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Volume 12, Number 3, May-Jun 2008 Previous Issue / Next Issue Genes SOCS2 (suppressor of cytokine signaling 2) (12q21.33). Leandro Fernández-Pérez, Amilcar Flores-Morales. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 351-355. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/SOCS2ID44123ch12q21.html PTHLH (parathyroid hormone-like hormone) (12p11.22). Sai-Ching Jim Yeung. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 356-367. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PTHLHID41897ch12p11.html MUC17 (mucin 17, cell surface associated) (7q22.1). Wade M Junker, Nicolas Moniaux, Surinder K Batra. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 368-378. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/MUC17ID41456ch7q22.html MUC16 (mucin 16, cell surface associated) (19p13.2). Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh Jain, Surinder K Batra. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 379-384. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/MUC16ID41455ch19q13.html MAML2 (mastermind-like 2) (11q21) - updated. Kazumi Suzukawa, Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 385-390. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/MAML2ID472.html HYAL1 (hyaluronoglucosaminidase 1) (3p21.3). Demitrios H Vynios. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 391-396. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/HYAL1ID40903ch3p21.html HTATIP (HIV-1 Tat interacting protein, 60kDa) (11q13.1). Lise Mattera. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 397-405. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/HTATIPID40893ch11q13.html GRN (Granulin) (17q21.32). Hongyong Zhang, Chong-xian Pan, Liang Cheng. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 406-415. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/GRNID40757ch17q21.html CDH1 (cadherin 1, type 1, E-cadherin (epithelial)) (16q22.1). Marilia de Freitas Calmon, Paula Rahal. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 416-423. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 I URL : http://atlasgeneticsoncology.org/Genes/CDH1ID166ch16q22.html CD97 (CD97 molecule) (19p13). Gabriela Aust. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 424-429. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/CD97ID996ch19p13.html BRCA1 (breast cancer 1, early onset) (17q21.31). Sreeparna Banerjee. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 430-439. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/BRCA1ID163ch17q21.html BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3) (10q26.3). Sang-Gi Paik, Hayyoung Lee. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 440-445. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/BNIP3ID822ch10q26.html AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1) (Xq25). Victor J Yuste, Hans K Lorenzo, Santos A Susin. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 446-454. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/AIFM1ID44053chXq25.html Leukaemias t(6;7)(q23;q34). Emmanuelle Clappier, Jean Soulier. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 455-457. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0607q23q34ID1465.html t(3;9)(q26;p23). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 458. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0309q26p23ID1279.html t(3;5)(q26;q34). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 459-460. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0305q26q34ID1278.html t(3;17)(q26;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 461-462. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/t0317q26q22ID1282.html del(11)(p12p13). Pieter Van Vlierberghe, Jules PP Meijerink. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 463-464. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Anomalies/del11p12p13ID1351.html Solid Tumours Subungual exostosis with t(X;6)(q13;q22). Clelia Tiziana Storlazzi, Fredrik Mertens. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 465-467. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Tumors/SubungExosttX6ID5526.html Soft tissue tumors: Alveolar soft part sarcoma - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 468-472. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Tumors/AlveolSoftPartSID5125.html Cancer Prone Diseases Glomuvenous malformation (GVM). Virginie Aerts, Pascal Brouillard, Laurence M Boon, Miikka Vikkula. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 473-477. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Kprones/GlomuvenousID10120.html Deep Insights

Atlas Genet Cytogenet Oncol Haematol 2008; 3 II Case Reports Translocation t(1;6)(p35;p25) in B-cell lymphoproliferative disorder with evolution to Diffuse Large B-cell Lymphoma. Elvira D Rodrigues Pereira Velloso, Cristina Ratis, Sérgio A B Brasil, João Carlos Guerra, Nydia Bacal; Cristóvão P Mangueira LM Pitangueira. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 478-479. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Reports/0106RodriguesID100030.html Educational Items How human chromosome aberrations are formed. Albert Schinzel. Atlas Genet Cytogenet Oncol Haematol 2008; Vol (12): 480-497. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Educ/ChromAberFormedID30065ES.html

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Atlas Genet Cytogenet Oncol Haematol 2008; 3 III Atlas of Genetics and Cytogenetics in Oncology and Haematology

SOCS2 (suppressor of cytokine signaling 2)

Identity Other names CIS-2, Cytokine-inducible SH2 protein 2 CIS2, STAT induced STAT inhibitor-2 Cish2, STAT-induced STAT inhibitor 2 SOCS-2, suppressor of cytokine signaling 2 SSI-2, suppressor of cytokine signaling-2 SSI2 STATI2 Hugo SOCS2 Location 12q21.33 By cytogenetic and radiation hybrid mapping, SOCS-2 has been mapped to Local_order chromosome 12q21.3-q23 (Yandava et al., 1999). DNA/RNA Description 6,38 kb ; 3 Exons. Mouse SOCS2 gene is composed of 3 exons and 2 introns (Metcalf et al., 2000). Human SOCS-2 is a functioning gene that comprises 3 exons spanning roughly 6,38 kb of genomic DNA. Transcription 2210 bp mRNA. 1 protein (22.2 kDa; 198 aa). Although constitutively expressed SOCS2 mRNA has been detected in several tissues and cell types, its expression is, in general, induced by stimulation with different cytokines and hormones (Rico-Bautista et al., 2006). SOCS2 promoter analysis indicates the presence of AhR and STAT5 binding sites that confer responsiveness to dioxin (Boverhof et al., 2004) and GH (Vidal et al., 2006), respectively. Protein

Diagram representing the structure of SOCS proteins. At least eight proteins belonging to the SOCS family of proteins are shown (upper panel). They are characterized by the presence of an SH2 central domain and the SOCS box domain at the C-terminus. A small domain called kinase inhibitory region (KIR), only found in SOCS1 and SOCS3, is shown as a small box at the N-terminal region. SOCS proteins can interact with phosphotyrosine phosphorylated proteins through their SH2 domain and with Elongin BC through their SOCS box domain. Other proteins containing a SOCS box domain but lacking a SH2 domain are also shown (lower panel). Adapted from Elliot and Johnston (Elliott and Johnston, 2004) with modifications.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 351 Description 22.2 kDa; 198 aa. Expression SOCS mRNA and protein levels are constitutively low in unstimulated cells, but their expression is rapidly induced upon cytokine stimulation, thereby creating a negative feedback loop. Its expression is, in general, induced by stimulation with different cytokines and hormones (Rico-Bautista et al., 2006). Localisation Intracellular, cytoplasm. Function SOCS mechanisms of action rely on their ability to bind tyrosine phosphorylated proteins through their SH2 domains, but also to bind Elongin BC through their SOCS box domains. SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction (Rico-Bautista et al., 2006). SOCS2 appears to be a negative regulator in the growth hormone/IGF1 signaling pathway (Metcalf et al., 2000). SOCS2 appear to be involved in regulating protein turnover, targeting proteins for proteasome-mediated degradation (Rico-Bautista et al., 2004). Mutations Note SNP: increasing the risk of type 2 diabetes. Implicated in Entity Diabete Note Susceptibility: to type 2 diabetes (Kato et al., 2006). Entity Metabolism Note SOCS2 null mice are giants but not obese (Metcalf et al., 2000). SOCS2 deficient mice have some metabolic characteristics that can be related to the enhanced GH actions (Rico-Bautista et al., 2005). Entity Bone Note Analysis of SOCS2 null mice have revealed that the absence of SOCS2 induces a reduction in the trabecular and cortical volumetric bone mineral density (Lorentzon et al., 2005). SOCS2 induces the differentiation of C2C12 mesenchymal cells into myoblasts or osteoblasts (Ouyang et al., 2006). Entity Neural development Note SOCS2 plays a critical role in neuronal development, growth, and stem cell differentiation (Turnley et al., 2002). Entity Cancer Note SOCS2 has been associated with cancer such as myeloid leukaemia, pulmonary adenocarcinoma, and ovarian cancer, breast cancer, and anal cancer. External links Nomenclature Hugo SOCS2 GDB SOCS2 Entrez_Gene SOCS2 8835 suppressor of cytokine signaling 2 Cards Atlas SOCS2ID44123ch12q21 GeneCards SOCS2 Ensembl SOCS2 [Search_View] ENSG00000120833 [Gene_View] Genatlas SOCS2 GeneLynx SOCS2 eGenome SOCS2 euGene 8835 Genomic and cartography SOCS2 - 12q21.33 chr12:92487729-92494109 + 12q [Description] (hg18- GoldenPath Mar_2006) Ensembl SOCS2 - 12q [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene SOCS2 Gene and transcription Genbank AB004903 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 352 Genbank AB006966 [ ENTREZ ] Genbank AF020590 [ ENTREZ ] Genbank AF037989 [ ENTREZ ] Genbank AK290546 [ ENTREZ ] RefSeq NM_003877 [ SRS ] NM_003877 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_019546 [ SRS ] NT_019546 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView SOCS2 AceView - NCBI Unigene Hs.485572 [ SRS ] Hs.485572 [ NCBI ] HS485572 [ spliceNest ] Fast-db 11538 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O14508 [ SRS] O14508 [ EXPASY ] O14508 [ INTERPRO ] Prosite PS50001 SH2 [ SRS ] PS50001 SH2 [ Expasy ] Prosite PS50225 SOCS [ SRS ] PS50225 SOCS [ Expasy ] Interpro IPR000980 SH2 [ SRS ] IPR000980 SH2 [ EBI ] Interpro IPR001496 SOCS_C [ SRS ] IPR001496 SOCS_C [ EBI ] CluSTr O14508 Pfam PF00017 SH2 [ SRS ] PF00017 SH2 [ Sanger ] pfam00017 [ NCBI-CDD ] PF07525 SOCS_box [ SRS ] PF07525 SOCS_box [ Sanger ] pfam07525 [ NCBI- Pfam CDD ] Smart SM00252 SH2 [EMBL] Smart SM00253 SOCS [EMBL] Prodom PD000093 SH2[INRA-Toulouse] O14508 SOCS2_HUMAN [ Domain structure ] O14508 SOCS2_HUMAN Prodom [ sequences sharing at least 1 domain ] Blocks O14508 PDB 2C9W [ SRS ] 2C9W [ PdbSum ], 2C9W [ IMB ] 2C9W [ RSDB ] HPRD 05490 Protein Interaction databases DIP O14508 IntAct O14508 Polymorphism : SNP, mutations, diseases OMIM 605117 [ map ] GENECLINICS 605117 SNP SOCS2 [dbSNP-NCBI] SNP NM_003877 [SNP-NCI] SNP SOCS2 [GeneSNPs - Utah] SOCS2] [HGBASE - SRS] HAPMAP SOCS2 [HAPMAP] COSMIC SOCS2 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD SOCS2 General knowledge Family Browser SOCS2 [UCSC Family Browser] SOURCE NM_003877 SMD Hs.485572 SAGE Hs.485572 GO regulation of cell growth [Amigo] regulation of cell growth GO SH3/SH2 adaptor activity [Amigo] SH3/SH2 adaptor activity GO growth hormone receptor binding [Amigo] growth hormone receptor binding GO prolactin receptor binding [Amigo] prolactin receptor binding insulin-like growth factor receptor binding [Amigo] insulin-like growth factor receptor GO binding GO protein binding [Amigo] protein binding

Atlas Genet Cytogenet Oncol Haematol 2008; 3 353 GO cytoplasm [Amigo] cytoplasm GO ubiquitin cycle [Amigo] ubiquitin cycle GO anti-apoptosis [Amigo] anti-apoptosis GO intracellular signaling cascade [Amigo] intracellular signaling cascade GO JAK-STAT cascade [Amigo] JAK-STAT cascade JAK pathway signal transduction adaptor activity [Amigo] JAK pathway signal GO transduction adaptor activity negative regulation of signal transduction [Amigo] negative regulation of signal GO transduction KEGG Jak-STAT signaling pathway KEGG Insulin signaling pathway KEGG Type II diabetes mellitus PubGene SOCS2 TreeFam SOCS2 CTD 8835 [Comparative Genomics Database] Other databases Probes Probe SOCS2 Related clones (RZPD - Berlin) PubMed PubMed 29 Pubmed reference(s) in LocusLink Bibliography Radiation hybrid and cytogenetic mapping of SOCS1 and SOCS2 to chromosomes 16p13 and 12q, respectively. Yandava CN, Pillari A, Drazen JM Genomics. 1999 ; 61 (1) : 108-111. PMID 10512686

Gigantism in mice lacking suppressor of cytokine signalling-2. Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola NA, Hilton DJ, Alexander WS Nature. 2000 ; 405 (6790) : 1069-1073. PMID 10890450

Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Turnley AM, Faux CH, Rietze RL, Coonan JR, Bartlett PF Nature neuroscience. 2002 ; 5 (11) : 1155-1162. PMID 12368809

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells. Boverhof DR, Tam E, Harney AS, Crawford RB, Kaminski NE, Zacharewski TR Molecular pharmacology. 2004 ; 66 (6) : 1662-1670. PMID 15371557

SOCS: role in inflammation, allergy and homeostasis. Elliott J, Johnston JA Trends in immunology. 2004 ; 25 (8) : 434-440. PMID 15275643

Downregulation of the growth hormone-induced Janus kinase 2/signal transducer and activator of transcription 5 signaling pathway requires an intact actin cytoskeleton. Rico-Bautista E, Negrˆ‚n-Martˆ‚nez C, Novoa-Mogollˆ„n J, Fernˆ°ndez-Perez L, Flores-Morales A Experimental cell research. 2004 ; 294 (1) : 269-280. PMID 14980520

Reduced bone mineral density in SOCS-2-deficient mice. Lorentzon M, Greenhalgh CJ, Mohan S, Alexander WS, Ohlsson C Pediatric research. 2005 ; 57 (2) : 223-226.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 354 PMID 15585682

Suppressor of cytokine signaling-2 deficiency induces molecular and metabolic changes that partially overlap with growth hormone-dependent effects. Rico-Bautista E, Greenhalgh CJ, Tollet-Egnell P, Hilton DJ, Alexander WS, Norstedt G, Flores- Morales A Molecular endocrinology (Baltimore, Md.). 2005 ; 19 (3) : 781-793. PMID 15563548

Association of single-nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese. Kato H, Nomura K, Osabe D, Shinohara S, Mizumori O, Katashima R, Iwasaki S, Nishimura K, Yoshino M, Kobori M, Ichiishi E, Nakamura N, Yoshikawa T, Tanahashi T, Keshavarz P, Kunika K, Moritani M, Kudo E, Tsugawa K, Takata Y, Hamada D, Yasui N, Miyamoto T, Shiota H, Inoue H, Itakura M Genomics. 2006 ; 87 (4) : 446-458. PMID 16406727

SOCS-2 interferes with myotube formation and potentiates osteoblast differentiation through upregulation of JunB in C2C12 cells. Ouyang X, Fujimoto M, Nakagawa R, Serada S, Tanaka T, Nomura S, Kawase I, Kishimoto T, Naka T Journal of cellular physiology. 2006 ; 207 (2) : 428-436. PMID 16419040

Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Rico-Bautista E, Flores-Morales A, Fernˆ°ndez-Pˆ©rez L Cytokine & growth factor reviews. 2006 ; 17 (6) : 431-439. PMID 17070092

In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. Vidal OM, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia DJ, Woelfle J, Ono M, Lenhard B, Norstedt G, Rotwein P, Flores-Morales A Molecular endocrinology (Baltimore, Md.). 2007 ; 21 (1) : 293-311. PMID 17008382

