferon alpha and beta transcription. Furthermore, it has been shown to play a role in the regulation of tumour suppression. IRF1 lies between interleukin (IL)-5 and CDC25C and is centromeric to IL-3 and GM-CSF. A number of mechanisms have been identified through which IRF1 is inactivated in various cancers. These, mechanisms include, deletion of the IRF1 region of chromosome 5q31; expression of IRF2; exon-skipping; binding of nucleophosmin; inactivation of tumour suppression by human papilloma viral oncogene, E7; and alternative splice variants lacking exons 7, 8, 9. DNA/RNA
Description 7.72 kb with 10 exons and 9 introns. Transcription 2.035kb mRNA. Coding sequence: CDS 198-1175. IRF1 mRNA is expressed in low levels in a variety of tissues including, heart, lung, thymus, kidney and activated spleen. Protein Description IRF1 protein has an half-life of approximately 30 min. Localisation Nucleus Function Transcriptional activator of type I interferons. Mutations Note Deletion in 5q rearrangement of IRF1 are associated with preleukemic myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The most commonly reported cytogenetic abnormalities in leukaemia and preleukaemic myelodysplastic syndromes are found within 5q or loss of the entire choromosome 5. The most commonly deleted region was found to be 5q31. Willman et al. reported the tumour suppressor gene, IRF1 is situated within this 5q31 region. A common translocation found in AML is between chromosome 8q22 and chromosome 21q22. This translocation is found in approximately 40% of FAB-M2 AML and 8-20% of all AML. Implicated in Entity Acute Myeloid Leukaemia (AML) Disease AML is an heterogenous disease representating clonal haematopoietic stem cell disorders. Initially classified under a French-American-British (FAB) co-operative group describing eight categories dependent on cell morphology on May-Grunwald-Giemsa (MGG) staining of peripheral blood and bone marrow smears. More recently, the World
Atlas Genet Cytogenet Oncol Haematol 2008; 5 728 Health Organisation (WHO) proposed a new classification dependent on morphological, cytochemical, immunophenotypic, cytogenetic and molecular determinants that incorporates more recent developments in this disease and thereby reduce the limitations experienced under the FAB classification. Activation of the mutant N-ras gene in some myeloid cell lines induced growth suppression through IRF1. Prognosis Prognosis is poor for most AML patients, depending on age and other unfavorable biological features. Cytogenetics Translocations: t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q22;q21), t(11;17)(q23;q21), or 11q23 rearrangements Entity Preleukaemic Myelodysplastic Syndromes (MDS) Note 30% of patients exhibit a deletion in chromosome 5q Disease MDS is an heterogenous group of diseases representing clonal bone marrow disorders. They are characterised by cytopenias with ineffective haematopoisis often progressing despite bone marrow transplants and may result in acute myeloid leukaemia. Chromosomal abnormalities are commonly found in this disease. Entity Breast Cancer Disease The transcriptional regulation of human caspase-8 gene expression in the breast tumour cell line, MCF-7 was studied and found to be induced by IFN-gamma inducible transcription factor IRF1. Further studies have shown that IRF1 behaves as a tumour suppressor gene in breast cancer through caspase activation and induction of apoptosis. This suppression of apoptosis was observed independently of p53. Pizzoferrato et al., showed that ectopic expression of IRF1 using an adenovirus delivery system led to a decrease in survivin expression and an increase in cell death in breast cancer cell lines. This study also showed that p21 was up-regulated in IRF1-infected breast cancer cells independent of p53 modulation. Microarray analysis of clinically defined invasive breast carcinoma identified a negative correlation with IRF1 expression and tumour grade. High-grade breast carcinomas were found not to maintain IRF1 expression. IRF1 has also been shown to induce ligand-independent fas-associated death domain/caspase-8 mediated apoptosis in breast cancer cells. Cytogenetics A single nucleotide polymorphism, A4396G in IRF1 was found to occur more frequently in breast cancer cell lines than in the general population. In addition, this polymorphism was more frequently expressed in the African American population than the European population. Entity Cervical cancer Note Alternative splicing of exons 7, 8 and 9 is implicated in cervical cancer. Disease Lee et al., demonstrated that p27Kip1 inhibits hTERT mRNA expression and telomerase activity through post-transcriptional up-regulation by IFN-gamma/IRF-1 signalling. Entity Gastric cancer Note A point mutation in the second exon of the IRF1 gene with a methionine substituted with leucine at codon 8 was identified. Disease Loss of heterozygosity at the IRF1 locus was found in 9 cases of histologically differentiated gastric adenocarcinomas. A mis-sense mutation in the residual allele was found in one case. This mutation in IRF1 was reported by Nozawa et al. to lead to reduced transcriptional activity but no change in its DNA-binding activity was observed. The loss of functional IRF1 is a key factor in development human gastric cancer. Entity Oesophageal Cancer Disease Oesophageal cancer is an aggressive tumour with two subtypes described, including: oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma. Following IFNgamma stimulation of three oesophageal cancer cell lines IRF1 was produced but did not lead to cell death. In contrast, adenoviral-IRF1 (Ad-IRF1) infection of these cell lines induced high IRF1 production resulting in apoptosis. Furthermore, a murine model of oesophageal cancer injected with Ad-IRF1 moderately inhibited tumour growth but did not induce tumour regression. Analysis of primary samples of oesophageal squamous cell carcinoma revealed decreased IRF1 expression and increased IRF2 expression compared to adjacent normal oesophageal tissue. In addition, overexpression of IRF1 inhibited tumorigenicity of ESCC cells when injected in vivo in nude mice. Prognosis Ranked eighth most common malignancy and sixth most frequent cause of cancer
Atlas Genet Cytogenet Oncol Haematol 2008; 5 729 worldwide. Cytogenetics The most frequent occurance is loss of heterozygosity either single or multiple loci on chromosome 5q. The smallest deletion is found at 5q31.1 the same position for the IRF1 gene. Entity Ovarian Cancer Disease Interferon gamma has been shown to inhibit proliferation of a number of ovarian cancer cell lines in vitro. This growth inhibition and apoptotic effect in ovarian cancer cells was associated with a sustained increase in both IRF1 and p21. Kim et al., proposed a role for IRF1 in mediating IFNgamma-induced apoptosis through activation of caspase-1 gene expression in IFNgamma-sensitive ovarian cancer cells. IFNgamma was shown to induce IRF1 through the IFNgamma signalling pathway which in turn activated caspase-1. This was shown to lead to apoptosis of ovarian cancer cells, 2774 and PA-1, both sensitive to IFNgamma. Prognosis Early stage diagnosis of epithelial ovarian cancer one can anticipate 90% survival. However, only 20-30% of patients with stage III epithelial ovarian carcinoma survive after 5 years. Entity Melanoma Disease Lowney et al., described evidence showing IRF1 protein expression correlated to morphologic characteristics associated with less advanced disease in human melanoma. Entity Bladder Cancer Disease Bladder cancer is ranked 9th in worldwide cancer incidence. A recent study determined that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and downstream TRAIL-regulated apoptotic mechanisms are involved in IFNalpha-induced cell death in human bladder cancer cell line through a STAT1/IRF1-dependent pathway. External links Nomenclature HGNC IRF1 6116 Entrez_Gene IRF1 3659 interferon regulatory factor 1 Cards Atlas IRF1ID40990ch5q23 GeneCards IRF1 Ensembl IRF1 [Search_View] ENSG00000125347 [Gene_View] Genatlas IRF1 GeneLynx IRF1 eGenome IRF1 euGene 3659 Genomic and cartography IRF1 - 5q23.3 chr5:131846684-131854326 - 5q23-q31 [Description] (hg18- GoldenPath Mar_2006) Ensembl IRF1 - 5q23-q31 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene IRF1 Gene and transcription Genbank AB103081 [ ENTREZ ] Genbank AB209624 [ ENTREZ ] Genbank AK314025 [ ENTREZ ] Genbank BC009483 [ ENTREZ ] Genbank BT019755 [ ENTREZ ] RefSeq NM_002198 [ SRS ] NM_002198 [ ENTREZ ] RefSeq AC_000048 [ SRS ] AC_000048 [ ENTREZ ] RefSeq AC_000137 [ SRS ] AC_000137 [ ENTREZ ] RefSeq NC_000005 [ SRS ] NC_000005 [ ENTREZ ] RefSeq NT_034772 [ SRS ] NT_034772 [ ENTREZ ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 730 RefSeq NW_001838952 [ SRS ] NW_001838952 [ ENTREZ ] RefSeq NW_922784 [ SRS ] NW_922784 [ ENTREZ ] AceView IRF1 AceView - NCBI Unigene Hs.436061 [ SRS ] Hs.436061 [ NCBI ] HS436061 [ spliceNest ] Fast-db 9544 (alternative variants) Protein : pattern, domain, 3D structure P10914 [ SRS] P10914 [ EXPASY ] P10914 [ INTERPRO ] P10914 SwissProt [ UNIPROT ] Prosite PS00601 IRF [ SRS ] PS00601 IRF [ Expasy ] Interpro IPR017431 Interferon_reg_1/2-typ [ SRS ] IPR017431 Interferon_reg_1/2-typ [ EBI ] Interpro IPR001346 IRF [ SRS ] IPR001346 IRF [ EBI ] Interpro IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Wing_hlx_DNA_bd [ EBI ] CluSTr P10914 Pfam PF00605 IRF [ SRS ] PF00605 IRF [ Sanger ] pfam00605 [ NCBI-CDD ] Smart SM00348 IRF [EMBL] Prodom PD002355 IRF[INRA-Toulouse] P10914 IRF1_HUMAN [ Domain structure ] P10914 IRF1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P10914 HPRD 00961 Protein Interaction databases DIP P10914 IntAct P10914 Polymorphism : SNP, mutations, diseases OMIM 137215;147575;153550 [ map ] GENECLINICS 137215;147575;153550 SNP IRF1 [dbSNP-NCBI] SNP NM_002198 [SNP-NCI] SNP IRF1 [GeneSNPs - Utah] IRF1] [HGBASE - SRS] HAPMAP IRF1 [HAPMAP] COSMIC IRF1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD IRF1 General knowledge Family Browser IRF1 [UCSC Family Browser] SOURCE NM_002198 SMD Hs.436061 SAGE Hs.436061 GO transcription factor activity [Amigo] transcription factor activity GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding positive regulation of interleukin-12 biosynthetic process [Amigo] positive regulation of GO interleukin-12 biosynthetic process GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter PubGene IRF1 TreeFam IRF1 CTD 3659 [Comparative ToxicoGenomics Database] Other databases Probes Probe IRF1 Related clones (RZPD - Berlin)
Atlas Genet Cytogenet Oncol Haematol 2008; 5 731 PubMed PubMed 109 Pubmed reference(s) in Entrez Bibliography Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN- beta gene regulatory elements. Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y, Miyata T, Taniguchi T Cell. 1988 ; 54 (6) : 903-913. PMID 3409321
Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Harada H, Willison K, Sakakibara J, Miyamoto M, Fujita T, Taniguchi T Cell. 1990 ; 63 (2) : 303-312. PMID 2208287
Human interferon regulatory factor 1: intron-exon organization. Cha Y, Sims SH, Romine MF, Kaufmann M, Deisseroth AB DNA and cell biology. 1992 ; 11 (8) : 605-611. PMID 1382447
Allelic loss of IRF1 in myelodysplasia and acute myeloid leukemia: retention of IRF1 on the 5q- chromosome in some patients with the 5q- syndrome. Boultwood J, Fidler C, Lewis S, MacCarthy A, Sheridan H, Kelly S, Oscier D, Buckle VJ, Wainscoat JS Blood. 1993 ; 82 (9) : 2611-2616. PMID 8219215
Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Willman CL, Sever CE, Pallavicini MG, Harada H, Tanaka N, Slovak ML, Yamamoto H, Harada K, Meeker TC, List AF Science (New York, N.Y.). 1993 ; 259 (5097) : 968-971. PMID 8438156
Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia/leukemia; a possible mechanism of tumor suppressor inactivation. Harada H, Kondo T, Ogawa S, Tamura T, Kitagawa M, Tanaka N, Lamphier MS, Hirai H, Taniguchi T Oncogene. 1994 ; 9 (11) : 3313-3320. PMID 7936656
Common deleted region on the long arm of chromosome 5 in esophageal carcinoma. Ogasawara S, Tamura G, Maesawa C, Suzuki Y, Ishida K, Satoh N, Uesugi N, Saito K, Satodate R Gastroenterology. 1996 ; 110 (1) : 52-57. PMID 8536888
Identification and characterization of nucleophosmin/B23/numatrin which binds the anti- oncogenic transcription factor IRF-1 and manifests oncogenic activity. Kondo T, Minamino N, Nagamura-Inoue T, Matsumoto M, Taniguchi T, Tanaka N Oncogene. 1997 ; 15 (11) : 1275-1281. PMID 9315094
Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer. Nozawa H, Oda E, Ueda S, Tamura G, Maesawa C, Muto T, Taniguchi T, Tanaka N International journal of cancer. Journal international du cancer. 1998 ; 77 (4) : 522-527. PMID 9679752