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Contributor(s) Written 10-2007 Leandro Fernández-Pérez, Amilcar Flores-Morales University of Las Palmas de GC, Faculty of Health Sciences, Molecular and Translational Endocrinology Group, c/ Dr. Pasteur s/n - Campus San Cristobal, 35016 - Las Palmas, Spain, (LFP); Department of Molecular Medicine and Surgery, Karolinska Institute, 17176 Stockholm, Sweden (AFM) Citation This paper should be referenced as such : Fernández-Pérez L, Flores-Morales A . SOCS2 (suppressor of cytokine signaling 2). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/SOCS2ID44123ch12q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 355 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PTHLH (parathyroid hormone-like hormone)

Identity Other names PTHLP (parathyroid hormone-like protein) PTHRP (parathyroid hormone-related protein) PTHrP PTH-rP (PTH-related protein) PTHR HHM (humoral hypercalcemia of malignancy) Osteostatin PLP (parathyroid-like protein) MGC14611 Hugo PTHLH Location 12p11.22 DNA/RNA Description PTHLP is encoded by a single gene that is highly conserved among species. The gene is composed of 7 exons spanning a region of 13,899 bases (Start: 28,002,284 bp from pter; End: 28,016,183 bp from pter). Orientation: minus strand. The genomic DNA for the PTHLP gene was isolated from a human placental genomic library. Transcription The sequence is supported by 3 sequences from 3 cDNA clones. Pseudogene none. Protein

This diagram represents schematically one possible proteolytic processing pattern of PTHLP into 3 bioactive peptides. The mid-region of PTHLP contains the nuclear localization signal (NLS). Description Size: 177 amino acids, 20194 Da. The PTHLP gene has seven exons, and its transcripts are processed by alternative splicing into three isoforms, encoding proteins with 139, 173 and 141 amino acids. The pattern of expression of PTHLP mRNA isoforms may be cell type-specific. Although different tumors may have different PTHLP splicing patterns, there are no tumor- specific transcripts. PTHLP is processed into a set of distinct peptide hormones by endoproteolytic cleavage of the initial translation products: mature N-terminal, mid-region and C- terminal secretory peptides, each having its own distinct function. The distribution of the endopeptidase processing enzymes (PTP (prohormone thiol protease), prohormone convertases 1 and 2 (PC1 and PC2)) may vary in different tissues. PTP cleaved the PTHLP precursor at the multibasic, dibasic, and monobasic residue cleavage sites to generate the NH2-terminal peptide (residues 1-37, having PTH-like

Atlas Genet Cytogenet Oncol Haematol 2008; 3 356 and growth regulatory activities), the mid-region domain (residues 38-93, regulating calcium transport and cell proliferation), and the COOH-terminal domain (residues 102-141, modulating osteoclast activity). Expression PTHLP is a protein polyhormone produced by most if not all tissues in the body. It is secreted during both fetal and postnatal life. Although PTHLP is found in the circulation, most of its activity appears to be paracrine. A complex of transcription factors and coactivators (CREB, Etsl and CBP) regulates PTHLP transcription and may contribute to the alterations associated with the promotion of carcinogenesis. Disruption of the normal regulation during cancer progression may in part be associated with TGF-beta1-induced changes in PTHLP mRNA isoform expression and stability. TGF-beta activates PTHLP expression increasing transcription from the P3 promoter through a synergistic interaction of Smad3 and Ets1. ERK1/ERK2-dependent Ets2/PKCepsilon synergism also appears to regulate PTHLP expression in breast cancer cells. The PTHLP gene is also under the transcriptional control of glucocorticoids and vitamin D. 1,25-dihydroxy vitamin D3 treatment increases PTHLP mRNA expression and blocks the stimulatory effect of TGF-beta on PTHLP mRNA expression. Glucocortical steroid hormone can suppress PTHLP mRNA expression and release of bioactive PTHLP in certain PTHLP-producing tumors. The regulation of PTHLP expression by female sex steroid hormones is still unclear. PTHLP is a downstream target for RAS and SRC, K-ras mutation increases PTHLP expression while a farnesyltransferase inhibitor known to inhibit RAS function can decrease PTHLP expression. The von Hippel-Lindau tumor suppressor protein also negatively regulates PTHLP expression at the post-transcriptional level. Localisation PTHLP is a secreted polyhormone and is localized in the Golgi apparatus in the cytoplasm. However, in some cells, PTHLP can be detected in the nucleus by immunochemistry. The growth-inducing effect of NLS-containing mid-region PTHLP peptide in breast cancer is dependent on both internalization into the cytoplasm and subsequent translocation to the nucleus. PTHLP travels from the cytosol to the nucleus with the help of the nuclear transport factor importin beta1. Importin beta1 enhanced the association of PTHLP with microtubules, and the microtubule cytoskeleton plays an important role in protein transport to the nucleus. The site of recognition of PTHLP is the N-terminal half of importin, which can also bind Ran and nucleoporin, and is sufficient for PTHLP nuclear import. Function PTHLP is a growth factor, a PTH-like calciotropic hormone, a developmental regulatory molecule, and a muscle relaxant. The diverse activities of PTHLP result not only from processing of the precursor into multiple hormones, but from use of multiple receptors. It is clear that the Type 1 Parathyroid Hormone Receptor (PTH1R), binding both PTH (1-34) and PTHLP (1-36), is the receptor mediating the function of PTHLP (1-36), and it is the only cloned receptor for PTHLP so far. PTHLP also binds to a type of receptor in some tissues that does not bind PTH. PTHLP (67-86) activates phospholipase C signaling pathways through a receptor distinct from that activated by PTHLP (1-36) in the same cells. Unlike PTH, picomolar concentrations of the PTHLP (107-111) fragment to can activate membrane-associated PKC in osteosarcoma cells. PTHLP (107-139) exerts effects through the PKC/ERK pathway. Thus, it is highly likely that the mid-region and osteostatin peptides bind other, unique receptors, but those receptors have yet to be cloned and identified. In contrast to the receptor-mediated endrocrine and paracrine action, the mid-region PTHLP peptide contains a classic bipartite nuclear localization signal (NLS) which upon entering the nuclear compartment confers "intracrine" actions. Details of the nuclear action of PTHLP are still lacking, but overall, nuclear PTHLP appears to be mitogenic. The translation of PTHLP initiates from both the methionine-coding AUG and a leucine- coding CUGs further downstream in its signal sequence. It appeared that when translation was initiated from CUGs, PTHLP accumulated in the nucleoli, and that when translation was initiated from AUG, PTHLP localized in both the Golgi apparatus and nucleoli. Thus, nucleolar PTHLP appears to be derived from translation initiating from both AUG and CUGs. Modulation of cell adhesion by PTHLP localized in the nucleus is a normal physiological action of PTHLP, mediated by increasing integrin gene transcription. The promotion by PTHLP in cancer growth and metastasis may be mediated by upregulating integrin alpha6beta4 expression and activating Akt.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 357 PTHLP also interacts with beta-arrestin 1B, an important component of MAPK signaling and G-protein-coupled receptor desensitization, and this interaction requires residues 122-141 of PTHLP. Therefore, beta-arrestin 1 may mediate a novel regulatory function of PTHLP in intracellular signaling.

PTHLP also play a major role in development of several tissues and organs. PTHLP stimulates the proliferation of chondrocytes and suppresses their terminal differentiation. PTHLP (107-139) is a substrate for secPHEX, and osteocalcin, pyrophosphate and phosphate are inhibitors of secPHEX activity; thus PHEX activity and PTHLP are part of a complex network regulating bone mineralization. PTHLP plays a central role in the physiological regulation of bone formation, by promoting recruitment and survival of osteoblasts, and probably plays a role in the physiological regulation of bone resorption, by enhancing osteoclast formation. Signaling by fibroblast growth factor receptor 3 and PTHLP coordinate in cartilage and bone development. PTHLP is also an essential physiological regulator of adult bone mass.

PTHLP aids in normal mammary gland development and lactation as well as placental transfer of calcium. Mammary gland development depends upon a complex interaction between epithelial and mesenchymal cells that requires PTHLP. The calcium sensor (CaR) regulates PTHLP production as well as transport of calcium in the lactating mammary gland. In normal animals, mammary epithelial cells secrete a lot of PTHLP, which helps to adjust maternal metabolism to meet the calcium demands of lactation. The mid-region PTHLP peptide has also been shown to control the normal maternal-to- fetal pumping of calcium across the placenta. PTHLP is secreted from smooth muscle in many organs, usually in response to stretching. PTHLP relaxes smooth muscle. Transgenic mice that express PTHLP in vascular smooth muscle have hypotension, being consistent with a vasodilating effect of PTHLP.

PTHLP is highly expressed in the skin. EGF and other similar ligands can potentially activate PTHLP gene expression in the epidermis. PTHLP can inhibit hair growth and is required for tooth eruption as shown by mouse models that manipulated the PTHLP gene. Implicated in Entity Humoral hypercalcemia of malignancy Disease Humoral hypercalcemia of malignancy (HHM) was first described by Albright in 1941, and is a well-known complication among cancer patients. This syndrome is commonly encountered in advanced cancer of epithelial origin, especially squamous cell carcinoma of the lung. Studies of the "humors" secreted by cancer that causes hypercalcemia led to the discovery of 3 classes of peptides: parathyroid-like peptides, growth factor-like peptides, and bone-resorbing factors. Then protein purification led to molecular studies that cloned cDNAs for PTHLH. A study suggested that the PTHLH may be responsible for the abnormal calcium metabolism in HHM. Prognosis The median survival after the first occurrence of hypercalcemia is 66 days in patients with serum PTHLP inferior or equal to 21 pmol/L and 33 days in patients with PTHLP superior to 21 pmol/L. In hypercalcemia of malignancy, raised serum levels of PTHLP indicate a more advanced tumor state and an extremely poor prognosis. Entity Autocrine promotion of tumor progression Prognosis In the absence of hypercalcemia, approximately 17% of patients with gastroesophageal carcinoma have elevated levels of PTHLP, and the increase in PTHLP was associated with a poor prognosis. Oncogenesis mRNA for the PTH1R was detected many tumors expressing PTHLP; thus the PTHLP produced by these tumors may act in an autocrine or paracrine fashion. PTHLP (1-34) treatment resulted in an increase in proliferation in prostate cancer cells which may require androgen in some cell lines. In breast cancer cells, PTHLP regulates CDC2 and CDC25B via PTH1R in a cAMP-independent manner, and PTHLP promotes cell migration through induction of ITGA6, PAI-1, and KISS-1, and promotes proliferation

Atlas Genet Cytogenet Oncol Haematol 2008; 3 358 through induction of KISS-1. These pieces of evidence together suggest that PTHLP and PTH1R together play an important role in the autocrine/paracrine promotion of tumor proliferation in some cancers. Entity Bone metastasis Disease Breast cancer

The interactions among breast cancer cells, osteoblasts and osteoclasts define a feedback loop that promotes breast cancer growth in the bone microenvironment. Oncogenesis PTHLP is a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTHLP-expressing breast carcinoma are more likely to develop bone metastasis, and bone metastasis expresses PTHLP in more than 90% of cases as compared with less than 20% of cases of metastasis to other sites. In breast cancer, osteolytic metastases are the most common. PTHLP is a common osteolytic factor, and other osteolytic factors include vascular endothelial growth factor and interleukin 8 and interleukin 11. Since osteoblasts are the main regulators of osteolytic osteoclasts, stimulation of osteoblasts can paradoxically increase osteoclast function. Simultaneous expression of osteoblastic and osteolytic factors can produce mixed metastases. PTHLP expression by cancer cells may provide a selective growth advantage in bone because PTHLP stimulates osteoclastic bone resorption to release growth factors such as TGF-beta from the bone matrix. TGF-beta in turn will activate by osteoclastic bone resorption and enhance PTHLP expression and tumor cell growth, thus completing a vicious cycle (See diagram). Taken together, PTHLP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Alternatively, cytokines such as IL-8 initiate the process of osteoclastic bone resorption in the early stages of breast cancer metastasis, and PTHLP expression is induced to stimulate the vicious cycle of osteolysis at a later stage. Certain cancer treatments, especially sex steroid hormone deprivation therapies, stimulate bone loss. Bone resorption will result in the release of bone growth factors, which may inadvertently facilitate bone metastasis. Treatment with bisphosphonates will prevent bone resorption and reduce the release of bone growth factors. Entity Cachexia in hypercalcemia of malignancy Oncogenesis PTHLP induces a wasting/cachectic syndrome. PTHLP leads to decreased physical

Atlas Genet Cytogenet Oncol Haematol 2008; 3 359 activity and lowered energy metabolism independently of the effects of hypercalcemia and proinflammatory cytokines. In a rodent model, PTHLP induces a cachectic syndrome (in addition to inducing hypercalcemia of malignancy) by changing the mRNA levels of orexigenic and anorexigenic peptides, except leptin and orexin. Expression of cachexia-inducing cytokines such as interleukin-6 and leukemia inhibitory factor is increased by PTHLP. Animal data suggest that humanized antibody against PTHLP may be effective for patients with hypercalcemia and cachexia in patients with humoral hypercalcemia of malignancy. External links Nomenclature Hugo PTHLH GDB PTHLH Entrez_Gene PTHLH 5744 parathyroid hormone-like hormone Cards Atlas PTHLHID41897ch12p11 GeneCards PTHLH Ensembl PTHLH [Search_View] ENSG00000087494 [Gene_View] Genatlas PTHLH GeneLynx PTHLH eGenome PTHLH euGene 5744 Genomic and cartography PTHLH - 12p11.22 chr12:28006522-28014161 - 12p12.1-p11.2 [Description] GoldenPath (hg18-Mar_2006) Ensembl PTHLH - 12p12.1-p11.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene PTHLH Gene and transcription Genbank AI569027 [ ENTREZ ] Genbank AI591151 [ ENTREZ ] Genbank AI760061 [ ENTREZ ] Genbank BC005961 [ ENTREZ ] Genbank BG676028 [ ENTREZ ] RefSeq NM_002820 [ SRS ] NM_002820 [ ENTREZ ] RefSeq NM_198964 [ SRS ] NM_198964 [ ENTREZ ] RefSeq NM_198965 [ SRS ] NM_198965 [ ENTREZ ] RefSeq NM_198966 [ SRS ] NM_198966 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_009714 [ SRS ] NT_009714 [ ENTREZ ] RefSeq NW_925328 [ SRS ] NW_925328 [ ENTREZ ] AceView PTHLH AceView - NCBI Unigene Hs.591159 [ SRS ] Hs.591159 [ NCBI ] HS591159 [ spliceNest ] Fast-db 4373 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P12272 [ SRS] P12272 [ EXPASY ] P12272 [ INTERPRO ] Prosite PS00335 PARATHYROID [ SRS ] PS00335 PARATHYROID [ Expasy ] Interpro IPR001415 Parathyrd_hrm [ SRS ] IPR001415 Parathyrd_hrm [ EBI ] Interpro IPR003626 PTH_related [ SRS ] IPR003626 PTH_related [ EBI ] CluSTr P12272 PF01279 Parathyroid [ SRS ] PF01279 Parathyroid [ Sanger ] pfam01279 [ NCBI- Pfam CDD ] Smart SM00087 PTH [EMBL]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 360 Prodom PD013225 PTH_related[INRA-Toulouse] P12272 PTHR_HUMAN [ Domain structure ] P12272 PTHR_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P12272 PDB 1BZG [ SRS ] 1BZG [ PdbSum ], 1BZG [ IMB ] 1BZG [ RSDB ] PDB 1ET3 [ SRS ] 1ET3 [ PdbSum ], 1ET3 [ IMB ] 1ET3 [ RSDB ] PDB 1M5N [ SRS ] 1M5N [ PdbSum ], 1M5N [ IMB ] 1M5N [ RSDB ] HPRD 01348 Protein Interaction databases DIP P12272 IntAct P12272 Polymorphism : SNP, mutations, diseases OMIM 168470 [ map ] GENECLINICS 168470 SNP PTHLH [dbSNP-NCBI] SNP NM_002820 [SNP-NCI] SNP NM_198964 [SNP-NCI] SNP NM_198965 [SNP-NCI] SNP NM_198966 [SNP-NCI] SNP PTHLH [GeneSNPs - Utah] PTHLH] [HGBASE - SRS] HAPMAP PTHLH [HAPMAP] HGMD PTHLH General knowledge Family Browser PTHLH [UCSC Family Browser] SOURCE NM_002820 SOURCE NM_198964 SOURCE NM_198965 SOURCE NM_198966 SMD Hs.591159 SAGE Hs.591159 GO hormone activity [Amigo] hormone activity GO calcium ion binding [Amigo] calcium ion binding GO extracellular region [Amigo] extracellular region GO extracellular space [Amigo] extracellular space GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm G-protein signaling, adenylate cyclase activating pathway [Amigo] G-protein signaling, GO adenylate cyclase activating pathway GO cell-cell signaling [Amigo] cell-cell signaling GO female pregnancy [Amigo] female pregnancy GO lactation [Amigo] lactation GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO epidermis development [Amigo] epidermis development GO cAMP metabolic process [Amigo] cAMP metabolic process PubGene PTHLH TreeFam PTHLH CTD 5744 [Comparative Genomics Database] Other databases Probes Probe PTHLH Related clones (RZPD - Berlin) PubMed PubMed 84 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2008; 3 361 Case records of the Massachusetts General Hospital (case 27461). Albright F New Eng J Med. 1941 ; 225 : 789-791.