Distinct regions of frequent loss of heterozygosity of chromosome 5p and 5q in human esophageal cancer. Peralta RC, Casson AG, Wang RN, Keshavjee S, Redston M, Bapat B International journal of cancer. Journal international du cancer. 1998 ; 78 (5) : 600-605.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 732 PMID 9808529
Cytotoxic response of ovarian cancer cell lines to IFN-gamma is associated with sustained induction of IRF-1 and p21 mRNA. Burke F, Smith PD, Crompton MR, Upton C, Balkwill FR British journal of cancer. 1999 ; 80 (8) : 1236-1244. PMID 10376977
Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31). Green WB, Slovak ML, Chen IM, Pallavicini M, Hecht JL, Willman CL Leukemia. 1999 ; 13 (12) : 1960-1971. PMID 10602416
Interferon regulatory factor-1 and -2 expression in human melanoma specimens. Lowney JK, Boucher LD, Swanson PE, Doherty GM Annals of surgical oncology. 1999 ; 6 (6) : 604-608. PMID 10493631
Alterations in IRF1/IRF2 expression in acute myelogenous leukemia. Preisler HD, Perambakam S, Li B, Hsu WT, Venugopal P, Creech S, Sivaraman S, Tanaka N American journal of hematology. 2001 ; 68 (1) : 23-31. PMID 11559933
Interferon regulatory factor-1 mediates interferon-gamma-induced apoptosis in ovarian carcinoma cells. Kim EJ, Lee JM, Namkoong SE, Um SJ, Park JS Journal of cellular biochemistry. 2002 ; 85 (2) : 369-380. PMID 11948692
Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin. Pizzoferrato E, Liu Y, Gambotto A, Armstrong MJ, Stang MT, Gooding WE, Alber SM, Shand SH, Watkins SC, Storkus WJ, Yim JH Cancer research. 2004 ; 64 (22) : 8381-8388. PMID 15548708
The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1. Ruiz-Ruiz C, Ruiz de Almodovar C, Rodriguez A, Ortiz-Ferron G, Redondo JM, Lopez-Rivas A The Journal of biological chemistry. 2004 ; 279 (19) : 19712-19720. PMID 14993214
Acute myeloid leukemia. Stone RM, O'Donnell MR, Sekeres MA Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2004 : 98-117. PMID 15561679
Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis. Bouker KB, Skaar TC, Riggins RB, Harburger DS, Fernandez DR, Zwart A, Wang A, Clarke R Carcinogenesis. 2005 ; 26 (9) : 1527-1535. PMID 15878912
Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays. Connett JM, Badri L, Giordano TJ, Connett WC, Doherty GM Journal of interferon & cytokine research. 2005 ; 25 (10) : 587-594. PMID 16241857
Atlas Genet Cytogenet Oncol Haematol 2008; 5 733 IFN-gamma/IRF-1-induced p27kip1 down-regulates telomerase activity and human telomerase reverse transcriptase expression in human cervical cancer. Lee SH, Kim JW, Oh SH, Kim YJ, Rho SB, Park K, Park KL, Lee JH FEBS letters. 2005 ; 579 (5) : 1027-1033. PMID 15710386
N-ras-induced growth suppression of myeloid cells is mediated by IRF-1. Passioura T, Dolnikov A, Shen S, Symonds G Cancer research. 2005 ; 65 (3) : 797-804. PMID 15705876
A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells. Passioura T, Shen S, Symonds G, Dolnikov A Oncogene. 2005 ; 24 (49) : 7327-7336. PMID 16007130
The role of IRF1 and IRF2 transcription factors in leukaemogenesis. Choo A, Palladinetti P, Passioura T, Shen S, Lock R, Symonds G, Dolnikov A Current gene therapy. 2006 ; 6 (5) : 543-550. PMID 17073600
Alternative splicing variants of IRF-1 lacking exons 7, 8, and 9 in cervical cancer. Lee EJ, Jo M, Park J, Zhang W, Lee JH Biochemical and biophysical research communications. 2006 ; 347 (4) : 882-888. PMID 16857162
Classification and scoring systems in myelodysplastic syndromes: a retrospective analysis of 311 patients. Navarro I, Ruiz MA, Cabello A, Collado R, Ferrer R, Hueso J, Martinez J, Miguel A, Orero MT, Perez P, Nolasco A, Carbonell F Leukemia research. 2006 ; 30 (8) : 971-977. PMID 16423393
Ad-IRF-1 induces apoptosis in esophageal adenocarcinoma. Watson GA, Queiroz de Oliveira PE, Stang MT, Armstrong MJ, Gooding WE, Kuan SF, Yim JH, Hughes SJ Neoplasia. 2006 ; 8 (1) : 31-37. PMID 16533423
The A4396G polymorphism in interferon regulatory factor 1 is frequently expressed in breast cancer cell lines. Bouker KB, Skaar TC, Harburger DS, Riggins RB, Fernandez DR, Zwart A, Clarke R Cancer genetics and cytogenetics. 2007 ; 175 (1) : 61-64. PMID 17498560
Interferon-alpha induces TRAIL expression and cell death via an IRF-1-dependent mechanism in human bladder cancer cells. Papageorgiou A, Dinney CP, McConkey DJ Cancer biology & therapy. 2007 ; 6 (6) : 872-879. PMID 17617740
Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts. Peterson LF, Boyapati A, Ahn EY, Biggs JR, Okumura AJ, Lo MC, Yan M, Zhang DE Blood. 2007 ; 110 (3) : 799-805. PMID 17412887
Recent advances in myelodysplastic syndromes. Shadduck RK, Latsko JM, Rossetti JM, Haq B, Abdulhaq H
Atlas Genet Cytogenet Oncol Haematol 2008; 5 734 Experimental hematology. 2007 ; 35 (4 Suppl 1) : 137-143. PMID 17379099
Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas- associated death domain pathway in breast cancer cells. Stang MT, Armstrong MJ, Watson GA, Sung KY, Liu Y, Ren B, Yim JH Oncogene. 2007 ; 26 (44) : 6420-6430. PMID 17452973
Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Wang Y, Liu DP, Chen PP, Koeffler HP, Tong XJ, Xie D Cancer research. 2007 ; 67 (6) : 2535-2543. PMID 17363571
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Contributor(s) Written 01-2008 Patricia Palladinetti, Geoff Symonds, Alla Dolnikov Children's Cancer Institute Australia for Medical Research, PO Box 81 (High St), Randwick, NSW 2031, Australia (PP, GS) ; Sydney Cord and Marrow Transplant Facility, Sydney Children's Hospital, High Street, Randwick NSW 2031, Australia (AD) Citation This paper should be referenced as such : Palladinetti P, Symonds G, Dolnikov A . IRF1 (interferon regulatory factor 1). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/IRF1ID40990ch5q23.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 735 Atlas of Genetics and Cytogenetics in Oncology and Haematology
EGLN1 (egl nine homolog 1 (C. elegans))
Identity Other names C1orf12 DKFZp761F179 ECYT3 HIFPH2 HPH-2 PHD2 SM-20 SM20 ZMYND6 HGNC EGLN1 Location 1q42.2 Location_base_pair Starts at 229568054 and ends at 229627413 bp from pter ( according to hg18- Mar_2006). DNA/RNA Description EGLN1 gene is located on chromosome 1, location 229568054-229627413. Gene spans 61293 bases and has 5 exons. Transcription PHD2 expression is strongly induced in hypoxia by the HIF-1α transcription factor. Primary transcript length is 5936 bases. On mRNA level two splice variants have been proposed, lacking exons 3 or 4, but these have not been confirmed on protein level. Protein Description PHD2 protein is 426 amino acids long and approximately 46 kDa. It has a zf-MYND domain (aa 21-58) and a 2-OG-FeII-oxygenase domain (aa205-391). Expression Ubiquitous. Localisation Predominantly cytoplasmic. Function PHD2 is a member of the 2-oxoglutarate-dependent, non-haem iron binding dioxygenases. PHD2 post-translationally regulates the levels of hypoxia-inducible factor-α (HIF-α) subunits in normoxic conditions by hydroxylating them in an oxygen-dependant manner on specific proline residues. This enables recognition of HIF by the VHL ubiquitin ligase complex and subsequent degradation of HIF by the proteasome. In hypoxic conditions the hydroxylation is significantly decreased, and the HIF-α subunits are stabilized. PHD2 is considered the main HIF-1α regulator in normoxic and mildly hypoxic conditions. Homology EGLN1 has two paralogs: EGLN2 and EGLN3 Homologs have been found in all multicellular organisms investigated. Mutations Note Homozygous deletion confers embryonic lethality in mouse. Germinal Heterozygous mutations have been associated with familial erythrocytosis. Currently three point mutations: G1112A ->Arg371His, C950G -> Pro317Arg, C1129T-> Gln377X, one deletion: 606delG -> frameshift, and one insertion: 840_841insA -> frameshift have been reported. Implicated in Entity Familial erythrocytosis (ECYT3) Note ECYT3 is characterized by increased serum hemoglobin and hematocrit, but with normal serum erythropoietin levels. Disease Characterized EGLN1 mutations result in the loss of catalytic function and thereby aberrant erythropoietin expression. Entity Head and neck squamous cell carcinoma
Atlas Genet Cytogenet Oncol Haematol 2008; 5 736 Note Increased expression levels and nuclear translocation have been associated with the aggressiveness of the carcinoma. External links Nomenclature HGNC EGLN1 1232 Entrez_Gene EGLN1 54583 egl nine homolog 1 (C. elegans) Cards Atlas EGLN1ID44140ch1q42 GeneCards EGLN1 Ensembl EGLN1 [Search_View] ENSG00000135766 [Gene_View] Genatlas EGLN1 GeneLynx EGLN1 eGenome EGLN1 euGene 54583 Genomic and cartography EGLN1 - 1q42.2 chr1:229568054-229627413 - 1q42.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl EGLN1 - 1q42.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM]
HomoloGene EGLN1 Gene and transcription Genbank AF229245 [ ENTREZ ] Genbank AF277174 [ ENTREZ ] Genbank AF277176 [ ENTREZ ] Genbank AF334711 [ ENTREZ ] Genbank AJ227859 [ ENTREZ ] RefSeq NM_022051 [ SRS ] NM_022051 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq AC_000133 [ SRS ] AC_000133 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004559 [ SRS ] NT_004559 [ ENTREZ ] RefSeq NW_001838549 [ SRS ] NW_001838549 [ ENTREZ ] RefSeq NW_927128 [ SRS ] NW_927128 [ ENTREZ ] AceView EGLN1 AceView - NCBI Unigene Hs.444450 [ SRS ] Hs.444450 [ NCBI ] HS444450 [ spliceNest ] Fast-db 17924 (alternative variants) Protein : pattern, domain, 3D structure Q9GZT9 [ SRS] Q9GZT9 [ EXPASY ] Q9GZT9 [ INTERPRO ] Q9GZT9 SwissProt [ UNIPROT ] Prosite PS01360 ZF_MYND_1 [ SRS ] PS01360 ZF_MYND_1 [ Expasy ] Prosite PS50865 ZF_MYND_2 [ SRS ] PS50865 ZF_MYND_2 [ Expasy ] Interpro IPR005123 2OG-FeII_Oase [ SRS ] IPR005123 2OG-FeII_Oase [ EBI ] Interpro IPR006620 Pro_4_hyd_alph [ SRS ] IPR006620 Pro_4_hyd_alph [ EBI ] Interpro IPR002893 Znf_MYND [ SRS ] IPR002893 Znf_MYND [ EBI ] CluSTr Q9GZT9 PF03171 2OG-FeII_Oxy [ SRS ] PF03171 2OG-FeII_Oxy [ Sanger ] pfam03171 Pfam [ NCBI-CDD ] Pfam PF01753 zf-MYND [ SRS ] PF01753 zf-MYND [ Sanger ] pfam01753 [ NCBI-CDD ] Smart SM00702 P4Hc [EMBL] Blocks Q9GZT9 PDB 2G19 [ SRS ] 2G19 [ PdbSum ], 2G19 [ IMB ] 2G19 [ RSDB ] PDB 2G1M [ SRS ] 2G1M [ PdbSum ], 2G1M [ IMB ] 2G1M [ RSDB ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 737 PDB 2HBT [ SRS ] 2HBT [ PdbSum ], 2HBT [ IMB ] 2HBT [ RSDB ] PDB 2HBU [ SRS ] 2HBU [ PdbSum ], 2HBU [ IMB ] 2HBU [ RSDB ] HPRD 06971 Protein Interaction databases DIP Q9GZT9 IntAct Q9GZT9 Polymorphism : SNP, mutations, diseases OMIM 606425;609820 [ map ] GENECLINICS 606425;609820 SNP EGLN1 [dbSNP-NCBI] SNP NM_022051 [SNP-NCI] SNP EGLN1 [GeneSNPs - Utah] EGLN1] [HGBASE - SRS] HAPMAP EGLN1 [HAPMAP] COSMIC EGLN1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD EGLN1 General knowledge Family Browser EGLN1 [UCSC Family Browser] SOURCE NM_022051 SMD Hs.444450 SAGE Hs.444450 1.14.11.- [ Enzyme-Expasy ] 1.14.11.- [ Enzyme-SRS ] 1.14.11.- [ IntEnz- Enzyme EBI ] 1.14.11.- [ BRENDA ] 1.14.11.- [ KEGG ] 1.14.11.- [ WIT ] GO response to hypoxia [Amigo] response to hypoxia GO embryonic placenta development [Amigo] embryonic placenta development GO iron ion binding [Amigo] iron ion binding GO protein binding [Amigo] protein binding GO cytosol [Amigo] cytosol GO heart development [Amigo] heart development GO zinc ion binding [Amigo] zinc ion binding GO oxidoreductase activity [Amigo] oxidoreductase activity oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen [Amigo] oxidoreductase activity, acting GO on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen GO protein metabolic process [Amigo] protein metabolic process GO L-ascorbic acid binding [Amigo] L-ascorbic acid binding GO peptidyl-proline dioxygenase activity [Amigo] peptidyl-proline dioxygenase activity GO oxygen homeostasis [Amigo] oxygen homeostasis negative regulation of transcription factor activity [Amigo] negative regulation of GO transcription factor activity GO metal ion binding [Amigo] metal ion binding GO oxidation reduction [Amigo] oxidation reduction KEGG Diterpenoid biosynthesis PubGene EGLN1 TreeFam EGLN1 CTD 54583 [Comparative ToxicoGenomics Database] Other databases Probes Probe EGLN1 Related clones (RZPD - Berlin)
PubMed PubMed 34 Pubmed reference(s) in Entrez Bibliography Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12,
Atlas Genet Cytogenet Oncol Haematol 2008; 5 738 and identification of a novel related gene, SCAND2. Dupuy D, Aubert I, Duperat VG, Petit J, Taine L, Stef M, Bloch B, Arveiler B Genomics. 2000 ; 69 (3) : 348-354. PMID 11056053
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ Cell. 2001 ; 107 (1) : 43-54. PMID 11595184
HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr Science (New York, N.Y.). 2001 ; 292 (5516) : 464-468. PMID 11292862
Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim Av, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ Science (New York, N.Y.). 2001 ; 292 (5516) : 468-472. PMID 11292861