A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY Science (New York, N.Y.). 1987 ; 237 (4817) : 893-896. PMID 3616618

Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF The New England journal of medicine. 1988 ; 319 (9) : 556-563. PMID 3043221

Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE Proceedings of the National Academy of Sciences of the United States of America. 1988 ; 85 (2) : 597-601. PMID 2829195

Transcriptional regulation of the parathyroid hormone-related peptide gene by glucocorticoids and vitamin D in a human C-cell line. Ikeda K, Lu C, Weir EC, Mangin M, Broadus AE The Journal of biological chemistry. 1989 ; 264 (27) : 15743-15746. PMID 2777759

Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects. Yasuda T, Banville D, Hendy GN, Goltzman D The Journal of biological chemistry. 1989 ; 264 (13) : 7720-7725. PMID 2708388

Effects of glucocorticoids and calcitonin on parathyroid hormone-related protein (PTHrP) gene expression and PTHrP release in human cancer cells causing humoral hypercalcemia. Kasono K, Isozaki O, Sato K, Sato Y, Shizume K, Ohsumi K, Demura H Japanese journal of cancer research : Gann. 1991 ; 82 (9) : 1008-1014. PMID 1938595

Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, Bennett RC, Martin TJ Cancer research. 1991 ; 51 (11) : 3059-3061. PMID 2032246

Protein kinase C-activating domains of parathyroid hormone-related protein. Gagnon L, Jouishomme H, Whitfield JF, Durkin JP, MacLean S, Neugebauer W, Willick G, Rixon RH, Chakravarthy B Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1993 ; 8 (4) : 497-503. PMID 8475799

Parathyroid hormone-related peptide is a downstream target for ras and src activation. Li X, Drucker DJ The Journal of biological chemistry. 1994 ; 269 (9) : 6263-6266. PMID 8119972

Atlas Genet Cytogenet Oncol Haematol 2008; 3 362 Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients. Pecherstorfer M, Schilling T, Blind E, Zimmer-Roth I, Baumgartner G, Ziegler R, Raue F The Journal of clinical endocrinology and metabolism. 1994 ; 78 (5) : 1268-1270. PMID 8175989

Alternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours. Southby J, O'Keeffe LM, Martin TJ, Gillespie MT British journal of cancer. 1995 ; 72 (3) : 702-707. PMID 7669584

Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, Yoneda T, Mundy GR The Journal of clinical investigation. 1996 ; 98 (7) : 1544-1549. PMID 8833902

A midregion parathyroid hormone-related peptide mobilizes cytosolic calcium and stimulates formation of inositol trisphosphate in a squamous carcinoma cell line. Orloff JJ, Ganz MB, Nathanson MH, Moyer MS, Kats Y, Mitnick M, Behal A, Gasalla-Herraiz J, Isales CM Endocrinology. 1996 ; 137 (12) : 5376-5385. PMID 8940360

Parathyroid hormone-related protein secretion is inhibited by oestradiol and stimulated by antioestrogens in KPL-3C human breast cancer cells. Kurebayashi J, Sonoo H British journal of cancer. 1997 ; 75 (12) : 1819-1825. PMID 9192988

Suppression of parathyroid hormone-related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues. Sugimoto T, Shiba E, Watanabe T, Takai S Breast cancer research and treatment. 1999 ; 56 (1) : 11-23. PMID 10517339

TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, Massaguˆ© J, Mundy GR, Guise TA The Journal of clinical investigation. 1999 ; 103 (2) : 197-206. PMID 9916131

Molecular mechanisms of osteolytic bone metastases. Guise TA Cancer. 2000 ; 88 (12 Suppl) : 2892-2898. PMID 10898330

Effect of parathyroid hormone related protein, and dihydrotestosterone on proliferation and ornithine decarboxylase mRNA in human prostate cancer cell lines. Asadi F, Faraj M, Malakouti S, Kukreja SC International urology and nephrology. 2001 ; 33 (3) : 417-422. PMID 12230264

Characterization of PHEX endopeptidase catalytic activity: identification of parathyroid- hormone-related peptide107-139 as a substrate and osteocalcin, PPi and phosphate as inhibitors. Boileau G, Tenenhouse HS, Desgroseillers L, Crine P The Biochemical journal. 2001 ; 355 (Pt 3) : 707-713. PMID 11311133

Atlas Genet Cytogenet Oncol Haematol 2008; 3 363

Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Clemens TL, Cormier S, Eichinger A, Endlich K, Fiaschi-Taesch N, Fischer E, Friedman PA, Karaplis AC, Massfelder T, Rossert J, Schlˆºter KD, Silve C, Stewart AF, Takane K, Helwig JJ British journal of pharmacology. 2001 ; 134 (6) : 1113-1136. PMID 11704631

The C-terminal region of PTHrP, in addition to the nuclear localization signal, is essential for the intracrine stimulation of proliferation in vascular smooth muscle cells. de Miguel F, Fiaschi-Taesch N, Lˆ„pez-Talavera JC, Takane KK, Massfelder T, Helwig JJ, Stewart AF Endocrinology. 2001 ; 142 (9) : 4096-4105. PMID 11517189

Comparative tissue distribution of the processing enzymes prohormone thiol protease, and prohormone convertases 1 and 2, in human PTHrP-producing cell lines and mammalian neuroendocrine tissues. Deftos LJ, Burton D, Hastings RH, Terkeltaub R, Hook VY Endocrine. 2001 ; 15 (2) : 217-224. PMID 11720250

Proteolysis of ProPTHrP(1-141) by prohormone thiol protease at multibasic residues generates PTHrP-related peptides: implications for PTHrP peptide production in lung cancer cells. Hook VY, Burton D, Yasothornsrikul S, Hastings RH, Deftos LJ Biochemical and biophysical research communications. 2001 ; 285 (4) : 932-938. PMID 11467841

Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen. Iguchi H, Onuma E, Sato K, Sato K, Ogata E International journal of cancer. Journal international du cancer. 2001 ; 94 (1) : 24-27. PMID 11668474

Higher expression of K-ras is associated with parathyroid hormone-related protein-induced hypercalcaemia in renal cell carcinoma. Kamai T, Arai K, Koga F, Abe H, Nakanishi K, Kambara T, Furuya N, Tsujii T, Yoshida KI BJU international. 2001 ; 88 (9) : 960-966. PMID 11851621

Effects of 1,25(OH)2D3, EB1089, and analog V on PTHrP production, PTHrP mRNA expression and cell growth in SCC 2/88. Kunakornsawat S, Rosol TJ, Capen CC, Middleton RP, Hannah SS, Inpanbutr N Anticancer research. 2001 ; 21 (5) : 3355-3363. PMID 11848494

Transforming growth factor beta regulates parathyroid hormone-related protein expression in MDA-MB-231 breast cancer cells through a novel Smad/Ets synergism. Lindemann RK, Ballschmieter P, Nordheim A, Dittmer J The Journal of biological chemistry. 2001 ; 276 (49) : 46661-46670. PMID 11590145

Biological action of parathyroid hormone (PTH)-related peptide (PTHrP) mediated either by the PTH/PTHrP receptor or the nucleolar translocation in chondrocytes. Amizuka N, Oda K, Shimomura J, Maeda T Anatomical science international / Japanese Association of Anatomists. 2002 ; 77 (4) : 225-236. PMID 12557418

The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta- arrestin 1B. Conlan LA, Martin TJ, Gillespie MT

Atlas Genet Cytogenet Oncol Haematol 2008; 3 364 FEBS letters. 2002 ; 527 (1-3) : 71-75. PMID 12220636

Nuclear transport of parathyroid hormone (PTH)-related protein is dependent on microtubules. Lam MH, Thomas RJ, Loveland KL, Schilders S, Gu M, Martin TJ, Gillespie MT, Jans DA Molecular endocrinology (Baltimore, Md.). 2002 ; 16 (2) : 390-401. PMID 11818509

Breast cancer metastasis to bone: it is not all about PTHrP. Bendre M, Gaddy D, Nicholas RW, Suva LJ Clinical orthopaedics and related research. 2003 : S39-S45. PMID 14600591

The hitchhiker's guide to the nucleus. Conti E Nature structural biology. 2003 ; 10 (1) : 8-9. PMID 12490886

Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells. Lindemann RK, Braig M, Hauser CA, Nordheim A, Dittmer J The Biochemical journal. 2003 ; 372 (Pt 3) : 787-797. PMID 12628005

Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti- parathyroid hormone-related protein antibody. Sato K, Onuma E, Yocum RC, Ogata E Seminars in oncology. 2003 ; 30 (5 Suppl 16) : 167-173. PMID 14613038

Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development. Amizuka N, Davidson D, Liu H, Valverde-Franco G, Chai S, Maeda T, Ozawa H, Hammond V, Ornitz DM, Goltzman D, Henderson JE Bone. 2004 ; 34 (1) : 13-25. PMID 14751559

Parathyroid hormone-related protein: an essential physiological regulator of adult bone mass. Bisello A, Horwitz MJ, Stewart AF Endocrinology. 2004 ; 145 (8) : 3551-3553. PMID 15265822

Regulation of parathyroid hormone-related protein gene expression by epidermal growth factor-family ligands in primary human keratinocytes. Cho YM, Lewis DA, Koltz PF, Richard V, Gocken TA, Rosol TJ, Konger RL, Spandau DF, Foley J The Journal of endocrinology. 2004 ; 181 (1) : 179-190. PMID 15072578

Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von Hippel-Lindau tumor suppressor gene. Massfelder T, Lang H, Schordan E, Lindner V, Rothhut S, Welsch S, Simon-Assmann P, Barthelmebs M, Jacqmin D, Helwig JJ Cancer research. 2004 ; 64 (1) : 180-188. PMID 14729622

Alternative splicing of parathyroid hormone-related protein mRNA: expression and stability. Sellers RS, Luchin AI, Richard V, Brena RM, Lima D, Rosol TJ Journal of molecular endocrinology. 2004 ; 33 (1) : 227-241. PMID 15291755

Atlas Genet Cytogenet Oncol Haematol 2008; 3 365 Modulation of parathyroid hormone-related protein levels (PTHrP) in anaplastic thyroid cancer. Dackiw A, Pan J, Xu G, Yeung SC Surgery. 2005 ; 138 (3) : 456-463. PMID 16213899

Serum parathyroid hormone-related peptide is associated with systemic inflammation and adverse prognosis in gastroesophageal carcinoma. Deans C, Wigmore S, Paterson-Brown S, Black J, Ross J, Fearon KC Cancer. 2005 ; 103 (9) : 1810-1818. PMID 15800880

Molecular mechanisms of breast cancer metastases to bone. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM Clinical breast cancer. 2005 ; 5 Suppl (2) : S46-S53. PMID 15807924

Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts. Onuma E, Tsunenari T, Saito H, Sato K, Yamada-Okabe H, Ogata E International journal of cancer. Journal international du cancer. 2005 ; 116 (3) : 471-478. PMID 15800941

Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo. Rabbani SA, Khalili P, Arakelian A, Pizzi H, Chen G, Goltzman D Endocrinology. 2005 ; 146 (7) : 2885-2894. PMID 15831570

The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland. Ardeshirpour L, Dann P, Pollak M, Wysolmerski J, VanHouten J Bone. 2006 ; 38 (6) : 787-793. PMID 16377269

Transient exposure to PTHrP (107-139) exerts anabolic effects through vascular endothelial growth factor receptor 2 in human osteoblastic cells in vitro. de Gortˆ°zar AR, Alonso V, Alvarez-Arroyo MV, Esbrit P Calcified tissue international. 2006 ; 79 (5) : 360-369. PMID 17120184

Parathyroid hormone-related protein regulates tumor-relevant genes in breast cancer cells. Dittmer A, Vetter M, Schunke D, Span PN, Sweep F, Thomssen C, Dittmer J The Journal of biological chemistry. 2006 ; 281 (21) : 14563-14572. PMID 16551631

Effects of anti-parathyroid hormone-related protein monoclonal antibody and osteoprotegerin on PTHrP-producing tumor-induced cachexia in nude mice. Iguchi H, Aramaki Y, Maruta S, Takiguchi S Journal of bone and mineral metabolism. 2006 ; 24 (1) : 16-19. PMID 16369893

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells. Kumari R, Robertson JF, Watson SA International journal of cancer. Journal international du cancer. 2006 ; 119 (1) : 49-59. PMID 16450371

PTH-related protein upregulates integrin alpha6beta4 expression and activates Akt in breast cancer cells.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 366 Shen X, Falzon M Experimental cell research. 2006 ; 312 (19) : 3822-3834. PMID 16965770

Characterisation of ligand binding to the parathyroid hormone/parathyroid hormone-related peptide receptor in MCF7 breast cancer cells and SaOS-2 osteosarcoma cells. Alokail MS, Peddie MJ Cell biochemistry and function. 2007 ; 25 (2) : 139-147. PMID 16170852

PTHrP increases transcriptional activity of the integrin subunit alpha5. Anderson JA, Grabowska AM, Watson SA British journal of cancer. 2007 ; 96 (9) : 1394-1403. PMID 17406357

Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. Gessi M, Monego G, Calviello G, Lanza P, Giangaspero F, Silvestrini A, Lauriola L, Ranelletti FO Acta neuropathologica. 2007 ; 114 (2) : 135-145. PMID 17372745

PTHrP P3 promoter activity in breast cancer cell lines: role of Ets1 and CBP (CREB binding protein). Hamzaoui H, Rizk-Rabin M, Gordon J, Offutt C, Bertherat J, Bouizar Z Molecular and cellular endocrinology. 2007 ; 268 (1-2) : 75-84. PMID 17321669

Parathyroid hormone-related protein induces cachectic syndromes without directly modulating the expression of hypothalamic feeding-regulating peptides. Hashimoto H, Azuma Y, Kawasaki M, Fujihara H, Onuma E, Yamada-Okabe H, Takuwa Y, Ogata E, Ueta Y Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 ; 13 (1) : 292-298. PMID 17200368

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Contributor(s) Written 10-2007 Sai-Ching Jim Yeung The University of Texas M. D. Anderson Cancer Center, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Boulevard, Unit 437, Houston, Texas 77030, USA Citation This paper should be referenced as such : Yeung SCJ . PTHLH (parathyroid hormone-like hormone). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PTHLHID41897ch12p11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 367 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MUC17 (mucin 17, cell surface associated)

Identity Other names MUC3 mucin-17 mouse Muc3 small intestinal mucin MUC3 membrane mucin 17 secreted mucin 17 intestinal membrane mucin MUC17 Hugo MUC17 Location 7q22.1 Note Mucin glycoproteins are a diverse family of high molecular mass, heavily glycosylated proteins differentially expressed in epithelial tissues of the gastrointestinal, reproductive and respiratory tracts. Membrane mucins such as MUC17 are expressed by epithelial cells to provide protection, maintain luminal structure, and provide signal transduction. Often these molecules are over- or aberrantly expressed in cancers of epithelial origin. Mucins confer anti-adhesive properties in cancer cells that lose their apical/basal polarization. They also provide adhesive properties towards endothelial cells favoring dissemination of mucin expressing cancer cells. MUC17 is a recently fully characterized mucin that belongs to the membrane-bound subfamily of mucin (Moniaux et al., 2006). It is a cell surface glycoprotein that is found on epithelial cells in select tissues of the body (wade need to precise the know profile). Its structure consists of an extracellular domain that extends above the cell surface and an intracellular domain of 80 amino acid residues. New evidence suggests its deregulation in pancreatic cancer (Moniaux et al., 2006; Moehle et al., 2006). The first partial length cDNA sequence, now known to correspond to MUC17, was identified by Van Klinken et al. (1997). At that time, van klinken isolated a chimeric cDNA clone overlapping MUC3 specific tandem repeat sequence and a new 59 aa sequence repeated in tandem. This sequence was therefore believed to be part of MUC3 until Gum and collaborators identified the carboxy terminal sequence of the 59 aa tandem repeat and identified this sequence has part of a new mucin called MUC17. Indeed, in 2002, driven with the hypothesis that the 177 bp tandem repeated sequences were part of a new unidentified mucin, Gum et al. screened the public GenBankTM database and the proprietary Lifeseq Gold database (Incyte Genomics Inc., CA). By database searching and RT-PCR they extended the partial mucin sequence found during analysis of MUC3 and cloned a MUC17 fragment of 3,807bp (accession number AF430017) (Gum et al., 2002). In 2006, Moniaux and Junker reported the complete coding sequence and organization of the MUC17 gene (Moniaux et al., 2006). DNA/RNA Note MUC17 was identified and localized to chromosome 7q22 by radiation hybridization mapping (Gum et al., BBRC, 2002) where it resided in a gene cluster with mucins MUC3A, MUC3B, and MUC11/12 (Figure 1). These mucins reside next to each other and have function in intestinal epithelium integrity, but are expressed in other different tissues and likely have different functions as well. The mucin genes within the cluster are transcribed independent of one another. MUC17 shows a low degree of VNTR (variable number of tandem repeats) polymorphism with only three different genomic DNA sizes detected for the large tandemly repeated extracellular domain in 24 cancer lines (pancreas, colon, and breast) and in four healthy individuals control samples (Moniaux et al., 2006).

Atlas Genet Cytogenet Oncol Haematol 2008; 3 368

Figure 1 - Chromosome location within the 7q22 mucin gene cluster. MUC17 resides in a gene cluster with mucins MUC3A, MUC3B, and MUC11/12 on chromosome 7 in the region q22.1. Upstream of the gene cluster 50 Kb is a potential open reading frame that shares similarity to MUC3. Approximately 26.7 Kb downstream of MUC17 reside TRIM56 and SERPINE1. Less that 1.2 Kb of genomic distance separates the 3' end of MUC12 from the beginning of MUC17. Figure 2 - MUC17 genomic and transcript bp size. The MUC17 gene encompasses (38,587 bp) 38.6 Kb of genomic sequence. The coding sequence contains 13 exons and is transcribed as a (14,360 bp) 14.4 Kb RNA that gives rise to full-length MUC17. The presence of an alternative splice site results in exclusion of exon 7, and produces a processed RNA that gives rise to a shorter MUC17/SEC.

Description Radiation hybridization mapping was performed using the GeneBridge4 radiation hybrid panel (Research Genetics, Huntsville, AL). Following hybridization, the MUC17 probe was detected in the panel of 93 independent human/hamster fusion clones with MUC17 specific primers, and data were analyzed using the GeneBridge4 server. This analysis indicated linkage to markers on chromosome 7q22 with an LOD score of 15. The presence or absence of MUC17 was concordant with STS (Sequence Tagged Site) marker D7S666 in 83 of 84 panel DNA samples that were unambiguous for both markers, thus positioning MUC17 near base 101,250,000 of chromosome 7 using the National Center for Biotechnology Information (NCBI) STS map. The NCBI electronic PCR server refined the interval to bases 98,871,000 and 99,054,000 of the STS map and positioned MUC17 approximately 2,000,000 bases telomeric of MUC3A on 7q22 (Gum et al., 2002). The MUC17 sequence has now been extended toward its 5'-extremity to complete the sequence and localize the promoter and regulatory elements. Rapid amplification of cDNA ends (RACE) and sequences from the Human Genome databases were used. The MUC17 gene is located within a 39-kb DNA fragment between MUC12 and SERPINE1 on chromosome 7 in the region q22.1 (Moniaux et al., 2006). Transcription The MUC17 full-length coding sequence is transcribed as a (14,360 bp) 14.4 Kb mRNA encompassing 13 exons from a (38,587 bp) 38.6 Kb genomic fragment (Figure 2). Alternate splicing generates two variants coding for a membrane-anchored and a secreted form of the protein (Moniaux et al., 2006) (Figure 3). The presence of an alternative splice event/site in the 3'-extremity of MUC17 was investigated by RT-PCR. RT-PCR was carried out on AsPC-1 cDNA. The generated amplification products were cloned into pCR® 2.1 and screened. Two distinct fragments were identified through sequencing. One of the fragments was 100% identical to the previous referenced sequence of MUC17 (accession number AJ606307). The second product revealed the occurrence of an alternative splice event that resulted in the skipping of exon 7. This alternative splice event generated a frame-shift which coded for the 21 (MUC17/SEC) specific amino acid residues and introduced a stop codon positioned 66 nucleotides after the junction. The resulting protein encodes a secreted form of MUC17 (accession

Atlas Genet Cytogenet Oncol Haematol 2008; 3 369 number AJ606308), lacking the second EGF domain, the transmembrane domain and cytoplasmic tail (Figure 3). RT-PCR was carried out in four distinct cell lines, (pancreatic AsPC-1, and colonic LS174T, CaCo-2, and Ls180), representing different tissues, i.e. pancreas and colon (Moniaux et al., 2006). Two amplification products were detected. Sequencing of the major amplification product identified it as the MUC17 sequence described by Gum et al. (accession number AF430017), while the other amplicon (minor) corresponded to an alternatively spliced variant (skipping of exon 7), the secreted form of MUC17, referred to as MUC17/SEC. The level of expression of MUC17/SEC seemed very low in the cell lines investigated; the intensity of the corresponding band was very faint as compared to the MUC17 fragment (Moniaux et al., 2006). MUC17 is expressed in select cell lines including pancreatic AsPC-1 and HPAF-II; and colon cancer cell lines LS174T, Caco-2, NCI-H498, and HM3 (Gum et al., 2002; Moniaux et al., 2006). Tissue expression was first shown by RNA dot blot analysis (Clontech multiple tissue expression blot). MUC17 is expressed in intestinal tissues, with the highest levels found in the duodenum (highest level) and in the transverse colon (85% of the level detected in duodenum). The only non-intestinal tissues found to express MUC17 in this analysis were stomach and fetal kidney. Both tissues showed approximately 7% of the expression level detected in the duodenum (Gum et al., 2002). In-situ hybridization was conducted to determine the cell specificity of MUC17 expression in the small intestine. In-situ hybridization showed MUC17 expression predominantly in the apical region of villi absorptive cells. Barely detectable expression was found in immature cells of the crypts. No expression was detected in goblet cells (Gum et al., 2002). Therefore, MUC17 expression is localized to the mature, absorptive cells of intestinal villi epithelium and is expressed in pancreatic cancer tissue (Moniaux et al., 2006). The MUC17 gene is located within a 39 Kb DNA fragment between MUC12 and SERPINE1 on chromosome 7. Approximately 1.2 Kb of sequence lies between the 3' end of MUC12 and the 5' UTR of the MUC17 gene. Expression of MUC17 is regulated by this 1,146-bp fragment upstream of MUC17 which contains various VDR/RXR, GATA, NFkB, and Cdx-2 response elements. Like mouse Muc3 (mMUC3), regulation of expression is controlled by both growth factors and cytokines (unpublished data, Junker and Batra, 2007). The mMuc3 promoter has consensus binding sites for , CREB, SP1, NF kappa B, GATA binding protein, and Cdx. Reporter constructs demonstrate that IL-4, IL-6, EGF, and PMA increase mMuc3 promoter activity 35-58% of control levels. TNF-a and IFN-g showed a lesser degree of stimulation (Shekels et al., 2003). Regulation of mMuc3 by cytokines and growth factors suggests an active role of mouse Muc3 and its human homologue, MUC17 in intestinal mucosal defense. A recent study conducted by Moehle et al. (2006) concerned the aberrant expression and allelic variants of mucin genes associated with inflammatory bowel disease (IBD). The aim of the study was to characterize changes in the expression profiles of genes related to intestinal epithelial function by comparing biopsy samples from patients with Ulcerative Colitis (UC) and Crohn's disease (CD), to controls; as the loss of intestinal mucosal integrity is an important factor in IBD. DNA-microarray analysis was applied and showed that mucin genes are differentially regulated in CD and UC. The loss of intestinal integrity is an important factor in the pathogenesis of inflammatory bowel disease. A coordinate down regulation of mucins was observed in a pool of biopsy RNAs (n=4) taken from affected and unaffected (control) regions of the terminal ileum and colon of CD and UC patients. No expression in the biopsy samples was detected for MUC6, MUC7, MUC8, MUC9, MUC11, MUC15, MUC16, and MUC18. Highest mucin expression values were displayed my MUC2, MUC13, and MUC17 in the ileum and the colon, while MUC12 was expressed in the colon. The relative expression levels for MUC1, MUC2, MUC4, MUC5B, MUC12, MUC13, MUC17, and MUC20 showed strong down regulation with decrease factors ranging from -1.3 to -48.5 fold. MUC17 showed a -4.3 and -2.6 fold decrease in Crohnís disease and Ulcerative Colitis respectively in the colon, but showed an apparent increase of 1.2 and 1.1 fold respectively in the same diseases in the ileum biopsy pooled RNAs. Real-time RT-PCR TaqMan assays were conducted to obtain a specific overview of mucin expression in human tissues. An initial analysis of nine mucin genes in a panel

Atlas Genet Cytogenet Oncol Haematol 2008; 3 370 of 26 different tissues was completed. The authors confirmed the relative expression values (average intensity) of DNA-microarray data (i.e., higher expression levels of MUC4, MUC5B, MUC12, and MUC20 were obtained in the colon compared to the ileum RNA; MUC17 was expressed higher in the ileum than in the colon). A meta- analysis of 11 genome-wide linkage studies for IBD revealed 38 significant IBD loci (Brant et al., 2004). Interestingly, all mucin family member loci reside within or directly beside these IBD candidate loci. Therefore, Moehle et al. performed allelic discrimination of one candidate exonic SNP within each mucin gene in UC (n=220), CD (n=181), and control (n=250) patient samples. Significant associations were detected for the MUC2, MUC4, and MUC13 mucin SNPs. The von Wildebrand Factor (vWF) domain of MUC2 (11p15, A/G, V116M) is associated with CD, the vWF domain of MUC4 (3q29, G/T, A585S) with UC, and the cytoplasmic tail domain of MUC13 (3q13.1, A/C, R502S) with UC. Unassessed SNPs in the mucin genes may still be associated and remain unchecked. The abundance of NFkB sites present in mucin promoters prompted the authors (Moehle et al., 2006) to explore regulation of mucin expression in the Ls174T colon cell line model. The ligands TNF-a, TGFb, and LPS induced expression of MUC17 as assayed by quantitative real-time PCR. TNF-a is able to induce a time-dependent upregulation of all the monitored mucin genes (MUC-1,-2, MUC-5AC, -5B, -12, -13, -17, -20). All monitored mucin genes showed increased expression with TGFb treatment. Cooperation of NFkB with TGFb signaling has been reported (Jono et al., 2002). Co- incubations of TGFb with NFkB pathway inhibitors (CAPE and MG132) resulted in a decrease of mucin expression, thus demonstrating a link between these two pathways with regards to mucin gene regulation. Treatment of the Ls174T colon cancer cell line with sodium butyrate had little or no effect on induction of MUC17 expression level but did induce expression of MUC3 which is not highly expressed in the cell line (Gum et al., 2002). Similarly, incubation of MUC17 non-expressing cell line, MiaPaCa, with HDAC inhibitor 5-aza-cytosine had little effect if any on MUC17 expression. Protein

Figure 3 - full length MUC17 and secreted MUC17/SEC. Full-length MUC17 contains a 25 amino acid leader peptide (secretion, membrane targeting signal), a central domain with tandemly repeated sequence, two EGF-like domains, a SEA domain, transmembrane domain, and an 80 amino acid cytoplasmic tail domain. Usage of an alternative splice site excludes exon 7 and introduces a frame shift that creates a premature stop codon 66 nucleotides after the splice junction, within the SEA domain coding sequence. This shorter transcript results in a secreted form of the protein, MUC17/SEC, which has 21 unique C-terminal amino acids, and lacks the second EGF domain, transmembrane domain, and C-terminal cytoplasmic tail. Note 4493 aa; 425.5 kDa (note: without modification such as glycosylation) Description MUC17 is classified as a membrane-bound mucin glycoprotein. The protein may serve as a cellular receptor. The deduced full-length membrane-bound amino acid sequence (4493 aa) shows the presence of various mucin domains (Figure 3). A signal sequence targets the protein to the plasma membrane. The majority of the molecule encodes the mucin central domain that is modified extensively by glycosylation and is displayed on the extracellular face of the cell. The central domain of MUC17 contains 63 repeats of 59 amino acid sequence (177 bp) that are repeated in tandem. This tandem repeat "central domain" is followed by a region of unique degenerate tandem repeats and mucin-like