Characterization and comparative analysis of the EGLN gene family. Taylor MS Gene. 2001 ; 275 (1) : 125-132. PMID 11574160
HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J The EMBO journal. 2003 ; 22 (16) : 4082-4090. PMID 12912907
Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J The Journal of biological chemistry. 2003 ; 278 (33) : 30772-30780. PMID 12788921
Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J Journal of cell science. 2003 ; 116 (Pt 7) : 1319-1326. PMID 12615973
Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM The Journal of biological chemistry. 2004 ; 279 (37) : 38458-38465. PMID 15247232
Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. Metzen E, Stiehl DP, Doege K, Marxsen JH, Hellwig-Burgel T, Jelkmann W The Biochemical journal. 2005 ; 387 (Pt 3) : 711-717. PMID 15563275
Atlas Genet Cytogenet Oncol Haematol 2008; 5 739 Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Jokilehto T, Rantanen K, Luukkaa M, Heikkinen P, Grenman R, Minn H, Kronqvist P, Jaakkola PM Clinical cancer research. 2006 ; 12 (4) : 1080-1087. PMID 16489060
A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS Proc Natl Acad Sci U S A. 2006 ; 103 (3) : 654-659. PMID 16407130
Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH Molecular and cellular biology. 2006 ; 26 (22) : 8336-8346. PMID 16966370
Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Al-Sheikh M, Moradkhani K, Lopez M, Wajcman H, Prehu C Blood cells, molecules & diseases. 2008 ; 40 (2) : 160-165. PMID 17933562
A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS Blood. 2007 ; 110 (6) : 2193-2196. PMID 17579185
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Contributor(s) Written 01-2008 Terhi Jokilehto, Panu M Jaakkola Hypoxia group, Turku centre for Biotechnology, Tykistokatu 6, 20520 Turku, Finland Citation This paper should be referenced as such : Jokilehto T, Jaakkola PM . EGLN1 (egl nine homolog 1 (C. elegans)). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/EGLN1ID44140ch1q42.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 740 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CDC6 (cell division cycle 6 homolog (S. cerevisiae))
Identity Other names CDC18L cdc6 hCDC6 HsCDC18 HsCDC6 p62 HGNC CDC6 Location 17q21.3 Location_base_pair Starts at 35697672 and ends at 35712939 bp from pter ( according to hg18- Mar_2006). Local_order centrosome ---- CASC3-RAPGEFL1-WIPF2-CDC6-RARA-TOP2A DNA/RNA Description The gene starts at 35697672 bp from pter and ends at 35712939 bp from pter. Its size is 15267 bases and its orientation lie at the plus strand. The 5' promoter region contains putative sites for transcriptional control, including an initiator element, a CHR element, two main binding sites for E2F, a putative Sp1 site, and a CCAAT region. No consensus TATA box is evident. This resembles the organization of other genes encoding proteins associated with the G1/S transition. Transcription The gene has 12 exons. The five putative transcripts (see table below) encode the same product of 560aa. There are about 230 EST sequences. Accession N Transcript Notes ° length (bp) NM_001254 3053 RefSeq CR598029 1802 mRNA BC025232 2861 mRNA HSU77949 2653 mRNA AF022109 2021 mRNA Pseudogene there are no known pseudogenes Protein Description The CDC6 protein or p62 is composed of 560 amino acids with a molecular weight of 62720 Da. The central portion of the protein contains a conserved nucleotide binding/ATPase domain, which classifies it to a large superfamily of ATPases known as "ATPases associated with various cellular activities" (AAA) proteins and specifically to the AAA+ subfamily. The Walker-A motif GXXGXGK(T/S) (nucleotide binding) of the AAA+ domain spans aa 202-209, while the Walker-B motif D(D/E)XX (nucleotide hydrolysis) spans aa 284-287. The domain contains also a leucine zipper (aa 306-327), and a caspase dependent cleavage site DQL290DS. The N-terminal domain contains: three consensus phosphorylation sites at serine (S)54, S74 and S106, which are phosphorylated in vivo by CDK-related activity at the G1/S boundary; a putative conserved nuclear localization sequence ((S/T)PXK57R58(L/I)); two putative destruction boxes (D-box (aa 56-64) and KEN box (aa 81-83)), which target CDC6 for proteolysis by APCCDH1 during early G1 or G0, but not S, G2 or M; and a cyclin binding domain mapped to a Cy-motif (aa 93-100) that is similar to the cyclin binding regions in p21/WAF1/SDI1 and E2F-1. The C-terminal domain contains: a putative classical nuclear export signal (NES) between residues 462-488 (ILVCSLMLLIRQLKI), a caspase dependent cleavage site SEV442DG, and a conserved winged-helix domain (WHD) with unknown function; it possibly mediates protein-protein interactions or a direct interaction with the DNA helix.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 741 Expression It is expressed in all proliferating cells but not in quiescent or differentiated cells. Localisation Even though it was believed at first that p62CDC6 was nuclear during G1 and cytoplasmic during S and G2, lately it has been found that there is an endogenous fraction of the protein that remains chromatin-bound throughout the cell cycle. Function - ATP binding - Chromatin binding - Nucleoside-triphosphatase activity - Nucleotide binding - Protein binding - Loading factor for MCM2-7: Cdc6/Cdc18 is recruited to replication origins by ORC. Once localized at replication origins, Cdc6 helps to recruit and load MCM factors onto DNA in a process that requires CDC6-mediated ATP hydrolysis. After loading of MCM2-7 on DNA, CDC6 is not necessary for origin firing and dissociates from the complex, through a phosphorylation-dependent procedure. It seems though that CDC6 has additional roles related to S/M checkpoint control. Accumulating evidence suggests that CDC6 is required for proper control of mitotic entry. Deregulation of CDC6 results in mitotic block, aberrant mitotic progression, or apoptosis. Homology ORC1 Mutations Note No known mutations Implicated in Entity Carcinogenesis Note Because of its key role in DNA replication, deregulation of CDC6 could lead to genomic instability fueling the risk for neoplastic transformation. Indeed, CDC6 upregulation has been observed in many cancerous lesions, including brain tumors, non-small cell lung carcinomas, mantle cell lymphomas, and various cervical neoplasias. Interestingly, in aggressive prostate cancer, CDC6 is downregulated. CDC6 encompasses certain oncogenic characteristics that manifest themselves when CDC6 expression is deregulated. For example, CDC6 induces DNA replication in quiescent cells, while in certain occasions overexpression of CDC6 leads to DNA overreplication in tumour cells. While cells have mechanisms to prevent aberrant DNA replication, deregulation of CDC6, or /and its partner in pre-RCs, CDT1 may lead to abrogation of the antitumor barriers of senescence and apoptosis. In addition their stable expression in premalignant papilloma cells lead to transformation of these cells, which upon injection into nude mice produce tumors, an activity that clearly portrays the oncogenic potential of CDC6 deregulation. Moreover, deregulation of CDC6 may lead to inactivation of the INK4/ARF locus through recruitment of histone deacetylases HDAC1 and HDAC2 and heterochromatinization of the INK4/ARF locus. This locus encodes the tumour suppressor genes p16INK4a, p15INK4b, and ARF, and inactivation of this locus is closely related to cancer. External links Nomenclature HGNC CDC6 1744 Entrez_Gene CDC6 990 cell division cycle 6 homolog (S. cerevisiae) Cards Atlas CDC6ID40014ch17q21 GeneCards CDC6 Ensembl CDC6 [Search_View] ENSG00000094804 [Gene_View] Genatlas CDC6 GeneLynx CDC6 eGenome CDC6 euGene 990 Genomic and cartography CDC6 - 17q21.3 chr17:35697672-35712939 + 17q21.3 [Description] (hg18- GoldenPath Mar_2006)
Atlas Genet Cytogenet Oncol Haematol 2008; 5 742 Ensembl CDC6 - 17q21.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CDC6 Gene and transcription Genbank AA210818 [ ENTREZ ] Genbank AF022109 [ ENTREZ ] Genbank AK313620 [ ENTREZ ] Genbank BC025232 [ ENTREZ ] Genbank BE296640 [ ENTREZ ] RefSeq NM_001254 [ SRS ] NM_001254 [ 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 CDC6 AceView - NCBI Unigene Hs.405958 [ SRS ] Hs.405958 [ NCBI ] HS405958 [ spliceNest ] Fast-db 9812 (alternative variants) Protein : pattern, domain, 3D structure Q99741 [ SRS] Q99741 [ EXPASY ] Q99741 [ INTERPRO ] Q99741 SwissProt [ UNIPROT ] Interpro IPR003593 AAA+_ATPase_core [ SRS ] IPR003593 AAA+_ATPase_core [ EBI ] Interpro IPR003959 AAA_ATPase_core [ SRS ] IPR003959 AAA_ATPase_core [ EBI ] Interpro IPR016314 Cdc6 [ SRS ] IPR016314 Cdc6 [ EBI ] Interpro IPR015163 Cdc6_C [ SRS ] IPR015163 Cdc6_C [ EBI ] CluSTr Q99741 Pfam PF00004 AAA [ SRS ] PF00004 AAA [ Sanger ] pfam00004 [ NCBI-CDD ] Pfam PF09079 Cdc6_C [ SRS ] PF09079 Cdc6_C [ Sanger ] pfam09079 [ NCBI-CDD ] Smart SM00382 AAA [EMBL] Blocks Q99741 PDB 2CCH [ SRS ] 2CCH [ PdbSum ], 2CCH [ IMB ] 2CCH [ RSDB ] PDB 2CCI [ SRS ] 2CCI [ PdbSum ], 2CCI [ IMB ] 2CCI [ RSDB ] HPRD 04022 Protein Interaction databases DIP Q99741 IntAct Q99741 Polymorphism : SNP, mutations, diseases OMIM 602627 [ map ] GENECLINICS 602627 SNP CDC6 [dbSNP-NCBI] SNP NM_001254 [SNP-NCI] SNP CDC6 [GeneSNPs - Utah] CDC6] [HGBASE - SRS] HAPMAP CDC6 [HAPMAP] COSMIC CDC6 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD CDC6 General knowledge Family Browser CDC6 [UCSC Family Browser] SOURCE NM_001254 SMD Hs.405958 SAGE Hs.405958 GO DNA replication checkpoint [Amigo] DNA replication checkpoint
Atlas Genet Cytogenet Oncol Haematol 2008; 5 743 regulation of cyclin-dependent protein kinase activity [Amigo] regulation of cyclin- GO dependent protein kinase activity GO nucleotide binding [Amigo] nucleotide binding GO chromatin binding [Amigo] chromatin binding GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO nucleoplasm [Amigo] nucleoplasm GO cytoplasm [Amigo] cytoplasm GO spindle [Amigo] spindle GO cytosol [Amigo] cytosol GO cell cycle [Amigo] cell cycle GO mitosis [Amigo] mitosis traversing start control point of mitotic cell cycle [Amigo] traversing start control point GO of mitotic cell cycle GO negative regulation of DNA replication [Amigo] negative regulation of DNA replication GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO nucleoside-triphosphatase activity [Amigo] nucleoside-triphosphatase activity GO cell division [Amigo] cell division BIOCARTA CDK Regulation of DNA Replication [Genes] KEGG Cell cycle PubGene CDC6 TreeFam CDC6 CTD 990 [Comparative ToxicoGenomics Database] Other databases Probes Probe CDC6 Related clones (RZPD - Berlin) PubMed PubMed 56 Pubmed reference(s) in Entrez Bibliography A human protein related to yeast Cdc6p. Williams RS, Shohet RV, Stillman B Proc Natl Acad Sci U S A. 1997 ; 94 (1) : 142-147. PMID 8990175
Cell cycle-regulated expression of mammalian CDC6 is dependent on E2F. Hateboer G, Wobst A, Petersen BO, Le Cam L, Vigo E, Sardet C, Helin K Molecular and cellular biology. 1998 ; 18 (11) : 6679-6697. PMID 9774682
Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F. Ohtani K, Tsujimoto A, Ikeda M, Nakamura M Oncogene. 1998 ; 17 (14) : 1777-1785. PMID 9778043
Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A Molecular and cellular biology. 1998 ; 18 (5) : 2758-2767. PMID 9566895
Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS Proc Natl Acad Sci U S A. 1998 ; 95 (7) : 3603-3608. PMID 9520412
Atlas Genet Cytogenet Oncol Haematol 2008; 5 744 Cell cycle regulation of human CDC6 protein. Intracellular localization, interaction with the human mcm complex, and CDC2 kinase-mediated hyperphosphorylation. Fujita M, Yamada C, Goto H, Yokoyama N, Kuzushima K, Inagaki M, Tsurumi T The Journal of biological chemistry. 1999 ; 274 (36) : 25927-25932. PMID 10464337
The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells. Herbig U, Marlar CA, Fanning E Molecular biology of the cell. 1999 ; 10 (8) : 2631-2645. PMID 10436018
Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6. Jiang W, Wells NJ, Hunter T Proc Natl Acad Sci U S A. 1999 ; 96 (11) : 6193-6198. PMID 10339564
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. Petersen BO, Lukas J, Sorensen CS, Bartek J, Helin K The EMBO journal. 1999 ; 18 (2) : 396-410. PMID 9889196
Identification of the sequence responsible for the nuclear localization of human Cdc6. Takei Y, Yamamoto K, Tsujimoto G FEBS letters. 1999 ; 447 (2-3) : 292-296. PMID 10214964
Chromatin-bound Cdc6 persists in S and G2 phases in human cells, while soluble Cdc6 is destroyed in a cyclin A-cdk2 dependent process. Coverley D, Pelizon C, Trewick S, Laskey RA Journal of cell science. 2000 ; 113 ( Pt 11) : 1929-1938. PMID 10806104
Mutation of cyclin/cdk phosphorylation sites in HsCdc6 disrupts a late step in initiation of DNA replication in human cells. Herbig U, Griffith JW, Fanning E Molecular biology of the cell. 2000 ; 11 (12) : 4117-4130. PMID 11102512
Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mendez J, Stillman B Molecular and cellular biology. 2000 ; 20 (22) : 8602-8612. PMID 11046155
Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC- CDH1. Petersen BO, Wagener C, Marinoni F, Kramer ER, Melixetian M, Lazzerini Denchi E, Gieffers C, Matteucci C, Peters JM, Helin K Genes & development. 2000 ; 14 (18) : 2330-2343. PMID 10995389
Multiple mechanisms regulate subcellular localization of human CDC6. Delmolino LM, Saha P, Dutta A The Journal of biological chemistry. 2001 ; 276 (29) : 26947-26954. PMID 11346650
Cdc6 expression as a marker of proliferative activity in brain tumors. Ohta S, Koide M, Tokuyama T, Yokota N, Nishizawa S, Namba H Oncology reports. 2001 ; 8 (5) : 1063-1066.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 745 PMID 11496317
Synthesis and turn-over of the replicative Cdc6 protein during the HeLa cell cycle. Biermann E, Baack M, Kreitz S, Knippers R European journal of biochemistry / FEBS. 2002 ; 269 (3) : 1040-1046. PMID 11846807
Targeted destruction of DNA replication protein Cdc6 by cell death pathways in mammals and yeast. Blanchard F, Rusiniak ME, Sharma K, Sun X, Todorov I, Castellano MM, Gutierrez C, Baumann H, Burhans WC Molecular biology of the cell. 2002 ; 13 (5) : 1536-1549. PMID 12006651
Immunohistochemical localization of cdc6 in squamous and glandular neoplasia of the uterine cervix. Bonds L, Baker P, Gup C, Shroyer KR Archives of pathology & laboratory medicine. 2002 ; 126 (10) : 1164-1168. PMID 12296751
Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. Cook JG, Park CH, Burke TW, Leone G, DeGregori J, Engel A, Nevins JR Proc Natl Acad Sci U S A. 2002 ; 99 (3) : 1347-1352. PMID 11805305
Nuclear organization of DNA replication initiation proteins in mammalian cells. Fujita M, Ishimi Y, Nakamura H, Kiyono T, Tsurumi T The Journal of biological chemistry. 2002 ; 277 (12) : 10354-10361. PMID 11779870
Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer. Robles LD, Frost AR, Davila M, Hutson AD, Grizzle WE, Chakrabarti R The Journal of biological chemistry. 2002 ; 277 (28) : 25431-25438. PMID 12006585
Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism that implicates Chk1. Clay-Farrace L, Pelizon C, Santamaria D, Pines J, Laskey RA The EMBO journal. 2003 ; 22 (3) : 704-712. PMID 12554670
Down to the origin: Cdc6 protein and the competence to replicate. Pelizon C Trends in cell biology. 2003 ; 13 (3) : 110-113. PMID 12628342
A p53-dependent checkpoint pathway prevents rereplication. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, Wagle N, Hwang DS, Dutta A Molecular cell. 2003 ; 11 (4) : 997-1008. PMID 12718885
The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. Cook JG, Chasse DA, Nevins JR The Journal of biological chemistry. 2004 ; 279 (10) : 9625-9633. PMID 14672932
Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 746 Karakaidos P, Taraviras S, Vassiliou LV, Zacharatos P, Kastrinakis NG, Kougiou D, Kouloukoussa M, Nishitani H, Papavassiliou AG, Lygerou Z, Gorgoulis VG The American journal of pathology. 2004 ; 165 (4) : 1351-1365. PMID 15466399
CDKs give Cdc6 a license to drive into S phase. Ayad NG Cell. 2005 ; 122 (6) : 825-827. PMID 16179249 p53-Dependent regulation of Cdc6 protein stability controls cellular proliferation. Duursma A, Agami R Molecular and cellular biology. 2005 ; 25 (16) : 6937-6947. PMID 16055707
CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C- dependent proteolysis. Mailand N, Diffley JF Cell. 2005 ; 122 (6) : 915-926. PMID 16153703
Quantitation of CDC6 and MCM5 mRNA in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix. Murphy N, Ring M, Heffron CC, Martin CM, McGuinness E, Sheils O, O'Leary JJ Modern pathology. 2005 ; 18 (6) : 844-849. PMID 15696126
Recruitment of ORC or CDC6 to DNA is sufficient to create an artificial origin of replication in mammalian cells. Takeda DY, Shibata Y, Parvin JD, Dutta A Genes & development. 2005 ; 19 (23) : 2827-2836. PMID 16322558
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M Nature. 2006 ; 440 (7084) : 702-706. PMID 16572177
The functional role of Cdc6 in S-G2/M in mammalian cells. Lau E, Zhu C, Abraham RT, Jiang W EMBO reports. 2006 ; 7 (4) : 425-430. PMID 16439999
Unbalanced expression of licensing DNA replication factors occurs in a subset of mantle cell lymphomas with genomic instability. Pinyol M, Salaverria I, Bea S, Fernandez V, Colomo L, Campo E, Jares P International journal of cancer. 2006 ; 119 (12) : 2768-2774. PMID 17036332
Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. Yim H, Hwang IS, Choi JS, Chun KH, Jin YH, Ham YM, Lee KY, Lee SK The Journal of cell biology. 2006 ; 174 (1) : 77-88. PMID 16801388
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Orntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis
Atlas Genet Cytogenet Oncol Haematol 2008; 5 747 VG Nature. 2006 ; 444 (7119) : 633-637. PMID 17136093
CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Borlado LR, Mendez J Carcinogenesis. 2008 ; 29 (2) : 237-243. PMID 18048387
Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Hall JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q, Cook JG Molecular biology of the cell. 2007 ; 18 (9) : 3340-3350. PMID 17567951
Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG Cancer research. 2007 ; 67 (22) : 10899-10909. PMID 18006835
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Contributor(s) Written 01-2008 Michael Zachariadis, Vassilis G Gorgoulis University of Athens, Faculty of Medicine, Department of Anatomy (MZ) ; Department of Histology and Embryology, Molecular Carcinogenesis Group (VGG) Citation This paper should be referenced as such : Zachariadis M, Gorgoulis VG . CDC6 (cell division cycle 6 homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/CDC6ID40014ch17q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 748 Atlas of Genetics and Cytogenetics in Oncology and Haematology
AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease))
Identity Other names AIS DHTR HUMARA KD NR3C4 RP11-383C12.1 SBMA SMAX1 TFM HGNC AR Location Xq12 Location_base_pair Starts at 66680599 and ends at 66860844 bp from pter ( according to hg18- Mar_2006). Note (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease). (1 copy in males; 1 functional copy/cell in females due to X-inactivation). DNA/RNA Description 180 kb gene consisting of 8 exons. Transcription 4,314 bp mRNA, 2,762 bp open reading frame. Protein
Layout of the AR gene, mRNA and protein with indicated regulatory regions. Borrowed from Litvinov, et al. 2003, with permission. Description 919 amino acids (NCBI: P10275), MW = 99,187.57 daltons; -1.5 charge with an isoelectric pt = 6.3797; 10.6 kb AR transcript (NCBI: NM_000044 - partial sequence): 1.1kb 5' Untranslated Region (UTR) followed by the 2.7 kb Open Reading Frame (ORF) followed by the 6.8kb 3' UTR. AR: AR isoform 1 [Homo sapiens] NP_000035 920 aa AR45: AR isoform 2 [Homo sapiens] NP_001011645 388 aa
Atlas Genet Cytogenet Oncol Haematol 2008; 5 749 The AR coding sequence contains variable poly-aminoacid repeats in the amino- terminal domain: 1. poly-glutamine (CAG: Glu-Q): avg 22 repeats with normal polymorphic range from 8 to 35, shorter (<18) associated with increased AR transactivation and prostate cancer risk. CAG repeats in spinal and bulbar muscular atrophy patients range from 38 to 62. 2. poly-proline (Pro-P): avg 8. 3. poly-glycine (GGC: Gly-G): avg 23, with normal range from 10 to 31. Expression Embryonic tissue, prostate, testis, liver, eye, kidney, adrenal glands, thyroid, heart, breast/mammary gland, uterus, skeletal muscle, specific regions of the brain (CNS) including spinal and bulbar motor neurons. Localisation Cytoplasm and nucleus. Function AR is a member of the steroid hormone receptor family of ligand-dependent nuclear receptors. AR functions include gene expression via actions as a DNA-binding transcription factor, cell cycle/proliferation regulation, cell-to-cell signaling, and intracellular signal transduction, leading to the regulation of biological processes such as development, cellular proliferation, differentiation and apoptosis. Some of the main target genes transcriptionally regulated by AR include AR, prostate specific antigen (PSA/hKlk3), hKlk2, hKlk4, prostate specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), cell cycle regulator p27, vascular endothelial growth factor (VEGF), TMPRSS2, and Nkx3.1. Prostate organogenesis: The presence of AR is required in the mesodermal-derived embryonic urogenital sinus mesenchyme to trigger branching morphogenesis of endodermal-derived epithelial cells in the presence of androgens; subsequent AR expression in the developing epithelium drives secretory protein production. AR also plays an important role in the development of primary and secondary sexual characteristics, spermatogenesis, hormonal regulation of sexual drive, muscle growth, and male patterning of the brain. Recent identification of the gene fusion between the 5' end of the AR-regulated serine protease TMPRSS2 (21q22.2) and the 3' end of ETS family of transcription factors ETV1 (7p21.3) and ERG (21q22.3) in a large frequency of prostate cancer cases raises new questions regarding AR function in prostate cancer. The gene rearrangement is thought to result in AR-induced expression of the suspected ETV1 or ERG oncogenes. Homology zebrafish (Danio rerio), dog (Canis familiaris), African clawed frog (Xenopus laevis), chimpanzee (Pan troglodytes), mouse (Mus musculus), chicken (Gallus gallus), rat (Rattus norvegicus), rainbow trout (Oncorhynchus mykiss). No similarity-to-human data found for AR for: pig (Sus scrofa), cow (Bos taurus), fruit fly (Drosophila melanogaster), worm (Caenorhabditis elegans), baker's yeast (Saccharomyces cerevisiae), tropical clawed frog (Silurana tropicalis), African malaria mosquito (Anopheles gambiae), thale cress (Arabidopsis thaliana), green algae (Chlamydomonas reinhardtii), soybean (Glycine max), barley (Hordeum vulgare), tomato (Lycopersicon esculentum), rice blast fungus (Magnaporthe grisea), rice (Oryza sativa), sugarcane (Saccharum officinarum), loblolly pine (Pinus taeda), corn (Zea mays), wheat (Triticum aestivum), Alicante grape (Vitis vinifera), bread mold (Neurospora crassa), fission yeast (Schizosaccharomyces pombe), sea squirt (Ciona intestinalis), amoeba (Dictyostelium discoideum), A. gosspyii yeast (Ashbya gossypii), K. lactis yeast (Kluyveromyces lactis), medicago trunc (Medicago truncatula), malaria parasite (Plasmodium falciparum), schistosome parasite (Schistosoma mansoni), sorghum (Sorghum bicolor), toxoplasmosis (Toxoplasma gondii). Mutations Germinal Germ-line loss of function mutations in AR result in non-lethal loss of AR expression, a hallmark of androgen insensitivity syndrome. Individuals with AIS have a Y chromosome and functional testes, which produce high levels of testosterone; however, they lack male sex accessory organs, such as seminal vesicles and prostate, and are thus phenotypically female in both behavior and appearance. Somatic Various somatic AR mutations have been identified, some of which are associated with prostate cancer, including the T877A mutation in the prostate cancer LNCaP cell line, which permits AR activation by progestins, estrogen, adrenal androgens, and anti- androgen hydroxyflutamide; however, the overall frequency of AR mutations in early,