Atlas Genet Cytogenet Oncol Haematol 2008; 3 371 sequences (i.e. that are repetitive, G/C rich, and contain a high content of threonine, serine, and proline amino acids). Two EGF-like domains flank both sides of a SEA module and precede the transmembrane domain. Putative N-glycosylation sites occur near the carboxyl terminus. The 80 amino acid C-terminal cytoplasmic domain has potential serine and tyrosine phosphorylation sites. Expression RNA blot analysis and RT-PCR suggests MUC17 is expressed in the digestive tract, primarily in the duodenum (highest level) and the transverse colon (85% of the level detected in duodenum) (Gum et al., 2002). Expression is also reported in the terminal ileum (Moehle et al., 2006) with MUC17 expressed higher in the ileum than in the colon (quantitative RT-PCR, microarray analysis). Many colon and pancreatic cancer cell lines do express varied levels of MUC17((Gum et al., 2002; Moniaux et al., 2006). An overexpression of MUC17 by Western blot and immunohistochemical analyses in pancreatic tumor cell lines and tumor tissues compared to normal pancreas samples is seen (Moniaux et al., 2006). Localisation Surface localization of the smaller subunit of MUC17 is reported to be dependent on its N- glycosylation status (Ho et al., 2003). MUC17 contains a SEA domain, a transmembrane domain, and putative N-glycosylation sites in the carboxyl terminus. Mucins that possess a SEA domain usually undergo an auto-proteolytic cleavage event within the domain (Macao et al., 2006) to yield two subunits, the smaller of which is associated with the surface membrane. Ho and colleagues reported that the ASPC-1 pancreatic cancer cell line shows three main bands (38, 45, and 49 kDa) of immunoreactivity with an antibody directed against a site downstream of the postulated SEA cleavage site (Ho et al., 2003). Treatment with N-glycan specific hydrolases showed the 38 kDa band contained high mannose glycans, whereas the 45 and 49 kDa bands contained complex-type glycans. Surface biotinylation studies revealed that only forms possessing complex-type N-glycans were localized to the cell surface. Both tunicamycin (N-glycosylation inhibitor) and brefeldin A (an inhibitor of protein transport) reduced surface localization. Surface localization of the smaller subunit of MUC17 therefore appears to be dependent on its N-glycosylation status in AsPC-1 pancreatic cancer cells. Immunohistochemical analysis of mouse Muc3 (the homologue of MUC17) revealed strong staining in goblet cells and patchy staining of surface columnar cells in the duodenum, small intestine, caecum, colon and rectum (Shekels et al., 1998). Northern blot analysis indicates that the mRNA is approximately 13.5 kb. Highest expression was detected in the caecum with lesser amounts detected in the colon and small intestine. No message was found in mouse stomach, trachea, lung, kidney, esophagus or pancreas (Shekels et al., 1998). In-situ hybridization studies show expression at the tips of villi, in the upper crypts, and in surface cells of the caecum and colon (Shekels et al., 1998). Rodent (mouse) mMuc3 and (rat) rMuc3 are assumed to represent secretory mucins expressed in columnar and goblet cells of the intestine. In-situ hybridization with a 3'-probe localized (rat) rMuc3 expression generally to columnar cells. Two antibodies specific for the C-termini of rat rMuc3 localized the protein to apical membranes and cytoplasm of columnar cells. An antibody to the tandem repeat sequence, however, localized the protein to both columnar and goblet cells. Cesium chloride ultracentrifugation was used to isolate both light- and heavy-density fractions. A full-length membrane-associated form (light density) was found in columnar cells, whereas, the carboxyl-truncated soluble form of rat Muc3 (heavy density) was present in goblet cells (Wang et al., 2002). A similar localization of human MUC17 may exist as the splice variant, MUC17SEC, encodes a truncated protein that is missing the second EGF-like domain, the transmembrane domain, and the cytoplasmic tail. The MUC17/SEC protein is believed to be a soluble protein as the absence of the transmembrane domain would result in its secretion from the cell. In a mouse model of human cystic fibrosis, both soluble Muc3 and goblet cell Muc2 are increased and hyper-secreted contributing to the excess intestinal mucus of cystic fibrosis mice (Khatri et al., 2001). Function MUC17 is a membrane-bound glycoprotein that may serve as a cellular receptor through its extended, repetitive extracellular glycosylation domain. The extracellular domain may serve a lubricant functionality and provide a signal transduction capability. Membrane mucins, such as MUC17, function in epithelial cells to provide cytoprotection, maintain luminal structure, provide signal transduction, and confer anti-adhesive properties to cancer cells which lose their apical/basal polarization. Outside-in signaling may be transduced by the protein's interaction with extracellular matrix constituents including

Atlas Genet Cytogenet Oncol Haematol 2008; 3 372 growth factors and cytokines and/or potentially binding of Ca2+ or EGF ligands to extracellular displayed EGF-like domains. The 80 amino acid cytoplasmic domain has potential serine and tyrosine phosphorylation sites to convey extracellular signals. Analysis of mouse Muc3 showed that a definitive proteolytic cleavage occurs during processing in the endoplasmic reticulum. Recombinant products consisted of a V5-tagged 30 kDa extracellular glycopeptide and a Myc-tagged 49 kDa membrane-associated glycopeptide. Throughout their cellular transport to the plasma membrane, the two fragments remained associated by non-covalent SDS-sensitive interactions. Site-specific mutagenesis showed requirement for glycine and serine residues in the cleavage sequence Leu-Ser-Lys-Gly-Ser-Ile-Val-Val, which is found in the SEA domain between the two EGF-like motifs of the mucin. A similar cleavage sequence has been reported in human MUC1 and analogous sites are present in human MUC3, MUC12, MUC16 and MUC17. Proteolytic cleavage may be a conserved characteristic of the membrane-bound mucins, and possibly precedes the release of their large extracellular domains at cell surfaces (Wang et al., 2002). Homology The similarity of human MUC17 to rodent Muc3 (mouse and rat) was first reported by JR Gum Jr and colleagues. This similarity was represented by a cladogram calculated using sequences initiating at the start of the second EGF-like domain and continuing through to the carboxy-termini of the proteins. The analysis suggests that MUC17 diverged from human MUC3 earlier in evolution than the divergence of primates and rodents, and suggests that MUC17 is the true structural homolog of rodent Muc3 (Gum et al., 2002). Whether MUC17 is the functional homolog of rodent Muc3 is still unclear, however, and needs to be experimentally proven. Chromosome computer analysis assigns mouse Muc3 to mouse chromosome 5, a region of synteny to human chromosome 7, the location of the human MUC3, MUC12, and MUC17 mucin genes. NCBI HomoloGene reports MUC17 is conserved in Coelomata or in organisms higher than coelenterates and certain primitive worms. Expression of the mouse Muc3 mucin has been characterized in terms of regulation of its promoter by cytokines and growth factors. Mouse Muc3 is now believed to be the true structural homologue of human MUC17 due to higher sequence similarity to MUC17 than human MUC3 (Moniaux et al., 2006). The N-terminal domain for MUC17 is coded by two exons, whereas for MUC3, it is coded by a single exon. Gum and colleagues (2002) showed that the degree of sequence homology between the carboxy-extremity of MUC17 and mMuc3 was higher than that between MUC3 and mMUC3. An alignment of the amino- extremities of MUC17, MUC3, and mMuc3 is shown. No similarity is shown by MUC3 and mMuc3, but a high degree of identity exists between MUC17 and mMUC3. Their similar structural organization and high degree of identity show that MUC17 is the human homologue of mMuc3. A search of the National Center for Bioinformatics HomoloGene and UniGene databases returned the following suggested sequences for comparison. HomoloGene:88635. Gene conserved in Coelomata

Atlas Genet Cytogenet Oncol Haematol 2008; 3 373 Chimpanz ee (West P.troglodytes MUC17 mucin 17, chromosome 7, GeneID: 740201 African) Mouse M.musculus Muc3 mucin 3, intestinal Rhesus Macaca chromosome 3 monkey mulatta Homo membrane mucin MUC17 (Homo sapiens) Human CAE54435 sapiens gi/51869309/emb/CAE54435.1/(51869309) Homo secreted mucin MUC17 (Homo sapiens) gi/ Human CAE54436 sapiens 51869311/emb/CAE54436.1/(51869311) intestinal membrane mucin MUC17 (Homo Homo sapiens) Human AAL89737 sapiens gi/19526645/gb/AAL89737.1/AF430017_1( 19526645) Homo MUC17 protein (Homo sapiens) Human AAI26316 sapiens gi/118835615/gb/AAI26316.1/(118835615) Homo NP_0010351 mucin 17 (Homo sapiens) gi/91982772/ref/ Human sapiens 94 NP_001035194.1/(91982772) Chimpanz PREDICTED: mucin 17 (Pan troglodytes) Pan XP_00114208 ee (West gi/114615083/ref/XP_001142083.1/ troglodytes 3 African) (114615083) Opossum PREDICTED: similar to membrane mucin (gray Monodelphis XP_00137522 MUC17 (Monodelphis domestica) short- domestica 1 gi/126323716/ref/XP_001375221.1/ tailed) (126323716) Opossum PREDICTED: similar to MUC17 protein (gray Monodelphis XP_00137134 (Monodelphis domestica) gi/126309309/ref/ short- domestica 6 XP_001371346.1/(126309309) tailed) PREDICTED: similar to intestinal XP_00123366 membrane mucin MUC17, partial (Gallus Chicken Gallus gallus 7 gallus) gi/118121828/ref/XP_001233667.1/ (118121828) secreted mucin MUC17, putative (Aedes Aedes mosquito EAT36316 aegypti), gi/108872091/gb/EAT36316.1/ aegypti (108872091) Opossum similar to MUC17 protein (Monodelphis (gray Monodelphis LOC1000179 domestica) , Chromosome: 2, GeneID: short- domestica 48 100017948 tailed) similar to intestinal membrane mucin Chicken Gallus gallus LOC770330 MUC17 (Gallus gallus), Chromosome: Un, GeneID: 770330 Opossum similar to membrane mucin MUC17 (gray Monodelphis LOC1000237 (Monodelphis domestica), Chromosome: 3, short- domestica 79 GeneID: 100023779 tailed) Chimpanz similar to membrane mucin MUC17 (Pan Pan ee (West LOC463614 troglodytes), Chromosome: 7, GeneID: troglodytes African) 463614 Rat Muc17_predicted and Name: mucin 17 Rattus Muc17_predic (Brown (predicted) (Rattus norvegicus), norvegicus ted Norway) Chromosome: 7, GeneID: 295035 D.melanoga Salivary gland secretion 1, 25B2-3 puff, Fruit Fly Sgs1 ster salivary glands,third instar Select Atlas Genet Cytogenet Oncol Haematol 2008; 3 374 Implicated in Entity Pancreatic Adenocarcinoma Disease Worldwide, pancreatic cancer is the eleventh most common cancer. In the United States of America, pancreatic cancer is the fourth leading cause of cancer related death. Pancreatic cancer presents a 5-year survival rate of just 5%. The incidence and age-adjusted mortality rate (approximatively 95%) are almost equal, underscoring the aggressive nature of the disease. Prognosis Currently, no approved diagnostic biomarker for pancreatic cancer is licensed in the United States. The CA19-9 mucin epitope is used for the diagnosis of ovarian cancer and other mucins are being developed for the detection of breast cancer (MUC1) and pancreatic cancer (MUC1, MUC4, MUC3, MUC17). The DUPAN-2 antibody recognizes a tumor-associated antigen carried by the MUC4 protein and is used as a clinical diagnostic for pancreatic adenocarcinoma in Japan. MUC4 is aberrantly expressed in 80% of pancreatic adenocarcinomas and is not expressed in the normal pancreas or benign pancreatitis. In addition MUC4 is expressed early in the onset of pancreatic cancer (detected in pancreatic intraepithelial neoplasia (PanIN) stage I disease). Similarly, MUC17 is aberrantly expressed in pancreatic adenocarcinomas as compared to no expression in the normal pancreas or benign pancreatitis. MUC17 is expressed early in the progression of pancreatic cancer with localization to well defined pancreatic ductal structures undergoing malignant transformation (Moniaux et al., 2006). Oncogenesis In an in vivo model, subcutaneous injection of MUC17 AsPC-1 knock-down cells show slight increase in tumorigenicity in relation to parental control cells; although no significant difference was detected due to large variation in tumor weights. A xenograph model with knock-down cell lines injected orthotopically into the pancreas head showed an increased potential to metastasize to the peritoneal cavity and increased tumor mass (weight) in relation to mice injected with the parental cell line (control group) transfected with a scrambled RNAi sequence (unpublished data, Junker and Batra, 2007). To be noted Conserved in Coelomata. From (HomoloGene: 88635. Gene conserved in Coelomata) Coelome: the cavity within the body of all animals higher than the coelenterates and certain primitive worms, formed by the splitting of the embryonic mesoderm into two layers. In mammals, the coelome forms the peritoneal, pleural, and pericardial cavities. External links Nomenclature Hugo MUC17 GDB MUC17 Entrez_Gene MUC17 140453 mucin 17, cell surface associated Cards Atlas MUC17ID41456ch7q22 GeneCards MUC17 MUC17 [Search_View] ENSG00000169876 Ensembl [Gene_View] Genatlas MUC17 GeneLynx MUC17 eGenome MUC17 euGene 140453 Genomic and cartography MUC17 - 7q22.1 chr7:100450084-100488860 + GoldenPath 7q22.1 [Description] (hg18-Mar_2006) Ensembl MUC17 - 7q22.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MUC17 Gene and transcription Genbank AF016692 [ ENTREZ ] Genbank AF016693 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 375 Genbank AF016694 [ ENTREZ ] Genbank AF430017 [ ENTREZ ] Genbank AJ606307 [ ENTREZ ] NM_001040105 [ SRS ] NM_001040105 RefSeq [ ENTREZ ] RefSeq AC_000050 [ SRS ] AC_000050 [ ENTREZ ] RefSeq AC_000068 [ SRS ] AC_000068 [ ENTREZ ] RefSeq NC_000007 [ SRS ] NC_000007 [ ENTREZ ] RefSeq NT_007933 [ SRS ] NT_007933 [ ENTREZ ] RefSeq NT_079596 [ SRS ] NT_079596 [ ENTREZ ] RefSeq NW_923618 [ SRS ] NW_923618 [ ENTREZ ] AceView MUC17 AceView - NCBI Hs.271819 [ SRS ] Hs.271819 [ NCBI ] Unigene HS271819 [ spliceNest ] Fast-db 9923 (alternative variants) Protein : pattern, domain, 3D structure HPRD 16335 Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 608424 [ map ] GENECLINICS 608424 SNP MUC17 [dbSNP-NCBI] SNP NM_001040105 [SNP-NCI] MUC17 [GeneSNPs - Utah] MUC17] [HGBASE - SNP SRS] HAPMAP MUC17 [HAPMAP] HGMD MUC17 General knowledge Family Browser MUC17 [UCSC Family Browser] SOURCE NM_001040105 SMD Hs.271819 SAGE Hs.271819 GO cellular_component [Amigo] cellular_component GO biological_process [Amigo] biological_process extracellular matrix constituent, lubricant activity GO [Amigo] extracellular matrix constituent, lubricant activity PubGene MUC17 TreeFam MUC17 CTD 140453 [Comparative Genomics Database] Other databases http://human.genelynx.org/cgi-bin/record? Other database glid=4025 Probes Probe MUC17 Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography Molecular cloning of human MUC3 cDNA reveals a novel 59 amino acid tandem repeat region. Van Klinken BJ, Van Dijken TC, Oussoren E, Bˆºller HA, Dekker J, Einerhand AW Biochemical and biophysical research communications. 1997 ; 238 (1) : 143-148. PMID 9299468

Cloning and characterization of mouse intestinal MUC3 mucin: 3' sequence contains epidermal-growth-factor-like domains.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 376 Shekels LL, Hunninghake DA, Tisdale AS, Gipson IK, Kieliszewski M, Kozak CA, Ho SB The Biochemical journal. 1998 ; 330 ( Pt 3) : 1301-1308. PMID 9494100

Characteristics of rodent intestinal mucin Muc3 and alterations in a mouse model of human cystic fibrosis. Khatri IA, Ho C, Specian RD, Forstner JF American journal of physiology. Gastrointestinal and liver physiology. 2001 ; 280 (6) : G1321-G1330. PMID 11352827

MUC17, a novel membrane-tethered mucin. Gum JR Jr, Crawley SC, Hicks JW, Szymkowski DE, Kim YS Biochemical and biophysical research communications. 2002 ; 291 (3) : 466-475. PMID 11855812