Atlas Genet Cytogenet Oncol Haematol 2008; 5 750 primary prostate cancer is <10%. Polymorphic CAG repeats in exon 1 encoding a polyglutamine tract of variable length give rise to AR peptides of varying lengths: Shorter length (fewer CAG repeats) is associated with increased prostate cancer risk; increased length (greater CAG repeats) is associated with spinal and bulbar muscular atrophy and androgen insensitivity syndrome. For a more complete list of identified mutations, please visit http://androgendb.mcgill.ca/map.gif. Implicated in Disease Androgenic alopecia, spinal and bulbar muscular dystrophy, androgen insensitivity syndrome due to AR mutations, benign prostatic hyperplasia, prostate adenocarcinoma Entity Prostate adenocarcinoma (PCa) Disease PCa is the most commonly diagnosed cancer in American men and the second leading cause of cancer-related deaths. PCa predominantly occurs in the peripheral zone of the human prostate, with roughly 5 to 10% of cases found in the central zone. Disease development involves the temporal and spatial loss of the basal epithelial compartment accompanied by increased proliferation and de-differentiation of the luminal (secretory) epithelial cells. PCa is a slow developing disease that is typically found in men greater than 40 years of age, with an increasing rate of occurrence with increasing age. Prognosis Serum PSA testing combined with digital-rectal exams (DRE) are used to screen for the presence of disease. Given a positive DRE exam, additional tests including needle core biopsies are taken to histologically assess disease stage and grade. Localized, prostate-restricted disease is theoretically curable with complete removal of the prostate (radical prostatectomy). Patients with extra-prostatic disease are treated with chemotherapy, hormone (androgen ablation) therapy, radiation, and/or antiandrogens; however, no curative treatments are available for non-organ confined, metastatic disease. Cytogenetics Various forms of aneuploidy. Abnormal Unknown. Protein Oncogenesis Alterations in AR function are associated with the development of PCa due to a transition from paracrine AR signaling, traditionally involving the supporting mesenchyme instructing the terminal differentiation of the luminal epithelial cells, to autocrine AR signaling in luminal epithelial cells that promotes cell proliferation. Roughly 10% of PCa patients harbor AR mutations, suggesting that the prevalence of AR mutations, clinically, is low. Mutations that increase the signaling promiscuity of AR, AR gene amplification, as well as alterations in proteins that regulate AR levels/function contribute to de-regulated AR signaling. Entity Benign Prostatic Hyperplasia (BPH) Disease Benign growth of the prostate, primarily occurring in the transitional zone of the prostate, results in urinary obstruction and lower urinary tract symptoms. AR function is associated with increased rates of epithelial cell proliferation, leading to increased size of the prostate gland. Originally thought of as benign prostatic hypertrophy, BPH has since been correctly characterized as a hyperplastic condition. Prognosis Patients with BPH are primarily treated with 2 types of agents to help reduce the size of the prostate, including Alpha-blockers: Flomax (tamsulosin), Uroxatral (alfuzosin), Hytrin (terazosin), Cardura (doxazosin); and 5-Alpha Reductase Inhibitors: Avodart (dutasteride), Proscar (finasteride). For symptoms unabated by medications, minimally invasive procedures: Transurethral microwave therapy (TUMT) and Transurethral needle ablation (TUNA) exist. More invasive surgeries: Transurethral resection of the prostate (TURP), Open prostatectomy (open surgery), Laser surgery, Transurethral incision of the prostate (TUIP) are available. Oncogenesis Occurring in the transitional zone of the prostate, it is currently believed that BPH does not lead to or initiate the development of PCa. Entity Spinal and bulbar muscular atrophy Note X-linked recessive form of spinal muscular atrophy Disease Spinal and bulbar muscular atrophy (SBMA, SMAX1), which is also known as Kennedy disease (KD), is caused by a trinucleotide CAG repeat expansion in exon 1 of the AR gene, resulting in decreased AR mRNA and protein levels. SBMA patients carry 38 to
Atlas Genet Cytogenet Oncol Haematol 2008; 5 751 62 CAG repeats; healthy individuals have 10 to 36. Prognosis SBMA is a neurodegenerative disease resulting in slow, progressive limb and bulbar muscle weakness, characterized by muscle atrophy due to neuron dysfunction. Also can cause gynecomastia. Current therapies include androgen deprivation therapy to curb the effects of pathologic AR signaling. Entity Androgen insensitivity syndrome (AIS) Note X-linked recessive disorder Disease Androgen insensitivity syndrome (AIS), Testicular feminization syndrome (TFM). Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male (2A + XY) karyotype. Caused by mutations in the gene for the androgen receptor. External links Nomenclature HGNC AR 644 AR 367 androgen receptor (dihydrotestosterone receptor; testicular feminization; Entrez_Gene spinal and bulbar muscular atrophy; Kennedy disease) Cards Atlas ARID685chXq12 GeneCards AR Ensembl AR [Search_View] ENSG00000169083 [Gene_View] Genatlas AR GeneLynx AR eGenome AR euGene 367 Genomic and cartography GoldenPath AR - Xq12 chrX:66680599-66860844 + Xq12 [Description] (hg18-Mar_2006) Ensembl AR - Xq12 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene AR Gene and transcription Genbank AF162704 [ ENTREZ ] Genbank AF321914 [ ENTREZ ] Genbank AF321915 [ ENTREZ ] Genbank AF321916 [ ENTREZ ] Genbank AF321917 [ ENTREZ ] RefSeq NM_000044 [ SRS ] NM_000044 [ ENTREZ ] RefSeq NM_001011645 [ SRS ] NM_001011645 [ ENTREZ ] RefSeq AC_000066 [ SRS ] AC_000066 [ ENTREZ ] RefSeq AC_000155 [ SRS ] AC_000155 [ ENTREZ ] RefSeq NC_000023 [ SRS ] NC_000023 [ ENTREZ ] RefSeq NT_011669 [ SRS ] NT_011669 [ ENTREZ ] RefSeq NW_001842373 [ SRS ] NW_001842373 [ ENTREZ ] RefSeq NW_927711 [ SRS ] NW_927711 [ ENTREZ ] AceView AR AceView - NCBI Unigene Hs.496240 [ SRS ] Hs.496240 [ NCBI ] HS496240 [ spliceNest ] Fast-db 9762 (alternative variants) Protein : pattern, domain, 3D structure P10275 [ SRS] P10275 [ EXPASY ] P10275 [ INTERPRO ] P10275 SwissProt [ UNIPROT ] PS00031 NUCLEAR_REC_DBD_1 [ SRS ] PS00031 NUCLEAR_REC_DBD_1 Prosite [ Expasy ] PS51030 NUCLEAR_REC_DBD_2 [ SRS ] PS51030 NUCLEAR_REC_DBD_2 Prosite [ Expasy ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 752 Interpro IPR001103 Andrgn_rcpt [ SRS ] IPR001103 Andrgn_rcpt [ EBI ] IPR008946 Nucl_hormone_rcpt_ligand-bd [ SRS ] IPR008946 Interpro Nucl_hormone_rcpt_ligand-bd [ EBI ] IPR000536 Nucl_hrmn_rcpt_lig-bd_core [ SRS ] IPR000536 Nucl_hrmn_rcpt_lig- Interpro bd_core [ EBI ] Interpro IPR001628 Znf_hrmn_rcpt [ SRS ] IPR001628 Znf_hrmn_rcpt [ EBI ] Interpro IPR013088 Znf_NHR/GATA [ SRS ] IPR013088 Znf_NHR/GATA [ EBI ] CluSTr P10275 PF02166 Androgen_recep [ SRS ] PF02166 Androgen_recep Pfam [ Sanger ] pfam02166 [ NCBI-CDD ] PF00104 Hormone_recep [ SRS ] PF00104 Hormone_recep [ Sanger ] pfam00104 Pfam [ NCBI-CDD ] Pfam PF00105 zf-C4 [ SRS ] PF00105 zf-C4 [ Sanger ] pfam00105 [ NCBI-CDD ] Smart SM00430 HOLI [EMBL] Smart SM00399 ZnF_C4 [EMBL] Prodom PD000035 Znf_C4steroid[INRA-Toulouse] P10275 ANDR_HUMAN [ Domain structure ] P10275 ANDR_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P10275 PDB 1E3G [ SRS ] 1E3G [ PdbSum ], 1E3G [ IMB ] 1E3G [ RSDB ] PDB 1GS4 [ SRS ] 1GS4 [ PdbSum ], 1GS4 [ IMB ] 1GS4 [ RSDB ] PDB 1T5Z [ SRS ] 1T5Z [ PdbSum ], 1T5Z [ IMB ] 1T5Z [ RSDB ] PDB 1T63 [ SRS ] 1T63 [ PdbSum ], 1T63 [ IMB ] 1T63 [ RSDB ] PDB 1T65 [ SRS ] 1T65 [ PdbSum ], 1T65 [ IMB ] 1T65 [ RSDB ] PDB 1XJ7 [ SRS ] 1XJ7 [ PdbSum ], 1XJ7 [ IMB ] 1XJ7 [ RSDB ] PDB 1XOW [ SRS ] 1XOW [ PdbSum ], 1XOW [ IMB ] 1XOW [ RSDB ] PDB 1XQ3 [ SRS ] 1XQ3 [ PdbSum ], 1XQ3 [ IMB ] 1XQ3 [ RSDB ] PDB 1Z95 [ SRS ] 1Z95 [ PdbSum ], 1Z95 [ IMB ] 1Z95 [ RSDB ] PDB 2AM9 [ SRS ] 2AM9 [ PdbSum ], 2AM9 [ IMB ] 2AM9 [ RSDB ] PDB 2AMA [ SRS ] 2AMA [ PdbSum ], 2AMA [ IMB ] 2AMA [ RSDB ] PDB 2AMB [ SRS ] 2AMB [ PdbSum ], 2AMB [ IMB ] 2AMB [ RSDB ] PDB 2AO6 [ SRS ] 2AO6 [ PdbSum ], 2AO6 [ IMB ] 2AO6 [ RSDB ] PDB 2AX6 [ SRS ] 2AX6 [ PdbSum ], 2AX6 [ IMB ] 2AX6 [ RSDB ] PDB 2AX7 [ SRS ] 2AX7 [ PdbSum ], 2AX7 [ IMB ] 2AX7 [ RSDB ] PDB 2AX8 [ SRS ] 2AX8 [ PdbSum ], 2AX8 [ IMB ] 2AX8 [ RSDB ] PDB 2AX9 [ SRS ] 2AX9 [ PdbSum ], 2AX9 [ IMB ] 2AX9 [ RSDB ] PDB 2AXA [ SRS ] 2AXA [ PdbSum ], 2AXA [ IMB ] 2AXA [ RSDB ] PDB 2HVC [ SRS ] 2HVC [ PdbSum ], 2HVC [ IMB ] 2HVC [ RSDB ] PDB 2OZ7 [ SRS ] 2OZ7 [ PdbSum ], 2OZ7 [ IMB ] 2OZ7 [ RSDB ] PDB 2PIO [ SRS ] 2PIO [ PdbSum ], 2PIO [ IMB ] 2PIO [ RSDB ] PDB 2PIP [ SRS ] 2PIP [ PdbSum ], 2PIP [ IMB ] 2PIP [ RSDB ] PDB 2PIQ [ SRS ] 2PIQ [ PdbSum ], 2PIQ [ IMB ] 2PIQ [ RSDB ] PDB 2PIR [ SRS ] 2PIR [ PdbSum ], 2PIR [ IMB ] 2PIR [ RSDB ] PDB 2PIT [ SRS ] 2PIT [ PdbSum ], 2PIT [ IMB ] 2PIT [ RSDB ] PDB 2PIU [ SRS ] 2PIU [ PdbSum ], 2PIU [ IMB ] 2PIU [ RSDB ] PDB 2PIV [ SRS ] 2PIV [ PdbSum ], 2PIV [ IMB ] 2PIV [ RSDB ] PDB 2PIW [ SRS ] 2PIW [ PdbSum ], 2PIW [ IMB ] 2PIW [ RSDB ] PDB 2PIX [ SRS ] 2PIX [ PdbSum ], 2PIX [ IMB ] 2PIX [ RSDB ] PDB 2PKL [ SRS ] 2PKL [ PdbSum ], 2PKL [ IMB ] 2PKL [ RSDB ] PDB 2PNU [ SRS ] 2PNU [ PdbSum ], 2PNU [ IMB ] 2PNU [ RSDB ] PDB 2Q7I [ SRS ] 2Q7I [ PdbSum ], 2Q7I [ IMB ] 2Q7I [ RSDB ] PDB 2Q7J [ SRS ] 2Q7J [ PdbSum ], 2Q7J [ IMB ] 2Q7J [ RSDB ] PDB 2Q7K [ SRS ] 2Q7K [ PdbSum ], 2Q7K [ IMB ] 2Q7K [ RSDB ] PDB 2Q7L [ SRS ] 2Q7L [ PdbSum ], 2Q7L [ IMB ] 2Q7L [ RSDB ]
Atlas Genet Cytogenet Oncol Haematol 2008; 5 753 PDB 2Z4J [ SRS ] 2Z4J [ PdbSum ], 2Z4J [ IMB ] 2Z4J [ RSDB ] HPRD 02437 Protein Interaction databases DIP P10275 IntAct P10275 Polymorphism : SNP, mutations, diseases OMIM 176807;300068;300633;313200;313700 [ map ] GENECLINICS 176807;300068;300633;313200;313700 SNP AR [dbSNP-NCBI] SNP NM_000044 [SNP-NCI] SNP NM_001011645 [SNP-NCI] SNP AR [GeneSNPs - Utah] AR] [HGBASE - SRS] HAPMAP AR [HAPMAP] COSMIC AR [Somatic mutation (COSMIC-CGP-Sanger)] HGMD AR General knowledge Family Browser AR [UCSC Family Browser] SOURCE NM_000044 SMD Hs.496240 SAGE Hs.496240 GO transcription factor activity [Amigo] transcription factor activity GO transcription factor activity [Amigo] transcription factor activity GO receptor activity [Amigo] receptor activity GO androgen receptor activity [Amigo] androgen receptor activity GO androgen receptor activity [Amigo] androgen receptor activity GO androgen receptor activity [Amigo] androgen receptor activity GO receptor binding [Amigo] receptor binding GO steroid binding [Amigo] steroid binding GO androgen binding [Amigo] androgen binding GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO transport [Amigo] transport GO signal transduction [Amigo] signal transduction GO cell-cell signaling [Amigo] cell-cell signaling GO sex differentiation [Amigo] sex differentiation GO zinc ion binding [Amigo] zinc ion binding GO cell proliferation [Amigo] cell proliferation GO cell growth [Amigo] cell growth GO prostate gland development [Amigo] prostate gland development GO metal ion binding [Amigo] metal ion binding GO protein dimerization activity [Amigo] protein dimerization activity PubGene AR TreeFam AR CTD 367 [Comparative ToxicoGenomics Database] Other databases Probes Probe AR Related clones (RZPD - Berlin) PubMed PubMed 499 Pubmed reference(s) in Entrez
Atlas Genet Cytogenet Oncol Haematol 2008; 5 754 Bibliography Physiology and pathophysiology of androgen action. Hiort O, Holterhus PM, Nitsche EM Bailliere's clinical endocrinology and metabolism. 1998 ; 12 (1) : 115-132. PMID 9890064
Molecular genetics of prostate cancer. Abate-Shen C, Shen MM Genes & development. 2000 ; 14 (19) : 2410-2434. PMID 11018010
Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer. Hyytinen ER, Haapala K, Thompson J, Lappalainen I, Roiha M, Rantala I, Helin HJ, Janne OA, Vihinen M, Palvimo JJ, Koivisto PA Laboratory investigation. 2002 ; 82 (11) : 1591-1598. PMID 12429819
Formation of the androgen receptor transcription complex. Shang Y, Myers M, Brown M Molecular cell. 2002 ; 9 (3) : 601-610. PMID 11931767
Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling? Litvinov IV, De Marzo AM, Isaacs JT The Journal of clinical endocrinology and metabolism. 2003 ; 88 (7) : 2972-2982. PMID 12843129
Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. Cunha GR, Ricke W, Thomson A, Marker PC, Risbridger G, Hayward SW, Wang YZ, Donjacour AA, Kurita T The Journal of steroid biochemistry and molecular biology. 2004 ; 92 (4) : 221-236. PMID 15663986
[Paradigm shift in clinical trials for neurodegenerative diseases] Katsuno M, Banno H, Suzuki K, Takeuchi Y, Sobue G Brain and nerve. 2007 ; 59 (4) : 367-374. PMID 17447523
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Contributor(s) Written 01-2008 Jason D'Antonio The Johns Hopkins School of Medicine, Laboratory of John T. Isaacs, PhD, Cancer Research, Bldg 1, 1650 Orleans St., Rm 1M40, Baltimore, MD 21231, USA Citation This paper should be referenced as such : D'Antonio J . AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/ARID685chXq12.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 755 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(4;17)(q12;q21)
Clinics and Pathology Disease Juvenile myelomonocytic leukemia Epidemiology So far 1 case known.
Morphology of JMML. Bone marrow smears were stained with May-Grünwald-Giemsa and shown at 1000- fold magnification. Bd=band, Bl=myelomonoblast Eb=erythroblast, Mc=myelocyte, Mo=monocyte, Pm=promyelocyte, Se=segmented neutrophylic granulocyte. Evolution At relapse: 45,XY,-4,t(4;17)(q12;q21), add(5)(p15),del(7)(q22), -9, -16, -17, +3mar[19]/ 46,XY[5] Prognosis Patient succumbed after two SCT. Cytogenetics
Partial GTG-banded karyotype of t(4;17)(q12;q21).
FISH analysis using probe LSI RARA DC resulting in a fusion signal on chromosome 17 band q21, with a split 5'RARA red signal on der(17) and a 3'RARA green signal on der(4) (left panel). FISH analysis narrowing the 4q12 breakpoint to the proximity of FIP1L1 by using 4q12 specific BAC probes RP11-120K16/RP11-317M1 with a fusion signal on chromosome 4 band q12, with RP11-120K16 hybridizing to der(4)(green) and RP11-317M1 hybridizing to der(17)(red) (right panel).