Transforming growth factor-beta -Smad signaling pathway cooperates with NF-kappa B to mediate nontypeable Haemophilus influenzae-induced MUC2 mucin transcription. Jono H, Shuto T, Xu H, Kai H, Lim DJ, Gum JR Jr, Kim YS, Yamaoka S, Feng XH, Li JD The Journal of biological chemistry. 2002 ; 277 (47) : 45547-45557. PMID 12237307

C-terminal domain of rodent intestinal mucin Muc3 is proteolytically cleaved in the endoplasmic reticulum to generate extracellular and membrane components. Wang R, Khatri IA, Forstner JF The Biochemical journal. 2002 ; 366 (Pt 2) : 623-631. PMID 12027806

N-glycosylation is required for the surface localization of MUC17 mucin. Ho JJ, Jaituni RS, Crawley SC, Yang SC, Gum JR, Kim YS International journal of oncology. 2003 ; 23 (3) : 585-592. PMID 12888891

Characterization of the mouse Muc3 membrane bound intestinal mucin 5' coding and promoter regions: regulation by inflammatory cytokines. Shekels LL, Ho SB Biochimica et biophysica acta. 2003 ; 1627 (2-3) : 90-100. PMID 12818427

Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Brant SR, Shugart YY Inflammatory bowel diseases. 2004 ; 10 (3) : 300-311. PMID 15290927

Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin. Macao B, Johansson DG, Hansson GC, Hˆ§rd T Nature structural & molecular biology. 2006 ; 13 (1) : 71-76. PMID 16369486

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease. Moehle C, Ackermann N, Langmann T, Aslanidis C, Kel A, Kel-Margoulis O, Schmitz-Madry A, Zahn A, Stremmel W, Schmitz G Journal of molecular medicine (Berlin, Germany). 2006 ; 84 (12) : 1055-1066. PMID 17058067

Characterization of human mucin MUC17. Complete coding sequence and organization. Moniaux N, Junker WM, Singh AP, Jones AM, Batra SK The Journal of biological chemistry. 2006 ; 281 (33) : 23676-23685.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 377 PMID 16737958

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Contributor(s) Written 10-2007 Wade M Junker, Nicolas Moniaux, Surinder K Batra Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Durham Research Center 7005, Omaha, NE 68198-5870, USA (SKB) Citation This paper should be referenced as such : Junker WM, Moniaux N, Batra SK . MUC17 (mucin 17, cell surface associated). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/MUC17ID41456ch7q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 378 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MUC16 (mucin 16, cell surface associated)

Identity Other names CA125 FLJ14303 Mucin-16 Hugo MUC16 Location 19p13.2 Note MUC16 belongs to the subgroup of the membrane-anchored mucin. It is a type-1 glycopotein with heavy O- and N-type glycosylation. DNA/RNA

Shows the genomic organization of MUC16 gene.

Description In the genome, MUC16 is localized in 19p13.2 chromosome and is coded by sequences present within approximatively 179kb of genomic DNA. Transcription As per the present available information, there is a discrepancy regarding the total number of exons present in MUC16 genomic DNA. This discrepancy is due to the absence/presence of some of the genomic sequences (particularly for the repeat regions) in the available genomic databases. The terminal nine exons on both 5' and 3' ends code for the amino- and carboxy-terminal domains of MUC16, respectively. At the same time, it has been proposed that five consecutive exons code for a single repeat unit (SRU) of the central tandem repeat domain. Protein

Shows the structural organization of CA125/MUC16 protein.

Description MUC16 protein harbors a central tandem repeat region, N-terminal domain and carboxy terminal domain. The N-terminal domain has 12070 numbers of amino acids rich in serine/threonine residues and accounts for the major O-glycosylation known to be present in CA125. The MUC16 protein back bone is dominated by tandem repeat region, which has more than 60 repeat domains, each composed of 156 amino acids. Though all the individual repeat units are not similar, most of them occur more than once in the sequence. The repeat units are rich in serine, threonine and proline residues, which are typical for any mucins. Each repeat unit has some homology to the SEA (Sea-urchin sperm protein, Enterokinase and Agrin) module, whose exact biological function is not known.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 379 The epitopes for known anti-CA125 antibodies (OC125 and M11) are thought to be present on a small cysteine ring region present in the tandem-repeat region of MUC16. The carboxy-terminal domain has 284 aminoacids and can be divided into three different regions: extra cellular, transmembrane and cytoplasmic tail. The extracellular part of the carboxy-terminal domain has many N-glycosylation sites and some O- glycosyaltion sites. Several in silico analyses suggest a putative cleavage site in the extracellular part of carboxy-terminal domain. The MUC16 cytoplasmic tail is 31 amino acids long and has many possible phosphorylation sites. The phosphorylation of CA125 in WISH cells has been reported by labeling with 32PO43- and immunoprecipitaion analysis but the exact site of phosphorylation is yet to be mapped. Interestingly, CA125 contains a putative tyrosine phosphorylation site (RRKKEGY), which was first recognized in Src family protein. This sequence is conserved in the translated mouse EST (AK003577) that has homology with CA125/MUC16 at the C-terminal end. Recently, it has been shown that MUC16 cytoplasmic tail, which contains a polybasic aminoacid sequence, interacts with cytoskeleton through ERM (ezrin/radixin/moesin) actin-binding proteins. Expression The expression of MUC16 has been reported in human epithelia of conjunctiva, cornea, middle ear and trachea under normal physiological conditions. MUC16 is also expressed in ovarian carcinoma. Localisation It is a type I membrane-bound protein and due to cleavage gets secreted into the extracellular space. On the ocular surface, MUC16 is expressed on the tips of the microplicae of the ocular surface. Function MUC16 provides a disadhesive protective barrier to the ocular epithelial surface. Overexpression of CA125/MUC16 in ovarian cancer indicates its possible role in cancer pathogenesis. Studies have shown that CA125/MUC16 binds to mesothelin and galectin-1, which are overexpressed in ovarian cancer. It has also been shown that mesothelin-MUC16 interaction has significance in adhesion of ovarian cancer cells to mesothelial cells present on the inner wall of the peritoneum and on the surface of other abdominal organs. This cell to cell adhesion may help in ovarian cancer metastasis. It has been proposed that galectin-1 bound to MUC16 may cause apoptosis of T cells, and thus help in the suppression of the host immunity. Homology Similar to mucin 16 of Pan troglodytes, Canis lupus familiaris, Mus musculus, Rattus norvegicus and Gallus gallus. Implicated in Entity Ovarian cancer Disease Epithelial ovarian cancer is the most lethal gynaecologic malignancy in the United States and other parts of the world. In the United States, ovarian cancer accounts for approximately 22,000 new cases and 16,000 deaths occurring every year. The epithelial ovarian carcinomas represent approximately 90% of all types of ovarian malignant neoplasms. Due to lack of specific signs and symptoms of this disease, coupled with lack of reliable screening strategies most patients are diagnosed in the advanced stage of the disease, resulting in low overall cure rates. Ovarian cancer patients are generally treated with surgical resection and subsequent platinum-based chemotherapy. Although, many patients initially respond well to chemotherapy, long term survival remains poor due to eventual tumor recurrence and emergence of drug- resistant disease. Overall, the five year survival rate is 45%. Prognosis Since the last 20 years, CA125/MUC16 has been used as a well-established marker for diagnosis of ovarian cancer. It is mostly overexpressed in serous type of ovarian cancers and less likely to be expressed in mucinous tumors. More than 80% of ovarian cancer patients have elevated CA125 level during their treatment period. It has been shown that the disease progression is associated with an increase in serum CA125 level, while a decline in serum CA125 level is associated with response to therapy. In another finding, it has been shown that the trend of serum CA125 level during the first three courses of chemotherapy is a strong forecaster of re-examination findings in patients with ovarian carcinoma at the end of treatment. Interestingly, it has been shown that a normal CA125 level by the end of second or third chemotherapy is strongly linked to the survival of patients in stage 3 or stage 4 conditions. Also, variations in the CA125 value even within the normal range carry useful information regarding prediction of time to treatment failure. Additionally, in patients in stage 1

Atlas Genet Cytogenet Oncol Haematol 2008; 3 380 cancers it has been suggested that CA125 elevations are not related to the tumor mass volume. Recently, the potential of CA125/MUC16 as a therapeutic target has been harnessed by using an armed human antibody (3A5) against MUC16 protein. Oncogenesis There is no experimental evidence in the scientific literature for a role of MUC16 in oncogenesis. However, MUC16 possesses many structural similarities with other membrane bound mucins, like MUC1 and MUC4, which are already shown to be functionally involved in different cancers. Transmembrane mucins are hypothesized to serve as sensors of the external environment and can transduce signals via the post- translational modifications of their cytoplasmic tail. Phosphorylation of MUC16 protein has already been reported. Though the exact interacting partner and the site of phosphorylation are unknown, the presence of potential phosphorylation sites in MUC16 cytoplasmic tail indicates the possible role of MUC16 in downstream signal transduction. Further, it has been shown that MUC16 interacts with galectin-1 and mesothelin and these interactions may have a role in cancer progression. External links Nomenclature Hugo MUC16 GDB MUC16 Entrez_Gene MUC16 94025 mucin 16, cell surface associated Cards Atlas MUC16ID41455ch19q13 GeneCards MUC16 Ensembl MUC16 [Search_View] ENSG00000205631 [Gene_View] Genatlas MUC16 GeneLynx MUC16 eGenome MUC16 euGene 94025 Genomic and cartography MUC16 - 19p13.2 chr19:8820521-8953018 - 19p13.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl MUC16 - 19p13.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MUC16 Gene and transcription Genbank AF361486 [ ENTREZ ] Genbank AF414442 [ ENTREZ ] Genbank AK024365 [ ENTREZ ] Genbank AK056791 [ ENTREZ ] Genbank AK128681 [ ENTREZ ] RefSeq NM_024690 [ SRS ] NM_024690 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView MUC16 AceView - NCBI Unigene Hs.432676 [ SRS ] Hs.432676 [ NCBI ] HS432676 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q8WXI7 [ SRS] Q8WXI7 [ EXPASY ] Q8WXI7 [ INTERPRO ] Prosite PS50297 ANK_REP_REGION [ SRS ] PS50297 ANK_REP_REGION [ Expasy ] Prosite PS50088 ANK_REPEAT [ SRS ] PS50088 ANK_REPEAT [ Expasy ] Prosite PS50024 SEA [ SRS ] PS50024 SEA [ Expasy ] Interpro IPR002110 ANK [ SRS ] IPR002110 ANK [ EBI ] Interpro IPR000082 SEA [ SRS ] IPR000082 SEA [ EBI ] CluSTr Q8WXI7

Atlas Genet Cytogenet Oncol Haematol 2008; 3 381 Pfam PF01390 SEA [ SRS ] PF01390 SEA [ Sanger ] pfam01390 [ NCBI-CDD ] Smart SM00200 SEA [EMBL] Blocks Q8WXI7 Protein Interaction databases DIP Q8WXI7 IntAct Q8WXI7 Polymorphism : SNP, mutations, diseases OMIM 606154 [ map ] GENECLINICS 606154 SNP MUC16 [dbSNP-NCBI] SNP NM_024690 [SNP-NCI] SNP MUC16 [GeneSNPs - Utah] MUC16] [HGBASE - SRS] HAPMAP MUC16 [HAPMAP] HGMD MUC16 General knowledge Family Browser MUC16 [UCSC Family Browser] SOURCE NM_024690 SMD Hs.432676 SAGE Hs.432676 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 extrinsic to membrane [Amigo] extrinsic to membrane PubGene MUC16 TreeFam MUC16 CTD 94025 [Comparative Genomics Database] Other databases Probes Probe MUC16 Related clones (RZPD - Berlin) PubMed PubMed 34 Pubmed reference(s) in LocusLink Bibliography The CA 125 gene: an extracellular superstructure dominated by repeat sequences. O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD, York L Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2001 ; 22 (6) : 348-366. PMID 11786729

Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. Yin BW, Lloyd KO The Journal of biological chemistry. 2001 ; 276 (29) : 27371-27375. PMID 11369781

The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure. O'Brien TJ, Beard JB, Underwood LJ, Shigemasa K Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2002 ; 23 (3) : 154-169. PMID 12218296

Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Yin BW, Dnistrian A, Lloyd KO International journal of cancer. Journal international du cancer. 2002 ; 98 (5) : 737-740. PMID 11920644

Atlas Genet Cytogenet Oncol Haematol 2008; 3 382

The cancer antigen CA125 represents a novel counter receptor for galectin-1. Seelenmeyer C, Wegehingel S, Lechner J, Nickel W Journal of cell science. 2003 ; 116 (Pt 7) : 1305-1318. PMID 12615972

Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16). Maeda T, Inoue M, Koshiba S, Yabuki T, Aoki M, Nunokawa E, Seki E, Matsuda T, Motoda Y, Kobayashi A, Hiroyasu F, Shirouzu M, Terada T, Hayami N, Ishizuka Y, Shinya N, Tatsuguchi A, Yoshida M, Hirota H, Matsuo Y, Tani K, Arakawa T, Carninci P, Kawai J, Hayashizaki Y, Kigawa T, Yokoyama S The Journal of biological chemistry. 2004 ; 279 (13) : 13174-13182. PMID 14764598

Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith LM, Moniaux N, Batra SK Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2006 ; 19 (10) : 1386-1394. PMID 16880776

Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16. Duraisamy S, Ramasamy S, Kharbanda S, Kufe D Gene. 2006 ; 373 : 28-34. PMID 16500040

Methylation mediated silencing of TMS1/ASC gene in prostate cancer. Das PM, Ramachandran K, Vanwert J, Ferdinand L, Gopisetty G, Reis IM, Singal R Molecular cancer. 2006 ; 5 : page 28. PMID 16848908

Functions of MUC16 in corneal epithelial cells. Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR, Gilmore MS, Ramesh V, Gipson IK Investigative ophthalmology & visual science. 2007 ; 48 (10) : 4509-4518. PMID 17898272

Armed antibodies targeting the mucin repeats of the ovarian cancer antigen, MUC16, are highly efficacious in animal tumor models. Chen Y, Clark S, Wong T, Chen Y, Chen Y, Dennis MS, Luis E, Zhong F, Bheddah S, Koeppen H, Gogineni A, Ross S, Polakis P, Mallet W Cancer research. 2007 ; 67 (10) : 4924-4932. PMID 17510422

MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells. Davies JR, Kirkham S, Svitacheva N, Thornton DJ, Carlstedt I The international journal of biochemistry & cell biology. 2007 ; 39 (10) : 1943-1954. PMID 17604678

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Contributor(s) Written Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh 10-2007 Jain, Surinder K Batra Department of Biochemistry and Molecular Biology, University of Nebraska

Atlas Genet Cytogenet Oncol Haematol 2008; 3 383 Medical Center, 985870 Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA (SKB) Citation This paper should be referenced as such : Senapati S, Ponnusamy MP, Singh AP, Jain M, Batra SK . MUC16 (mucin 16, cell surface associated). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/MUC16ID41455ch19q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 384 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAML2 (mastermind-like 2)

Identity Other names hMam-3 KIAA1819 Hugo MAML2 Location 11q21 DNA/RNA Description Spans 365 kb; 5 exons. Transcription A major transcript of 7.5 kb. Protein Description 1153 aa, 125 kDa; conserved N-terminal basic domain (aa 29-92) which binds to the ankyrin repeat domain of Notch receptors; two acidic domains (aa 263-360 and 1124-1153) and a C-terminal transcriptional activation domain. Expression Widely expressed. Localisation Nuclear granules. Function Mastermind-like coactivator for all four Notch receptors; forms a complex with the Notch intracellular domain (Notch ICD) and the CSL family of transcription factors (CSL: CBF1/RBP-jk, Suppressor of Hairless, LAG1), resulting in activation of the Notch target genes HES1 and HES5; functions as a CSL-dependent transcriptional coactivator for ligand-stimulated Notch. Homology MAML1 and MAML3. Implicated in Entity mucoepidermoid carcinoma with t(11;19)(q21-22;p13). Disease - Most common type of malignant salivary gland tumor; - Second most frequent lung tumor of bronchial gland origin; - Rare tumour in the thyroid. The t(11;19) was found in samples from the three different sites. Prognosis - Mucoepidermoid carcinomas have an unpredictable behaviour. - The CRTC1-MAML2 fusion transcript was found equally in low, intermediate and high grade tumours; however, tumours lacking the fusion transcript were significantly associated with metastases; they may represent a subset of aggressive tumours. - In another study, the median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. Hybrid/Mutated CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2-5 of MAML2. Note: CRTC1 is also Gene known as MECT1, or WAMTP1. Abnormal CRTC1-MAML2. In the fusion protein, the first 171 aa including the basic domain of Protein MAML2 are replaced by 42 aa of CRTC1; there are no sequence similarities in the N- terminal domains of MAML2 and CRTC1. The fusion protein activates transcription of the Notch target gene HES1 independently of both Notch ligand and CSL. Transforming activity of CRTC1-MAML2 fusion oncoprotein is mediated by mimicking constitutive activation of cAMP signaling, by activating CREB directly. Entity Warthin's tumor with t(11;19)(q21-22;p13). Note In rare instances mucoepidermoid carcinoma may arise from or coexist with Warthin's tumors. Disease Warthin's tumor is a salivary gland neoplasm consisting of benign epithelial and lymphoid components; malignant transformation is extremely rare. Hybrid/Mutated CRTC1-MAML2 Gene Entity Clear Cell Hidradenomas of the skin with t(11;19)(q21-22;p13) Disease Clear Cell Hidradenomas of the skin are benign sweat gland tumors of eccrine duct origin.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 385 Hybrid/Mutated CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2 of MAML2. Gene Entity inv(11)(q21q23) in therapy related leukemias Disease therapy-related acute leukemia and MDS. Hybrid/Mutated MLL-MAML2; exon 1-7 of MLL fused to exons 2-5 of MAML2. Gene Abnormal Hybrid transcript MLL/MAML2 contains the following domains: from MLL: AT-hook, Protein DNA-Methyltransferase; from MAML2: Q rich domain, acidic domain.