Atlas Genet Cytogenet Oncol Haematol 2008; 5 756 Variants In APL 17q21 RARA frequent rearrangement in: t(15;17)(q22;q21), fused with PML; in related translocations, rarely observed, involve a common breakpoint in 17q21, within RARA, fused with different partners, in: t(11;17)(q23;q21), fusion with PLZF, t(5;17) (q35;q12), fusion with NPM1, in t(11;17)(q13;q21), fusion with NUMA and in dup(17) (q12q21), fusion with Stat5b. In myeloproliferative disease CEL 4q12 FIP1L1 rearrangement: fusion to PDGFRA due to 800 Kb interstitial deletion. Genes involved and Proteins Gene Name FIP1L1 Location 4q12 Protein FIP1L1 is a subunit of the cleavage and polyadenylation specific factor (CPSF) complex that binds to U-rich elements via arginine-rich RNA binding motif and interacts with poly(A)polymerase (PAP). Gene Name RARA Location 17q21 Protein Wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation. Result of the chromosomal anomaly
Hybrid gene
Description In-frame fusion of exon 15 of FIP1L1 to exon 3 of RARA Transcript 5'FIP1L1-3'RARA and 5'RARA-3'FIP1L1
Fusion Protein
FIP1L1: Conserved FIP domain; RARA; DBD DNA binding domain, LBD ligand binding domain. Description The fusion mRNA would encode a 832 amino acids FIP1L1/RARA chimeric protein containing the 428 amino-terminal amino acids of FIP1L, including the FIP homology domain and 403 carboxyl-terminal amino acids of RARA, including the DNA and ligand binding domains, with replacement of FIP1L1 amino acid 429 (Valine) and RARA amino acid 60 (Threonine) into an Alanine. Oncogenesis All known chimeric RARA fusion proteins provide additional homodimerization motifs, promoting formation of chimeric homodimers and thereby removing requirement of RXR for RARA to bind DNA. The homodimerization ability of RARA fusion proteins is critical for leukemic transformation. Recently, it was shown in a murine system that retroviral transduced FIP1L1/PDGFRA mediated transformation in vitro and in vivo, is FIP1L1 independent and results from disruption of the autoinhibitory JM domain of PDGFRA. However, observations using retroviral transduced FIP1L1/PDGFRA and FIP1L1/PDGFRA with an N-terminal deletion of the FIP1L1 moiety showed differences with respect to cytokine-independent colony formation and activation of multiple signalling pathways in human primary hematopoietic precursor cells, indicating that FIP1L1 contributes to FIP1L1/PDGFRA resulting in a myeloproliferative phenotype. Therefore the function of the FIP1L1 moiety remains to be resolved. External links Other t(4;17)(q12;q21) Mitelman database (CGAP - NCBI) database Other t(4;17)(q12;q21) CancerChromosomes (NCBI)
Atlas Genet Cytogenet Oncol Haematol 2008; 5 757 database To be noted We report on reciprocal FIP1L1/RARA fusion transcripts resulting from a novel t(4;17) (q12;q21) in a case of juvenile myelomonocytic leukemia (JMML). JMML is a pediatric myeloproliferative disease (MPD), characterized by proliferation of granulocytic and monocytic lineages. 17q12 RARA was demonstrated to be involved in t(15;17) (q22;q21), resulting in a PML/RARA fusion transcript. PML/RARA t(15;17) is the hallmark of acute promyelocytic leukemia (APL), characterized by a differentiation arrest of abnormal promyelocytes. Variant rearrangements involving 17q21 RARA in APL and APL-like (APL-L) disease are PLZF/RARA t(11;17)(q23;q21), NPM1/RARA t(5;17)(q35;q21), NUMA/RARA t(11;17)(q13;q21), STAT5b/RARA der(17) and t(3;17) (p25;q21). 4q12 FIP1L1 is fused to PDGFRA as a result of a del(4)(q12q12) in myeproliferative disorder CEL. 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 Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent. Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J Proc Natl Acad Sci U S A. 2006 ; 103 (21) : 8078-8083. PMID 16690743
Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Buijs A, Bruin M Leukemia. 2007 ; 21 (5) : 1104-1108. PMID 17301809
Regulation of mTOR by phosphatidic acid? Foster DA Cancer research. 2007 ; 67 (1) : 1-4. PMID 17210675
Contributor(s) Written 09-2007 Arjan Buijs, Marrie Bruin Department of Medical Genetics, University Medical Center Utrecht. PO BOX 85090, 3508 AB Utrecht, The Netherlands Citation This paper should be referenced as such : Buijs A, Bruin M . t(4;17)(q12;q21). Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0417q12q21ID1470.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 758 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(2;13)(p16;q12)
Clinics and Pathology Disease Myeloproliferative disorder (atypical chronic myelogenous leukaemia (a-CML)) Note BCR-ABL negative myeloproliferative disease undistinguishable from CML otherwise Epidemiology only one case to date, a 32 year old female patient Prognosis Unknown; the patient received bone marrow transplantation, relpapsed 4 years later, and was in complete remission 6 months after treatment of the relapse. Genes involved and Proteins Gene Name SPTBN1 Protein Scaffold protein; forms homo)tetrameres; non-erythrocytic beta-spectrin; joins the actin cytoskeleton to the plasma membrane Gene Name FLT3 Location 13q12 Protein Class III receptor tyrosine kinase (RTK); promotes signalling through posphorylation of multiple proteins and activation of several downstream signalling pathways, such as the Ras/Raf/MAPK and PI3 kinase cascades. Result of the chromosomal anomaly
Hybrid gene
Description fusion of exon 3 of SPTBN1 and exon 13 of FLT3
Fusion Protein
Description Encodes a 66 kDa protein which retains the 2 coiled-coil domains of SPTBN1 and the tyrosine kinase domain of FLT3 Expression Expresssion of the fusion protein transformed Ba/F3 cells to growth factor Localisation independance Oncogenesis Constitutive phosphorylation External links Other t(2;13)(p16;q12) Mitelman database (CGAP - NCBI) database Other t(2;13)(p16;q12) 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 A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy. Grand FH, Iqbal S, Zhang L, Russell NH, Chase A, Cross NC Experimental hematology. 2007 ; 35 (11) : 1723-1727. PMID 17764812
Contributor(s) Written 09-2007 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France
Atlas Genet Cytogenet Oncol Haematol 2008; 5 759 Citation This paper should be referenced as such : Huret JL . t(2;13)(p16;q12). Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0213p16q12ID1212.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 760 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(2;11)(q37;q23) in AML
Identity
t(2;11)(q37;q23) by G-banding and FISH with dual-color, break-apart MLL probe; Cecília, Manuel R Teixeira (left); partial GTG-banded karyotype of t(2;11)(q37;23) and FISH analysis using probe LSI MLL DCBA demonstrating a 11q23 MLL rearrangement with a fusion signal on the normal chromosome 11, a split 5'MLL signal on der(11) and a 3'MLL signal on der(2); courtesy Arjan Buijs and Ellen van Binsbergen (right). Clinics and Pathology Disease Rare type of acute non lymphocytic leukemia (ANLL) and therapy-related ANLL. Phenotype / No specific AML FAB sub-type (two cases M4, one M2, one M5a and one NOS). cell stem origin Etiology Either de novo or therapy-related (prior cancer is variable: breast cancer, non-Hodgkin lymphoma and LLA). Epidemiology Five cases known in the literature; four adults and one child, sex ratio 2M/3F; (age range 14.4-76).
Prognosis Two cases showed poor survival, 9 and 17 months respectively, one case achieved remission after stem cell transplantation. The prognosis may be likely to be comparable with that of other entities with 11q23/MLL involvement, and worse in therapy related leukemias. Genes involved and Proteins
Atlas Genet Cytogenet Oncol Haematol 2008; 5 761 Gene Name SEPT2 Location 2q37 The SEPT2 gene has 14 exons. Dna / Rna SEPT2 has four types of transcripts with 3.6 kb, 3.5 kb, 3.4 kb and 3.3 kb encoding the same protein, as a result of alternative splicing. Protein SEPT2 belongs to an evolutionarily conserved family of genes that encode a P loop- based GTP-binding domain flanked by a polybasic domain and (usually) a coiled-coil region, and assemble into homo- and hetero-oligomers and filaments with key roles in cell division cytoskeletal dynamics and secretion. The SEPT2 gene codes for a protein with 361 amino acids and a molecular weight of 41.5 kDa. SEPT2 was identified as a gene expressed in early embryonic mouse brain and down- regulated during development. It is ubiquitously expressed in cell lines and tissues with the highest protein levels found in brain tissue. The SEPT2 protein, like other septin family members, is thought to be cytoplasmic. SEPT2 co-localises with actin filaments in interphase cells, and in dividing cells concentrates at the cleavage furrow. SEPT2 is a multifunctional protein that was shown to be required for cytokinesis and to bind actin and associate with focal adhesions. Recent data support the idea that SEPT2 can have a role in chromosome congression and segregation. Additional functions have also been suggested; for instance, in rat brain lysates SEPT2 is part of a multi-septin complex that interacts with the exocyst complex, which plays a role in secretion and neurite outgrowth. SEPT2 has also been localised to senile plaques of brains in patients with Alzheimer¹s disease suggesting a role in neurodegeneration. The SEPT2 protein belongs to an evolutionarily family of proteins with at least 14 members and shares a very high homology with septin 1, septin 4 and septin 5. Gene Name MLL Location 11q23 37 exons, spanning over 100 kb. In a centromeric to telomeric direction; 13 and 15 kb; Dna / Rna coding sequence: 11.9 kb. Protein 3969 amino acids; 431 KDa; contains from N-term to C-term 3 AT hooks homologous to high mobility group proteins HMGA1 and HMGA2, binding to the minor grove of DNA; 2 speckled nuclear localisation signals; 2 repression domains RD1 and RD2: RD1 or CXXC: cystein methyl transferase, binds CpG rich DNA, has a transcriptional repression activity; RD2 recruits histone desacetylases HDAC1 and HDAC2; 3 plant homeodomains (cystein rich zinc finger domains, with homodimerization properties), 1 bromodomain (may bind acetylated histones), and 1 plant homeodomain; these domains may be involved in protein-protein interaction; a FYRN and a FRYC domain; a transactivation domain which binds CBP ; may acetylates H3 and H4 in the HOX area; a SET domain: methyltransferase; methyltates H3, including histones in the HOX area for allowing chromatin to be open to transcription. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus: a p300/320 N-term protein called MLL-N, and a p180 C-term protein, called MLL-C. The FYRN and a FRYC domains of native MLL associate MLL-N and MLL-C in a stable complex; they form a multiprotein complex with transcription factor TFIID. Result of the chromosomal anomaly
Hybrid gene
Atlas Genet Cytogenet Oncol Haematol 2008; 5 762
Description MLL-SEPT2. MLL exon 6 or 7 fused with SEPT2 exon 3.
Fusion Protein
Structure of the normal MLL and SEPT2 proteins and the resulting MLL-SEPT2 fusion protein. Description AT hook, SNL-1, SNL-2 and DNA methyltransferase domains from MLL fused to almost the entire open-reading frame of SEPT2, except for the first three aminoacids. External links Other t(2;11)(q37;q23) in AML Mitelman database (CGAP - NCBI) database Other t(2;11)(q37;q23) in AML 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 Translocation 2;11 and other significant chromosome changes in acute monoblastic leukemia (M5) with clonal evolution: sequential clinical and cytogenetic studies. DeLozier-Blanchet CD, Cabrol C, Werner-Favre C, Beris P, Engel E Cancer genetics and cytogenetics. 1985 ; 16 (2) : 95-102. PMID 3855693
Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. Winick NJ, McKenna RW, Shuster JJ, Schneider NR, Borowitz MJ, Bowman WP, Jacaruso D, Kamen BA, Buchanan GR Journal of clinical oncology. 1993 ; 11 (2) : 209-217. PMID 8426196
Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias. Fischer K, Frohling S, Scherer SW, McAllister Brown J, Scholl C, Stilgenbauer S, Tsui LC, Lichter P, Dohner H Blood. 1997 ; 89 (6) : 2036-2041.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 763 PMID 9058725
SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23). Cerveira N, Correia C, Bizarro S, Pinto C, Lisboa S, Mariz JM, Marques M, Teixeira MR Oncogene. 2006 ; 25 (45) : 6147-6152. PMID 16682951
A new subtype of MLL-SEPT2 fusion transcript in therapy-related acute myeloid leukemia with t(2;11)(q37;q23): a case report and literature review. van Binsbergen E, de Weerdt O, Buijs A Cancer genetics and cytogenetics. 2007 ; 176 (1) : 72-75. PMID 17574968
Contributor(s) Written 09-2007 Cecília Correia, Manuel R Teixeira Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal. Citation This paper should be referenced as such : Correia C, Teixeira MR . t(2;11)(q37;q23) in AML. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0211q37q23ANLLID1457.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 764 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(1;21)(q21;q22)
Clinics and Pathology Disease Acute myeloid leukaemia (AML) Epidemiology only one case to date, a 1 year old boy with M1 AML Prognosis no data Genes involved and Proteins Gene Name ZNF687 Location 1q21 Protein 10 zinc fingers; krueppel C2H2-type zinc-finger protein; transcription factor 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' ZNF687 External links Other t(1;21)(q21;q22) Mitelman database (CGAP - NCBI) database Other t(1;21)(q21;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 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
Contributor(s) Written 09-2007 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(1;21)(q21;q22). Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0121q21q22ID1446.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 765 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(1;21)(p35;q22)
Clinics and Pathology Disease Acute myeloid leukaemia (AML) Epidemiology only one case to date, a 68 year old male patient with M2 AML Prognosis no data Genes involved and Proteins Gene Name YTHDF2 Location 1p35 Protein possible role in immune response 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' ZNF687 External links Other t(1;21)(p35;q22) Mitelman database (CGAP - NCBI) database Other t(1;21)(p35;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 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
Contributor(s) Written 09-2007 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(1;21)(p35;q22). Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/t0121p35q22ID1447.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 766 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Digestive organs: Liver: Combined hepatocellular and cholangiocarcinoma
Identity Other names Hepatocholangiocellular carcinoma Note Defined as an intrahepatic tumor nodule that contains both hepatocellular carcinoma and cholangiocarcinoma. Classification Note Tumor staging is separated by TNM classification. TNM classifications for hepatocellular and cholangiocarcinomas of the liver. Clinics and Pathology Disease Combined hepatocellular and cholangiocarcinoma is a more aggressive malignancy with a poorer prognosis than ordinary hepatocellular carcinoma (HCC). Etiology The reported frequency of combined hepatocellular and cholangiocarcinoma (combined tumors) varies widely; 1.0-6.5% among patients with primary liver cancer. Statistical data indicate that combined tumors occur predominantly in men (reported ratio is ranged from 14:1 to 2:1). The mean age of onset is in the sixth decade. In Asian cases, a high incidence of hepatitis B or C virus infection and frequent association of chronic liver disease/cirrhosis have been reported. Conversely, in Western countries, these features are less common. Combined tumors exhibit an invasive character with frequent venous permeation and tumor microsatellite formation, features that are seen more frequently than in ordinary HCC. Epidemiology A rare subtype of primary liver cancer. Clinics The typical clinical symptom is abdominal pain. Complaints of fatigue and weakness are mostly attributable to compromised liver function. Jaundice is found in a much lower percentage of patients than of those with intrahepatic cholangiocarcinoma (CC). Chills and fever appear rarely. In combined tumors, HCC and CC areas rarely can be identified using imaging techniques such as ultrasonography, helical CT, and dynamic MRI. In many cases, even in tumor biopsy samples, the two components are not included or discriminated. Generally, final diagnosis is entrusted to pathological findings of surgically resected or autopsy samples. Pathology The histopathological classification reported by Goodman et al. is popular: type I, in which HCC and CC occur coincidentally and no transitional forms are observed; type II, in which there are areas of apparent transition between HCC and CC; type III, in which tumor cells resemble the fibrolamellar subtype of HCC but contain mucin-producing glands. Other classifications, reported by Allen and Lisa, and by Kojiro et al., are known.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 767
(A and B) Gross feature and schematic illustration of combined hepatocellular and cholangiocarcinoma. HCC: hepatocellular carcinoma, CC: cholangiocarcinoma. (C-E) Border zone between HCC and CC. Moderately differentiated HCC (right) with vague grandular component (left). The grandular tumor cells were positive for CK19 and HCC component was positive for Hep par-1. Treatment Surgical resection, chemotherapy, radiofrequency ablation, microwave coagulation, ethanol injection, transarterial embolization. Evolution Intrahepatic recurrence is common. Combined tumors have been reported to be more aggressive than HCC, with widespread metastasis and regional lymph node involvement. Prognosis The prognosis of combined tumors is poorer than that of HCC because of relatively frequent lymph node metastasis and vascular invasion. Survival rates of patients with combined tumors are generally poorer than those of patients with HCC. Cytogenetics Note Loss of heterozygosity (LOH) at 4q, 8p, 13q, 16q, and 17p is seen frequently in combined hepatocellular and cholangiocarcinoma similar to in HCC. LOH at 3p and 14q are reported to be specific in CC and combined hepatocellular-cholangiocarcinoma in contrast to HCC. Genes involved and Proteins Gene Name K-RAS Location 12p12.1 Dna / Rna 4 exons Protein Proto-oncogene. GTP-GDP binding protein with GTPase activity. The K-ras proto- oncogene is thought to exert control over some of the mechanisms of cell growth and differentiation. This gene is converted to an active oncogene by point mutations concentrated significantly in codons 12, 13, and 61. Mutations of the K-ras gene have been reported to be common (67-75%) in intrahepatic CC. Conversely, the mutations rarely have been found in HCC. K-ras mutations in combined hepatocellular and cholangiocarcinoma have been analyzed in Japanese cases and it has been reported that the mutations were found rarely, as in the case for HCC. This observation may reflect the background of Japanese patients; specifically, chronic hepatitis C infection and evidence of cirrhosis are found in a relatively high percentage of patients with combined hepatocellular and cholangiocarcinoma.