To be noted It is amazing that a similar fusion transcript (CRTC1-MAML2) can be seen both in a benign and in a malignant tumour of the same organ: Warthin's tumor, a benign salivary gland neoplasm, and mucoepidermoid carcinoma of the salivary gland: either another event differentiate the two, or the genetic event takes place in different cell types or in a given cell type at different states of differenciation. It has been hypothezised that CRTC1-MAML2 fusion is etiologically linked to benign and low-grade malignant tumors originating from diverse exocrine glands rather than being linked to a separate tumor entity. External links Nomenclature Hugo MAML2 GDB MAML2 Entrez_Gene MAML2 84441 mastermind-like 2 (Drosophila) Cards Atlas MAML2ID472 GeneCards MAML2 Ensembl MAML2 [Search_View] ENSG00000184384 [Gene_View] Genatlas MAML2 GeneLynx MAML2 eGenome MAML2 euGene 84441 Genomic and cartography MAML2 - 11q21 chr11:95351088-95715992 - 11q21 [Description] (hg18- GoldenPath Mar_2006) Ensembl MAML2 - 11q21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene MAML2 Gene and transcription Genbank AB058722 [ ENTREZ ] Genbank AY040322 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 386 Genbank AY186997 [ ENTREZ ] Genbank BC152449 [ ENTREZ ] Genbank CR627398 [ ENTREZ ] RefSeq NM_032427 [ SRS ] NM_032427 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_008984 [ SRS ] NT_008984 [ ENTREZ ] RefSeq NW_925173 [ SRS ] NW_925173 [ ENTREZ ] AceView MAML2 AceView - NCBI Unigene Hs.428214 [ SRS ] Hs.428214 [ NCBI ] HS428214 [ spliceNest ] Fast-db 13246 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q8IZL2 [ SRS] Q8IZL2 [ EXPASY ] Q8IZL2 [ INTERPRO ] CluSTr Q8IZL2 Blocks Q8IZL2 HPRD 09608 Protein Interaction databases DIP Q8IZL2 IntAct Q8IZL2 Polymorphism : SNP, mutations, diseases OMIM 607537 [ map ] GENECLINICS 607537 SNP MAML2 [dbSNP-NCBI] SNP NM_032427 [SNP-NCI] SNP MAML2 [GeneSNPs - Utah] MAML2] [HGBASE - SRS] HAPMAP MAML2 [HAPMAP] COSMIC MAML2 [Somatic mutation (COSMIC-CGP-Sanger)] TICdb MAML2 [Translocation breakpoints In Cancer] HGMD MAML2 General knowledge Family Browser MAML2 [UCSC Family Browser] SOURCE NM_032427 SMD Hs.428214 SAGE Hs.428214 GO transcription coactivator activity [Amigo] transcription coactivator activity GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO Notch signaling pathway [Amigo] Notch signaling pathway GO nuclear speck [Amigo] nuclear speck positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter KEGG Notch signaling pathway PubGene MAML2 TreeFam MAML2 CTD 84441 [Comparative Genomics Database] Other databases Probes Probe MAML2 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a

Atlas Genet Cytogenet Oncol Haematol 2008; 3 387 cystadenolymphoma (Warthin's tumor) of the parotid gland. Bullerdiek J, Haubrich J, Meyer K, Bartnitzke S Cancer genetics and cytogenetics. 1988 ; 35 (1) : 129-132. PMID 3180001

Chromosomal patterns in Warthin's tumor. A second type of human benign salivary gland neoplasm. Mark J, Dahlenfors R, Stenman G, Nordquist A Cancer genetics and cytogenetics. 1990 ; 46 (1) : 35-39. PMID 2331681

Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, Callahan R Genes & development. 1992 ; 6 (3) : 345-355. PMID 1372276

Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G Cancer genetics and cytogenetics. 1994 ; 74 (2) : 77-83. PMID 8019965

Conservation of the Notch signalling pathway in mammalian neurogenesis. de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA Development (Cambridge, England). 1997 ; 124 (6) : 1139-1148. PMID 9102301

A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma. Stenman G, Petursdottir V, Mellgren G, Mark J Virchows Archiv : an international journal of pathology. 1998 ; 433 (6) : 579-581. PMID 9870694

MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD Nature genetics. 2000 ; 26 (4) : 484-489. PMID 11101851

Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M The Journal of biological chemistry. 2002 ; 277 (52) : 50612-50620. PMID 12386158

Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD Molecular and cellular biology. 2002 ; 22 (21) : 7688-7700. PMID 12370315 t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ Nature genetics. 2003 ; 33 (2) : 208-213. PMID 12539049

Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 388 Enlund F, Behboudi A, Andrˆ©n Y, Oberg C, Lendahl U, Mark J, Stenman G Experimental cell research. 2004 ; 292 (1) : 21-28. PMID 14720503

A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands. Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J, Fonseca I The Journal of molecular diagnostics : JMD. 2004 ; 6 (3) : 205-210. PMID 15269296

Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1- MAML2 gene fusion. Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F, Stenman G Genes, chromosomes & cancer. 2005 ; 43 (2) : 202-205. PMID 15729701

Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD The EMBO journal. 2005 ; 24 (13) : 2391-2402. PMID 15961999

Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1- MAML2 fusion oncogene. Behboudi A, Enlund F, Winnes M, Andrˆ©n Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Mˆ§kitie A, Grenman R, Mark J, Stenman G Genes, chromosomes & cancer. 2006 ; 45 (5) : 470-481. PMID 16444749

Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T Genes, chromosomes & cancer. 2007 ; 46 (9) : 813-819. PMID 17551948

CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: implications for histogenesis and biologic behavior. Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK Genes, chromosomes & cancer. 2007 ; 46 (7) : 708-715. PMID 17437281

Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas. Winnes M, Mˆ ﾏ lne L, Suurkˆºla M, Andrˆ©n Y, Persson F, Enlund F, Stenman G Genes, chromosomes & cancer. 2007 ; 46 (6) : 559-563. PMID 17334997

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Contributor(s) Written 07-2003 Goran Stenman Lundberg Laboratory for Cancer Research, Department of Pathology, Goteborg University, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden Citation

Atlas Genet Cytogenet Oncol Haematol 2008; 3 389 This paper should be referenced as such : Stenman G . MAML2 (mastermind-like 2). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Genes/MAML2ID472.html Suzukawa K, Huret JL . MAML2 (mastermind-like 2). Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/MAML2ID472.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 390 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HYAL1 (hyaluronoglucosaminidase 1)

Identity Other names EC 3.2.1.35 HYAL-1 NT6 LUCA1 LUCA-1 FUS2 Hyaluronidase-1 precursor Hyaluronoglucosaminidase-1 Hs.75619 MGC45987 Hugo HYAL1 Location 3p21.3 The gene of Hyal1 is tightly clustered with HYAL-2 and HYAL-3. The gene for Hyal-2, Local_order HYAL2, the earliest known lysosomal hyaluronidase, resides immediately centromeric to HYAL1.

Note The HYAL1 gene was identified as identical with LUCA-1, a candidate tumour suppressor gene, especially for tobacco-related cancers. DNA/RNA Description The HYAL1 gene contains three exons and spans 12,492 bases (start: 50,312,324 bp to end 50,324,816 from 13pter) oriented at the minus strand. Transcription Eight alternatively spliced transcript variants of this gene encoding six distinct isoforms have been described. The longest transcript has a length of 2,518 bps, however it is not translated to protein, since, by retaining intron 1 (occurring within exon 1), it has a number of stop codons. The longest transcript that produces active HYAL1 has a length of 2075 bps. Pseudogene PHYAL1 Protein

Note HYAL1 is a secreted somatic tissue hyaluronidase, and the predominant hyaluronidase in human plasma. Although HYAL1 is predominantly secreted, it has an acid pH optimum in vitro. HYAL1 can degrade high molecular weight hyaluronan to small oligomers, primarily to tetrasaccharides, whereas HYAL2 (the other major human hyaluronidase) high molecular mass hyaluronan to an approximately 20 kDa product (approximatively 50 saccharide units). Description Size: 435 amino acids; Molecular mass: 48368 Da. The enzyme belongs to the group of carbohydrate-active enzymes (CASy), termed glycosyl hydrolase 56 family. Expression HYAL1 is highly expressed in liver, kidney and heart and weakly expressed in lung, placenta and skeletal muscle. No expression is detected in adult brain. Isoform 1 is expressed only in bladder and prostate cancer cells, G2/G3 bladder tumor tissues and lymph node specimens showing tumor invasive tumors cells. Isoform 3, isoform 4, isoform 5 and isoform 6 are expressed in normal bladder and bladder tumor tissues. HYAL1 expression has been described in squamous cell carcinoma, in small cell lung cancer and glioma lines. Localisation It is a secreted enzyme found in plasma and it is also present in lysosomes. Function It is a hydrolytic enzyme (endo-beta-acetyl-D-hexosaminidase) with optimum pH about 3.7, acting on hyaluronan, chondroitin and chondroitin sulphate. It possesses also

Atlas Genet Cytogenet Oncol Haematol 2008; 3 391 transglycosidase activity using hyaluronan and chondroitin sulphate or chondroitin as substrates. This reaction is not well understood, and the precise enzymatic mechanism is not known. Homology The enzyme possesses 70-80 % homology to orthologue hyaluronidases, 40% homology to paralogue hyaluronidases of the human and high homology with HYAL1 of other species. Mutations Somatic There are not extended reports regarding mutations of HYAL1 gene. The patient with hyaluronidase deficiency was a compound heterozygote for two mutations in the HYAL1 gene: a 1412G-A mutation that introduced a nonconservative amino acid substitution (glu268 to lys) in a putative active site residue, and a complex intragenic rearrangement, 1361del37ins14, that resulted in a premature termination codon. In addition, the mutated HYAL1 gene has a markedly different expression pattern than the normal one. Implicated in Entity Mucopolysaccharidosis type IX (MPS9). Note Defects in HYAL1 are the cause of mucopolysaccharidosis type IX, also called hyaluronidase deficiency. Disease The clinical features are periarticular soft tissue masses, mild short stature and acetabular erosions, absence of neurological or visceral involvement and high hyaluronan concentration in the serum. Entity Cancer Note HYAL1 is inactivated in most lung cancers in a conventional manner, by loss of heterozygosity or by homozygous deletion, at the DNA level. It is also inactivated in many head and neck carcinomas that are tobacco-related by aberrant splicing of the mRNA, so that only the nontranslatable form is transcribed. In addition, the expression of an alternative spliced isoform resulting in active enzyme may negatively regulate bladder tumor growth, infiltration, and angiogenesis. On the other hand, HYAL1 can function as oncogene in many cancers of the prostate and urinary tract and seems to play important role in squamous cell laryngeal carcinoma. External links Nomenclature Hugo HYAL1 GDB HYAL1 Entrez_Gene HYAL1 3373 hyaluronoglucosaminidase 1 Cards Atlas HYAL1ID40903ch3p21 GeneCards HYAL1 Ensembl HYAL1 [Search_View] ENSG00000114378 [Gene_View] Genatlas HYAL1 GeneLynx HYAL1 eGenome HYAL1 euGene 3373 Genomic and cartography HYAL1 - 3p21.3 chr3:50312325-50316008 - 3p21.3-p21.2 [Description] (hg18- GoldenPath Mar_2006) Ensembl HYAL1 - 3p21.3-p21.2 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene HYAL1 Gene and transcription Genbank AF118821 [ ENTREZ ] Genbank AF173154 [ ENTREZ ] Genbank AF502904 [ ENTREZ ] Genbank AF502905 [ ENTREZ ] Genbank AF502906 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 392 RefSeq NM_007312 [ SRS ] NM_007312 [ ENTREZ ] RefSeq NM_033159 [ SRS ] NM_033159 [ ENTREZ ] RefSeq NM_153281 [ SRS ] NM_153281 [ ENTREZ ] RefSeq NM_153282 [ SRS ] NM_153282 [ ENTREZ ] RefSeq NM_153283 [ SRS ] NM_153283 [ ENTREZ ] RefSeq NM_153284 [ SRS ] NM_153284 [ ENTREZ ] RefSeq NM_153285 [ SRS ] NM_153285 [ ENTREZ ] RefSeq NM_153286 [ SRS ] NM_153286 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView HYAL1 AceView - NCBI Unigene Hs.75619 [ SRS ] Hs.75619 [ NCBI ] HS75619 [ spliceNest ] Fast-db 7141 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q12794 [ SRS] Q12794 [ EXPASY ] Q12794 [ INTERPRO ] Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ] Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Interpro IPR013785 Aldolase_TIM [ SRS ] IPR013785 Aldolase_TIM [ EBI ] Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR013032 EGF_like_reg_CS [ SRS ] IPR013032 EGF_like_reg_CS [ EBI ] Interpro IPR001968 Glyco_hydro_56 [ SRS ] IPR001968 Glyco_hydro_56 [ EBI ] CluSTr Q12794 PF01630 Glyco_hydro_56 [ SRS ] PF01630 Glyco_hydro_56 Pfam [ Sanger ] pfam01630 [ NCBI-CDD ] Smart SM00181 EGF [EMBL] Prodom PD003549 Glyco_hydro_56[INRA-Toulouse] Q12794 HYAL1_HUMAN [ Domain structure ] Q12794 HYAL1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q12794 PDB 2PE4 [ SRS ] 2PE4 [ PdbSum ], 2PE4 [ IMB ] 2PE4 [ RSDB ] HPRD 06146 Protein Interaction databases DIP Q12794 IntAct Q12794 Polymorphism : SNP, mutations, diseases OMIM 601492;607071 [ map ] GENECLINICS 601492;607071 SNP HYAL1 [dbSNP-NCBI] SNP NM_007312 [SNP-NCI] SNP NM_033159 [SNP-NCI] SNP NM_153281 [SNP-NCI] SNP NM_153282 [SNP-NCI] SNP NM_153283 [SNP-NCI] SNP NM_153284 [SNP-NCI] SNP NM_153285 [SNP-NCI] SNP NM_153286 [SNP-NCI] SNP HYAL1 [GeneSNPs - Utah] HYAL1] [HGBASE - SRS] HAPMAP HYAL1 [HAPMAP] HGMD HYAL1 General knowledge