Gene Name p53 Location 17p13 Dna / Rna 11 exons
Atlas Genet Cytogenet Oncol Haematol 2008; 5 768 Protein Tumor suppressor. Wild-type p53 plays an important role in the regulation of the cell cycle process, cell growth, and apoptosis in the event of DNA damage. The aberrant proteins from the mutated genes disrupt critical growth-regulating mechanisms and may play a crucial role in the carcinogenesis. The reported incidence of p53 mutation is 11-37% in intrahepatic CC and 10-29% in combined hepatocellular and cholangiocarcinoma. In HCC, the frequency of p53 mutations varies among different geographic areas. p53 abnormalities appear not to be correlated with tumoral differentiation. Bibliography Combined hepatocellular and cholangiocarcinoma. Wittekind C, Fischer HP, Ponchon T In WHO classification tumors of the digestive system Hamilton, SR..
General roles for surgical and pathological studies on cancer of the biliary tract. Japanese Society of Biliary Surgery In Classification of biliary tract carcinoma Japanese Society of Biliary Surgery (. 1997.
Combined liver cell and bile duct carcinoma. ALLEN RA, LISA JR The American journal of pathology. 1949 ; 25 (4) : 647-655. PMID 18152860
Combined hepatocellular-cholangiocarcinoma. A histologic and immunohistochemical study. Goodman ZD, Ishak KG, Langloss JM, Sesterhenn IA, Rabin L Cancer. 1985 ; 55 (1) : 124-135. PMID 2578078
Cholangiocarcinomas in Japanese and Thai patients: difference in etiology and incidence of point mutation of the c-Ki-ras proto-oncogene. Tsuda H, Satarug S, Bhudhisawasdi V, Kihana T, Sugimura T, Hirohashi S Molecular carcinogenesis. 1992 ; 6 (4) : 266-269. PMID 1336666
Combined hepatocellular and cholangiocarcinoma: proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Maeda T, Adachi E, Kajiyama K, Sugimachi K, Tsuneyoshi M Human pathology. 1995 ; 26 (9) : 956-964. PMID 7545644
Mutational analysis of the p53 and K-ras genes and allelotype study of the Rb-1 gene for investigating the pathogenesis of combined hapatocellular-cholangiocellular carcinomas. Imai Y, Oda H, Arai M, Shimizu S, Nakatsuru Y, Inoue T, Ishikawa T Japanese journal of cancer research : Gann. 1996 ; 87 (10) : 1056-1062. PMID 8957064
A clinicopathological study on combined hepatocellular and cholangiocarcinoma. Taguchi J, Nakashima O, Tanaka M, Hisaka T, Takazawa T, Kojiro M Journal of gastroenterology and hepatology. 1996 ; 11 (8) : 758-764. PMID 8872774
Combined hepatocellular-cholangiocarcinoma: a clinicopathological study. Ng IO, Shek TW, Nicholls J, Ma LT Journal of gastroenterology and hepatology. 1998 ; 13 (1) : 34-40. PMID 9737569
Genetic classification of combined hepatocellular-cholangiocarcinoma. Fujii H, Zhu XG, Matsumoto T, Inagaki M, Tokusashi Y, Miyokawa N, Fukusato T, Uekusa T, Takagaki T, Kadowaki N, Shirai T Human pathology. 2000 ; 31 (9) : 1011-1017. PMID 11014564
Atlas Genet Cytogenet Oncol Haematol 2008; 5 769
Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors. Jarnagin WR, Weber S, Tickoo SK, Koea JB, Obiekwe S, Fong Y, DeMatteo RP, Blumgart LH, Klimstra D Cancer. 2002 ; 94 (7) : 2040-2046. PMID 11932907
Comparing combined hepatocellular-cholangiocarcinoma and cholangiocarcinoma: a clinicopathological study. Lee CC, Wu CY, Chen JT, Chen GH Hepato-gastroenterology. 2002 ; 49 (48) : 1487-1490. PMID 12397714
Combined hepatocellular and cholangiocarcinoma: a clinicopathologic study of 26 resected cases. Yano Y, Yamamoto J, Kosuge T, Sakamoto Y, Yamasaki S, Shimada K, Ojima H, Sakamoto M, Takayama T, Makuuchi M Japanese journal of clinical oncology. 2003 ; 33 (6) : 283-287. PMID 12913082
Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas. Cazals-Hatem D, Rebouissou S, Bioulac-Sage P, Bluteau O, Blanche H, Franco D, Monges G, Belghiti J, Sa Cunha A, Laurent-Puig P, Degott C, Zucman-Rossi J Journal of hepatology. 2004 ; 41 (2) : 292-298. PMID 15288479
Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Koh KC, Lee H, Choi MS, Lee JH, Paik SW, Yoo BC, Rhee JC, Cho JW, Park CK, Kim HJ American journal of surgery. 2005 ; 189 (1) : 120-125. PMID 15701504
Prognostic impact of cholangiocellular and sarcomatous components in combined hepatocellular and cholangiocarcinoma. Aishima S, Kuroda Y, Asayama Y, Taguchi K, Nishihara Y, Taketomi A, Tsuneyoshi M Human pathology. 2006 ; 37 (3) : 283-291. PMID 16613323
Combined hepatocellular and cholangiocarcinoma: clinical features and prognostic study in a Thai population. Chantajitr S, Wilasrusmee C, Lertsitichai P, Phromsopha N Journal of hepato-biliary-pancreatic surgery. 2006 ; 13 (6) : 537-542. PMID 17139428
Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Lee WS, Lee KW, Heo JS, Kim SJ, Choi SH, Kim YI, Joh JW Surgery today. 2006 ; 36 (10) : 892-897. PMID 16998683
Hepatic progenitor cells in human liver tumor development. Libbrecht L World journal of gastroenterology : WJG. 2006 ; 12 (39) : 6261-6265. PMID 17072946
A histopathological study on combined hepatocellular and cholangiocarcinoma: cholangiocarcinoma component is originated from hepatocellular carcinoma. Wakasa T, Wakasa K, Shutou T, Hai S, Kubo S, Hirohashi K, Umeshita K, Monden M Hepato-gastroenterology. 2007 ; 54 (74) : 508-513. PMID 17523309
Atlas Genet Cytogenet Oncol Haematol 2008; 5 770
Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma. Zuo HQ, Yan LN, Zeng Y, Yang JY, Luo HZ, Liu JW, Zhou LX Hepatobiliary & pancreatic diseases international : HBPD INT. 2007 ; 6 (2) : 161-165. PMID 17374575
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 09-2007 Munechika Enjoji, Shinichi Aishima Department of Hepatology and Pancreatology, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (ME); Department of Pathology, Hamanomachi Hospital, 3-5-27 Maizuru, Chuo-ku, Fukuoka 810-8539, Japan (SA) Citation This paper should be referenced as such : Enjoji M, Aishima S . Digestive organs: Liver: Combined hepatocellular and cholangiocarcinoma. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HepatoCholangioCarcID5331.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 771 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Holoprosencephaly-Diencephalic Hamartoblastoma (HDH).
Identity Holoprosencephaly-Diencephalic Hamartoblastoma association, Holoprosencephaly- Other names Hypothalamic Hamartoblastoma, Holoprosencephaly-Diencephalic Hamartoma Note HDH is an extremely rare developmental field defect primarily involving the prosencephalon. The most accredited hypothesis is that the hypothalamic hamartoma formation, which occurs early in embryogenesis, produces a cascading process of subsequent craniofacial defects including holoprosencephaly, microphthalmia, hemifacial microsomia, neuronal migration defects, and brainstem/posterior fossa and meningeal anomalies. Inheritance The inheritance pattern of HDH is still obscure and probably heterogeneous. Environmental/stochastic causes may also contribute for a significant proportion of cases. Clinics Phenotype and HDH equally affects males and females. Nearly 100% of the patients present some clinics features of holoprosencephaly. The spectrum of these anomalies is wide, ranging from alobar holoprosencephaly to microforms, such as isolated single central medial incisive, or cleft palate. The most consistent holoprosencephalic features are hypo/aplasia of the corpus callosum, arhinencephaly and premaxillary agenesis. Unilateral or bilateral microphathalmia and neuronal migration/cortical anomalies are quite common abnormalities. Additional findings include meningeal abnormalities, such as cysts and dysplasia, and brainstem and posterior fossa malformations. The first and second branchial arches derivatives may also be asymmetrically affected leading to a significant clinical overlap with the oculo-auriculo-vertebral spectrum. Fifty to sixty per cent of the patients also show extracephalic features, with an excess of midline and laterality determination abnormalities, thus configuring a polytopic developmental field defect. The axial skeleton is the most commonly involved structure, while heart, kidneys, gastrointestinal tract, genitourinary system and limbs are more rarely affected. Neoplastic risk On embryological perspective, hypothalamic hamartoma/hamartoblastoma is a malformation, not a true tumor. Other benign growth lesions, including meningeal angiomatosis, frontal lipoma, tongue cyst, epignathus and gum nodules, have been observed in about 20% of the cases. However, no increased risk of malignancies has been reported in HDH patients. Treatment In those patients who survive (see below), the treatment is usually conservative and symptomatic. Surgical repair could be requested for specific potentially life-treating or disfiguring malformations, such as cleft palate, congenital heart disease and genital anomalies. Invasive treatment of hypothalamic hamartomas is usually requested only in presence of intractable seizures. In this case, the experience is limited to non syndromic hamartomas and therapeutic options include surgical resection by conventional craniotomy, microsurgical technique via transcallosal approach and stereotactic radiofrequency thermocoagulation. Prognosis HDH usually has a poor prognosis and is lethal in about 50% of the cases. Mental retardation, epilepsy and precocious puberty are quite common complications (50-60%) in the surviving patients. Cytogenetics Note In one case a 7q36 terminal deletion was demonstrated, while another patient showed a 69, XXX triploid karyotype. Therefore, although rarely positive, standard karyotype and subtelomeric rearrangement analysis are recommended in all HDH patients. Genes involved and Proteins
Gene Name SHH
Atlas Genet Cytogenet Oncol Haematol 2008; 5 772 Location 7q36 Note Although mutations of this gene have not yet been identified in HDH, a terminal 7q deletion has been documented in one patient and an additional case, showing single central medial incisive and hypophyseal hamartoma, has been described with SHH heterozygous mutation. These evidences suggest that SHH is a potential candidate- gene for those HDH cases who still lack a known cause (e.g. chromosome imbalance or teratogenic exposure). Gene Name SOX2 Location 3q26.33 Note A single patient showing a SOX2 heterozygous mutation and presenting with hypothalamic hamartoma, unilateral microphthalmia, hypoplastic anterior hypophysis and corpus callosum has been described. Although the observed phenotype cannot be unambiguously interpreted as an atypical form of holoprosencephaly, future studies are expected to demonstrate a causal relationship between SOX2 mutations and HDH.
Bibliography Hamartoma of the hypothalamus; report of two cases with associated developmental defects. MARCUSE PM, BURGER RA, SALMON GW The Journal of pediatrics. 1953 ; 43 (3) : 301-308. PMID 13085273
Bilateral nasal proboscis associated with unilateral anophthalmia, unilateral diffuse pigmentation of the conjunctiva, and anomalies of the skull and brain. ROSEN Z, GITLIN G A.M.A. archives of otolaryngology. 1959 ; 70 : 545-550. PMID 14438899
Meningeal angiomatosis, arhinencephaly, agenesis of the corpus callosum and large hamartoma of the brain, with neoplasia, in an infant having bilateral nasal proboscis. GITLIN G, BEHAR AJ Acta anatomica. 1960 ; 41 : 56-79. PMID 13705778
Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly--a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD American journal of medical genetics. 1980 ; 7 (1) : 47-74. PMID 7211952
Solitary central maxillary incisor associated with precocious puberty and hypothalamic hamartoma. Winter WE, Rosenbloom AL, Maclaren NK, Mickle JP The Journal of pediatrics. 1982 ; 101 (6) : 965-967. PMID 7143176
Congenital hypothalamic hamartoma associated with severe midline defect: a developmental field defect. Report of a case. Hennekam RC, Beemer FA, Van Merrienboer F, Van Ketel BA, Kramer PP American journal of medical genetics. Supplement. 1986 ; 2 : 45-52. PMID 3146299
Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation. Anyane-Yeboa K, Collins M, Kupsky W, Maidman J, Malin J, Yeh M American journal of medical genetics. 1987 ; 26 (4) : 899-907. PMID 3296755
Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome).
Atlas Genet Cytogenet Oncol Haematol 2008; 5 773 Iafolla K, Fratkin JD, Spiegel PK, Cohen MM Jr, Graham JM Jr American journal of medical genetics. 1989 ; 33 (4) : 489-499. PMID 2688416
Pallister-Hall syndrome associated with unbalanced chromosome translocation. Golabi M, Kuller J, Cox K, KeilmanK, Schonberg S Am J Med Genet. 1991 ; 49.
Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form. Encha-Razavi F, Larroche JC, Roume J, Migne G, Delezoide AL, Gonzales M, Mulliez N American journal of medical genetics. 1992 ; 42 (1) : 44-50. PMID 1308364
Pallister-Hall syndrome associated with an unbalanced chromosome translocation. Kuller JA, Cox VA, Schonberg SA, Golabi M American journal of medical genetics. 1992 ; 43 (3) : 647-650. PMID 1605268
Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome. Verloes A, Gillerot Y, Langhendries JP, Fryns JP, Koulischer L American journal of medical genetics. 1992 ; 43 (4) : 669-677. PMID 1621756
Duplication of the pituitary gland as shown by MR. Ryals BD, Brown DC, Levin SW AJNR. American journal of neuroradiology. 1993 ; 14 (1) : 137-139. PMID 8427075
Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and mullerian regression: further delineation of a new syndrome? Verloes A, Narcy F, Fallet-Bianco C Clinical dysmorphology. 1995 ; 4 (1) : 33-37. PMID 7735503
Gelastic epilepsy, hypothalamic hamartoma, precocious puberty, and agenesis of the corpus callosum: a new association. Alikchanov AA, Petrukhin AS, Mukhin KYu, Nikanorov AYu Brain & development. 1998 ; 20 (4) : 239-241. PMID 9661969
Diencephalic neuronal hamartoma associated with congenital obstructive hydrocephalus, anophthalmia, cleft lip and palate and severe mental retardation: a possible new syndrome. Rossiter JP, Khalifa MM, Nag S Acta neuropathologica. 2000 ; 99 (6) : 685-690. PMID 10867803
Epignathus teratoma: report of three cases with a review of the literature. Vandenhaute B, Leteurtre E, Lecomte-Houcke M, Pellerin P, Nuyts JP, Cuisset JM, Soto-Ares G The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association. 2000 ; 37 (1) : 83-91. PMID 10670895
Gelastic seizure with tectal tumor, lobar holoprosencephaly, and subependymal nodules: clinical report. Akman CI, Schubert R, Duran M, Loh J Journal of child neurology. 2002 ; 17 (2) : 152-154.
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Hypothalamic hamartoma, gelastic epilepsy, precocious puberty--a diffuse cerebral dysgenesis. Gulati S, Gera S, Menon PS, Kabra M, Kalra V Brain & development. 2002 ; 24 (8) : 784-786. PMID 12453604
Hypothalamic hamartoma associated with a craniopharyngeal canal. Kizilkilic O, Yalcin O, Yildirim T, Sener L, Parmaksiz G, Erdogan B AJNR. American journal of neuroradiology. 2005 ; 26 (1) : 65-67. PMID 15661703
Single median maxillary central incisor, hypophyseal tumor, and SHH mutation. Ribeiro LA, Richieri-Costa A American journal of medical genetics. Part A. 2005 ; 136 (4) : 346-347. PMID 15942953
Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma. Saxonhouse MA, Yachnis AT, Burchfield DJ, Quisling R, Sullivan MP, Pincus DW Journal of neurosurgery. 2005 ; 103 (3 Suppl) : 277-281. PMID 16238084
Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary- gonadal axis in mice and humans. Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, Chong WK, Kirk JM, Achermann JC, Ross R, Carmignac D, Lovell-Badge R, Robinson IC, Dattani MT The Journal of clinical investigation. 2006 ; 116 (9) : 2442-2455. PMID 16932809
Reassessment of holoprosencephaly-diencephalic hamartoblastoma (HDH) association. Castori M, Douzgou S, Silvestri E, Encha-Razavi F, Dallapiccola B American journal of medical genetics. Part A. 2007 ; 143 (3) : 277-284. PMID 17230485
A triploid fetus further expands etiological heterogeneity in holoprosencephaly-diencephalic hamartoblastoma. Castori M, Silvestri E, Nunnari J, Grammatico P, Dallapiccola B American journal of medical genetics. Part A. 2007 ; 143 (12) : 1391-1393. PMID 17497722
Stereotactic radiofrequency thermocoagulation for hypothalamic hamartoma with intractable gelastic seizures. Homma J, Kameyama S, Masuda H, Ueno T, Fujimoto A, Oishi M, Fukuda M Epilepsy research. 2007 ; 76 (1) : 15-21. PMID 17643965
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 09-2007 Marco Castori, Paola Grammatico Medical Genetics, Institute of Experimental Medicine, Università La Sapienza, San Camillo-Forlanini Hospital, Rome, Italy Citation This paper should be referenced as such : Castori M, Grammatico P . Holoprosencephaly-Diencephalic Hamartoblastoma (HDH).. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HoloDienHamartoID10142.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 775 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Congenital Myofibromatosis
Identity Other names Infantile myofibromatosis Mesenchymal hamartomatosis Hemangiopericytoma Vascular leiomyoma of the newborn Congenital generalized fibromatosis Inheritance Postulated as autosomal dominant (AD) with variable expression or autosomal recessive (AR). Clinics Note Myofibromatosis or infantile myofibromatosis (IM) is one of the more common fibromatoses that present during childhood. Presentation may occur as an adult or even prenatally. These tumors grow and regress without known initiation factors, and the diagnostic classification depends solely upon the location of the tumors. Individuals with Solitary IM only have tumor involvement of the soft tissues. However, those individuals with Multiple IM have tumors within bone tissue, and those with Generalized IM demonstrate visceral tumors. Soft tissue involvement may occur in all three, and bone involvement may also be present in generalized IM.
Hematoxylin and eosin staining of infantile myofibromatosis (IM) biopsies. A: Family I (III-9), showing zonal pattern of spindle shaped cells with central necrosis and calcification. The lesion was subcutaneous scalp mass obtained at 4 months of age, and the diagnosis of IM was confirmed by outside consultation (Dr. C. Coffin, U. of Utah). B: Family II (IV-6), shoulder lesion obtained at 3 months of age, but present since birth. The sample demonstrates prominent vascularity. C: Family II (III-5), temporal lesion, biopsed at age 28 years. Diagnoses initially considered included fibroblastic meningioma, Schwanoma-neurilemmona, and IM. The patient has generalized IM confirmed by
Atlas Genet Cytogenet Oncol Haematol 2008; 5 776 multiple other biopsies of the deltoid, axilla, and shoulders. Note the architectural similarity of (B) and (C) despite their different origins. Neoplastic risk Risk for neoplasm is considered to be very low. In those individuals who have multiple tumors, pathogenesis appears to be related to multifocal potential, not metastatic potential. Treatment Treatment is based solely upon clinical presentation. Those tumors causing secondary pathology via mass affect are commonly removed. Others may be watched due to their potential to regress. Evolution The evolution of the tumor is not well understood. Pathologically, they are well circumscribed. Histopathologically, hematoxylin and eosin (H and E) staining demonstrates growth in a zonal pattern with more primative appearing cells located centrally and spindle shaped cells peripherally. The spindle shaped cells resemble fibroblasts but are often arranged in a pattern similar to fascicles - thus resembling myocytes. As some tumors may grow rapidly, it is also common to see areas of central necrosis and calcification. Prognosis Prognosis is usually based upon the secondary complications caused by the tumors. Individuals with multiple tumors or visceral involvement tend to have more complications due to either number the increased number or increased possibility of poor location. In general, most individuals with uncomplicated presentations have a good prognosis. Cytogenetics Note Unknown. Only two cytogenetic abnormalities in IM tissue have been reported: Monosomy 9q/trisomy 16q and an interstitial deletion on chromosome 6q. No comparison was made with the constitutive karyotype, and direct correlation was not able to be confirmed. It is presumed that the causative gene might allow for growth potential or affect cell cycle to account for the unique properties of both growth and regression of these tumors, but as of yet no gene has been identified. Bibliography Juvenile fibromatoses. STOUT AP Cancer. 1954 ; 7 (5) : 953-978. PMID 13199773
CONGENITAL MESENCHYMAL TUMORS. KAUFFMAN SL, STOUT AP Cancer. 1965 ; 18 : 460-476. PMID 14278043
Congenital generalized fibromatosis: an autosomal recessive condition? Baird PA, Worth AJ Clinical genetics. 1976 ; 9 (5) : 488-494. PMID 1269171
Infantile myofibromatosis. Chung EB, Enzinger FM Cancer. 1981 ; 48 (8) : 1807-1818. PMID 7284977
Infantile myofibromatosis. Evidence for an autosomal-dominant disorder. Jennings TA, Duray PH, Collins FS, Sabetta J, Enzinger FM The American journal of surgical pathology. 1984 ; 8 (7) : 529-538. PMID 6742314 del(6)(q12q15) as the sole cytogenetic anomaly in a case of solitary infantile myofibromatosis. Stenman G, Nadal N, Persson S, Gunterberg B, Angervall L Oncology reports. 1999 ; 6 (5) : 1101-1104. PMID 10425309
Monosomy 9q and trisomy 16q in a case of congenital solitary infantile myofibromatosis.
Atlas Genet Cytogenet Oncol Haematol 2008; 5 777 Sirvent N, Perrin C, Lacour JP, Maire G, Attias R, Pedeutour F Virchows Archiv. 2004 ; 445 (5) : 537-540. PMID 15365831
Autosomal dominant inheritance of infantile myofibromatosis. Zand DJ, Huff D, Everman D, Russell K, Saitta S, McDonald-McGinn D, Zackai EH American journal of medical genetics. Part A. 2004 ; 126 (3) : 261-266. PMID 15054839
A newborn with multiple fractures as first presentation of infantile myofibromatosis. Buonuomo PS, Ruggiero A, Zampino G, Maurizi P, Attina G, Riccardi R Journal of perinatology. 2006 ; 26 (10) : 653-655. PMID 17006529
Infantile visceral myofibromatosis--a rare cause of neonatal intestinal obstruction. Jones VS, Philip C, Harilal KR Journal of pediatric surgery. 2007 ; 42 (4) : 732-734. PMID 17448777
Multicentric infantile myofibromatosis: two perinatal cases. Pelluard-Nehme F, Coatleven F, Carles D, Alberti EM, Briex M, Dallay D European journal of pediatrics. 2007 ; 166 (10) : 997-1001. PMID 17186271
REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 09-2007 Dina J Zand, Elaine H Zackai Division of Genetics and Metabolism, Department of Pediatrics, Children's National Medical Center, Washington, DC, USA (DJZ); Division of Human and Molecular Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA (EHZ) Citation This paper should be referenced as such : Zand DJ, Zackai EH . Congenital Myofibromatosis. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CongMyofibromID10137.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
Atlas Genet Cytogenet Oncol Haematol 2008; 5 778 Atlas of Genetics and Cytogenetics in Oncology and Haematology
CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)
Translocation t(7;9)(q34;q32) found in pediatric T-cell Acute Lymphoblastic Leukemia
Jennifer JS Laffin, Randee J Blumer, Sara J Morrison-Delap, Elizabeth A Rauch, Eric B Johnson, Carol A Diamond, Kate J Thompson, Gordana Raca, Karen D Montgomery, Daniel F Kurtycz Clinics Age and sex : 4 year(s) old female patient. Previous History : no preleukemia no previous malignant disease no inborn condition of note Organomegaly : hepatomegaly ; splenomegaly ; enlarged lymph nodes ; no central nervous system involvement Blood WBC : 148 x 109/l; Hb : 9.8 g/dl; platelets : 13 x 109/l; Bone marrow : 100% Cyto pathology classification Cytology : L2 Immunophenotype : NK+, CD2, CD3, CD4, CD5, CD7, CD8, and TdT+ Precise diagnosis : Acute Lymphoblastic Leukemia, L2 Survival Date of diagnosis: 02-2006 Treatment : chemotherapy (intrathecal and systemic), cranial X-ray therapy, and allogenic stem cell transplant Relapse : + central nervous system (8/06 with cytogenetics) and bone marrow relapse Status : Alive 08-2007 Survival : 31 month(s) Karyotype Sample : diagnostic sample was of bone marrow ; culture time : analysis of diagnostic sample was performed on overnight colcemid, 18-hour and 72-hour cultures ; banding : 350 band level Results : 46,XX,t(7;9)(q34;q31~q32)[16]/46,XX[4] Karyotype at relapse : Date: 08-2006; Result: 46,XX,del(6)(q21),t(7;9)(q34;q31~q32)[cp2]/46,XX[19]
Partial karyotypes of metaphases from diagnostic sample overnight colcemid culture. Comments The patient presented in this case report has features consistent with other reported cases of T cell acute lymphoblastic leukemia (T-ALL) with t(7;9)(q34;q32) involving the TCRbeta locus on 7q34 and the TAL2 gene on 9q34. In particular, review of the literature revealed a case in a 3 year old male with similar clinical and hematological findings and the same additional cytogenetic anomaly, del(6)(q21). Approximately 60% of clinically normal individuals have t(7;9)(q34;q32) created by V(D)J recombination which uses a fortuitous recombination site (RSS) located 3'of the TAL2 oncogene. In T- ALL affected individuals a rare second rearrangement occurs between the junction point of the original t(7;9) and Jbeta2. This brings the TAL2 gene under the control of TCRbeta enhancer, and leads to its'
Atlas Genet Cytogenet Oncol Haematol 2008; 5 779 inappropriate expression. Internal links Atlas Card t(7;9)(q34;q32) Bibliography Clinical and biologic characterization of T-cell neoplasias with rearrangements of chromosome 7 band q34. Smith SD, Morgan R, Gemmell R, Amylon MD, Link MP, Linker C, Hecht BK, Warnke R, Glader BE, Hecht F Blood. 1988 ; 71 (2) : 395-402. PMID 2962650
Distinct t(7;9)(q34;q32) breakpoints in healthy individuals and individuals with T-ALL. Marculescu R, Vanura K, Le T, Simon P, Jager U, Nadel B Nature genetics. 2003 ; 33 (3) : 342-344. PMID 12567187
Contributor(s) Written Jennifer JS Laffin, Randee J Blumer, Sara J Morrison-Delap, Elizabeth A 09-2007 Rauch, Eric B Johnson, Carol A Diamond, Kate J Thompson, Gordana Raca, Karen D Montgomery, Daniel F Kurtycz Citation This paper should be referenced as such : Laffin JJS, Blumer RJ, Morrison-Delap SJ, Rauch EA, Johnson EB, Diamond CA, Thompson KJ, Raca G, Montgomery KD, Kurtycz DF . Translocation t(7;9)(q34;q32) found in pediatric T-cell Acute Lymphoblastic Leukemia. Atlas Genet Cytogenet Oncol Haematol. September 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0709LaffinID100032.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology
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