Atlas Genet Cytogenet Oncol Haematol 2008; 3 393 Family Browser HYAL1 [UCSC Family Browser] SOURCE NM_007312 SOURCE NM_033159 SOURCE NM_153281 SOURCE NM_153282 SOURCE NM_153283 SOURCE NM_153284 SOURCE NM_153285 SOURCE NM_153286 SMD Hs.75619 SAGE Hs.75619 3.2.1.35 [ Enzyme-SRS ] 3.2.1.35 [ Brenda-SRS ] 3.2.1.35 [ KEGG ] 3.2.1.35 [ WIT Enzyme ] GO hyalurononglucosaminidase activity [Amigo] hyalurononglucosaminidase activity GO extracellular region [Amigo] extracellular region GO extracellular space [Amigo] extracellular space GO lysosome [Amigo] lysosome GO carbohydrate metabolic process [Amigo] carbohydrate metabolic process GO metabolic process [Amigo] metabolic process hydrolase activity, acting on glycosyl bonds [Amigo] hydrolase activity, acting on GO glycosyl bonds KEGG Glycosaminoglycan degradation KEGG Glycan structures - degradation PubGene HYAL1 TreeFam HYAL1 CTD 3373 [Comparative Genomics Database] Other databases Probes Probe HYAL1 Related clones (RZPD - Berlin) PubMed PubMed 21 Pubmed reference(s) in LocusLink Bibliography Purification and microsequencing of hyaluronidase isozymes from human urine. Csˆ„ka AB, Frost GI, Wong T, Stern R FEBS letters. 1997 ; 417 (3) : 307-310. PMID 9409739

Purification, cloning, and expression of human plasma hyaluronidase. Frost GI, Csˆ„ka AB, Wong T, Stern R Biochemical and biophysical research communications. 1997 ; 236 (1) : 10-15. PMID 9223416

The hyaluronidase gene HYAL1 maps to chromosome 3p21.2-p21.3 in human and 9F1-F2 in mouse, a conserved candidate tumor suppressor locus. Csˆ„ka AB, Frost GI, Heng HH, Scherer SW, Mohapatra G, Stern R Genomics. 1998 ; 48 (1) : 63-70. PMID 9503017

HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. Lepperdinger G, Strobl B, Kreil G The Journal of biological chemistry. 1998 ; 273 (35) : 22466-22470. PMID 9712871

Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 394 Csˆ„ka AB, Scherer SW, Stern R Genomics. 1999 ; 60 (3) : 356-361. PMID 10493834

Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Triggs-Raine B, Salo TJ, Zhang H, Wicklow BA, Natowicz MR Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (11) : 6296-6300. PMID 10339581

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA. Frost GI, Mohapatra G, Wong TM, Csˆ„ka AB, Gray JW, Stern R Oncogene. 2000 ; 19 (7) : 870-877. PMID 10702795

The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Lerman MI, Minna JD Cancer research. 2000 ; 60 (21) : 6116-6133. PMID 11085536

The six hyaluronidase-like genes in the human and mouse genomes. Csoka AB, Frost GI, Stern R Matrix biology : journal of the International Society for Matrix Biology. 2001 ; 20 (8) : 499-508. PMID 11731267

Regulation of hyaluronidase activity by alternative mRNA splicing. Lokeshwar VB, Schroeder GL, Carey RI, Soloway MS, Iida N The Journal of biological chemistry. 2002 ; 277 (37) : 33654-33663. PMID 12084718

Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3. Shuttleworth TL, Wilson MD, Wicklow BA, Wilkins JA, Triggs-Raine BL The Journal of biological chemistry. 2002 ; 277 (25) : 23008-23018. PMID 11929860

Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines. Junker N, Latini S, Petersen LN, Kristjansen PE Oncology reports. 2003 ; 10 (3) : 609-616. PMID 12684632

Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysis. Jedrzejas MJ, Stern R Proteins. 2005 ; 61 (2) : 227-238. PMID 16104017

HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL Cancer research. 2005 ; 65 (17) : 7782-7789. PMID 16140946

Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma. Christopoulos TA, Papageorgakopoulou N, Theocharis DA, Mastronikolis NS, Papadas TA, Vynios DH

Atlas Genet Cytogenet Oncol Haematol 2008; 3 395 Biochimica et biophysica acta. 2006 ; 1760 (7) : 1039-1045. PMID 16713680

HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: a negative regulator of bladder cancer. Lokeshwar VB, Estrella V, Lopez L, Kramer M, Gomez P, Soloway MS, Lokeshwar BL Cancer research. 2006 ; 66 (23) : 11219-11227. PMID 17145867

Hyaluronidases: their genomics, structures, and mechanisms of action. Stern R, Jedrzejas MJ Chemical reviews. 2006 ; 106 (3) : 818-839. PMID 16522010

Structure of human hyaluronidase-1, a hyaluronan hydrolyzing enzyme involved in tumor growth and angiogenesis. Chao KL, Muthukumar L, Herzberg O Biochemistry. 2007 ; 46 (23) : 6911-6920. PMID 17503783

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Contributor(s) Written 10-2007 Demitrios H Vynios Department of Chemistry, University of Patras, 26500 Patras, Greece Citation This paper should be referenced as such : Vynios DH . HYAL1 (hyaluronoglucosaminidase 1). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HYAL1ID40903ch3p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 396 Atlas of Genetics and Cytogenetics in Oncology and Haematology

HTATIP (HIV-1 Tat interacting protein, 60kDa)

Identity Other names Tip60 Tip 60kDa Tat interacting protein HIV-1 Tat interacting protein cPLA(2) interacting protein iTip60 PLIP/Tip60b Tip60a Esa1 Hs.6364 Hugo HTATIP Location 11q13.1 DNA/RNA

Description The HTATIP gene consists of 14 exons. 7,586 bases. Transcription The predominant mRNA transcribed from this gene is 2,229 bp long. This is actually the isoform 2 of HTATIP. Two others isoforms generated by alternative splicing have been described:  Isoform 1 retains the alternatively spliced intron 1.  Isoform 3 lacks exon 5. Pseudogene No pseudogene is currently known. Protein

Atlas Genet Cytogenet Oncol Haematol 2008; 3 397

Description The Tip60 protein (isoform 2) is 513 amino acids long and its molecular weight is about 60 kDa. It was cloned and characterized in 1996 thanks to its interaction with the HIV-1 transactivator Tat protein. Isoform 1 produces a 546 amino acids long protein. Isoform 3 produces a 461 amino acids long protein. A novel isoform, Tip55, encodes a novel splicing variant corresponding to 103 amino acids of the C-terminus. The domain architectures of human TIP60 is similar to yeast Esa1 protein and consist of a chromodomain and a MYST domain harboring a zinc finger and an Acetyl-CoA binding site. Expression Tip60 is ubiquitously expressed. In mouse adult tissues Tip60 is expressed in the following decreasing order of intensity: testis, heart, brain, kidney, liver, lung, with little to no expression in spleen and skeletal muscle . In human, Tip60 (Isoform 2) and PLIP (Isoform 3) are expressed in human heart, kidney and brain tissue. With a half-life of approximately 30 minutes, Tip60 is very unstable. In normal conditions, the proteasome pathway permits to maintain low protein levels. Tip60 is ubiquitinated and targeted to proteasome-mediated degradation by Mdm2 but also by p300-associated E4 ubiquitin ligase. Tip60 is stabilized after DNA damage, and accumulates in cells. Moreover, Tip60 is the target of several post-translational modifications such as phosphorylation on serine 86 and 90 by cdc2 but also acetylation by p300/CBP acetyltransferases. Acetylation by p300/CBP occurs in the zinc finger of Tip60 but consequences of this modification are currently not known. Finally, a recent report shows that Tip60 is sumoylated at lysines 430 and 451 via Ubc9. No data are available about regulation of the Tip60 promoter. Localisation Tip60 (Isoform 2) is nuclear. PLIP (Isoform 3) is nuclear but also cytoplasmic. Function Tip60 is a Histone Acetyltransferase (HAT), which belongs to the MYST family. It participates in a multimolecular complex: The Tip60 complex, which contains proteins such as p400, Tip49a and Tip49b . Within this complex, Tip60 exerts its HAT activity on nucleosomal histone H4. Tip60 is involved in various cellular mechanisms:  In transcription: Tip60 acts as a coactivator. Indeed, Tip60 is able to interact with transcription factors, such as E2F-1 or c-Myc. Tip60 can be recruited to Myc and E2F-1 target promoters and enhances Myc transactivation. It also acetylates histone H4 on several E2F responsive genes. Moreover Tip60 was found to be involved in nuclear receptor (NR) signaling and to be a NR-coregulator.  In apoptosis and cell cycle arrest: Tip60 can interact with and acetylate the tumor suppressor p53. It enhances p53 binding to pro-apoptotic target genes like PUMA, Bax or Fas. Moreover, Tip60 is also required for cell growth arrest via the p21-dependent pathway.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 398  In DNA repair: Tip60 is involved in double strand breaks (DSB) repair. Interacting and acetylating ATM, Tip60 participates in DNA damage signaling. But, Tip60 is also involved directly in DSB repair since it is recruited, with TRRAP, to the DSB site. Tip60 interacts with the chromatin surrounding sites of DSBs and this recruitment is responsible for hyperacetylation of histone H4. Homology Tip60 CHROMO domain has been identified by sequence homology with the Heterochromatin-associated protein 1 (HP1) chromodomain, which recognizes methylated lysines. It also harbors the MYST domain, which is highly conserved from yeast to human. Homologs in other species:  S. Cerevisae: Esa1  D. Melanogaster: DmeI/Tip60  M. musculus: Htatip  R. norvegicus: Htatip Predicted:  P.troglodytes: HTATIP  M.mulatta: HTATIP Mutations Note No mutation in Tip60 protein has been currently described. Implicated in Entity Acquired Immunodeficiency Syndrome (AIDS) Disease Tip60 interacts with the HIV-1 transactivator Tat and this interaction inhibits Tip60 HAT activity. Moreover, in Jurkat cells, Tat enhances Tip60 turnover since it uses the p300/CBP-associated E4-type ubiquitin-ligase activity to induce polyubiquitynation and degradation of Tip60. This targeting by Tat induces an impairment of Tip60-dependent apoptosis after DNA damage. Entity Neurodegenerative diseases Entity Alzheimer¹s disease Disease In the nucleus of human H4 neuroglioma cells, TIP60 can interact with a free carboxyl- terminal intracellular fragment, APP-CT, which is generated by the cleavage of the Amyloid precursor protein APP by a gamma-secretase. This fragment induces apoptosis of neuroglioma and this cell death is enhanced when a wild type form of Tip60 is transfected. Thus Tip60 might play a role in Alzheimer¹s disease neurodegeneration. Entity Spinocerebellar ataxia type-1 Disease TIP60 participates in a complex with ATXN1 and ROR-alpha in a conditional transgenic mouse model of Spinocerebellar ataxia type-1 (SCA1), one of the nine inherited polyglutamine neurodegenerative diseases. Entity Cancers Entity Prostate cancer Disease Immunohistochemistry experiments have shown that Tip60 accumulates in the nucleus of hormone-refractory prostate cancer compared to prostate hyperplasia and primary prostate cancer. Entity Lung cancer and colon cancer Disease Real time RT-PCR experiments have shown that Tip60 mRNA is under expressed in colon and lung carcinomas. Entity Skin cancer Disease The expression levels of TIP60 protein, analyzed by western blot, were found to be greater in skin tumors as compared to adjacent non-tumor-bearing skin in a skin cancer mouse model (K6/ODC mouse). Additionally, the interaction between Tip60 and E2F1 is enhanced in these tumors. Entity HTLV-1 induced leukemogenesis Disease Enhancement of c-Myc transforming activity by HTLV-1 p30II oncoprotein in HeLa cells requires TIP60 HAT activity. External links Nomenclature Hugo HTATIP GDB HTATIP

Atlas Genet Cytogenet Oncol Haematol 2008; 3 399 Entrez_Gene HTATIP 10524 HIV-1 Tat interacting protein, 60kDa Cards Atlas HTATIPID40893ch11q13 GeneCards HTATIP Ensembl HTATIP [Search_View] ENSG00000172977 [Gene_View] Genatlas HTATIP GeneLynx HTATIP eGenome HTATIP euGene 10524 Genomic and cartography HTATIP - 11q13.1 chr11:65236065-65243650 + 11q13 [Description] (hg18- GoldenPath Mar_2006) Ensembl HTATIP - 11q13 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene HTATIP Gene and transcription Genbank AB209813 [ ENTREZ ] Genbank AK130717 [ ENTREZ ] Genbank AK225100 [ ENTREZ ] Genbank AK226002 [ ENTREZ ] Genbank BC000166 [ ENTREZ ] RefSeq NM_006388 [ SRS ] NM_006388 [ ENTREZ ] RefSeq NM_182709 [ SRS ] NM_182709 [ ENTREZ ] RefSeq NM_182710 [ SRS ] NM_182710 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_033903 [ SRS ] NT_033903 [ ENTREZ ] RefSeq NW_925106 [ SRS ] NW_925106 [ ENTREZ ] AceView HTATIP AceView - NCBI Unigene Hs.528299 [ SRS ] Hs.528299 [ NCBI ] HS528299 [ spliceNest ] Fast-db 9932 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q92993 [ SRS] Q92993 [ EXPASY ] Q92993 [ INTERPRO ] Interpro IPR000953 Chromodomain [ SRS ] IPR000953 Chromodomain [ EBI ] Interpro IPR002717 MOZ_SAS [ SRS ] IPR002717 MOZ_SAS [ EBI ] Interpro IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Wing_hlx_DNA_bd [ EBI ] CluSTr Q92993 PF01853 MOZ_SAS [ SRS ] PF01853 MOZ_SAS [ Sanger ] pfam01853 [ NCBI- Pfam CDD ] Smart SM00298 CHROMO [EMBL] Blocks Q92993 PDB 2OU2 [ SRS ] 2OU2 [ PdbSum ], 2OU2 [ IMB ] 2OU2 [ RSDB ] HPRD 03245 Protein Interaction databases DIP Q92993 IntAct Q92993 Polymorphism : SNP, mutations, diseases OMIM 601409 [ map ] GENECLINICS 601409 SNP HTATIP [dbSNP-NCBI] SNP NM_006388 [SNP-NCI] SNP NM_182709 [SNP-NCI] SNP NM_182710 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 400 SNP HTATIP [GeneSNPs - Utah] HTATIP] [HGBASE - SRS] HAPMAP HTATIP [HAPMAP] HGMD HTATIP General knowledge Family Browser HTATIP [UCSC Family Browser] SOURCE NM_006388 SOURCE NM_182709 SOURCE NM_182710 SMD Hs.528299 SAGE Hs.528299 2.3.1.48 [ Enzyme-SRS ] 2.3.1.48 [ Brenda-SRS ] 2.3.1.48 [ KEGG ] 2.3.1.48 [ WIT Enzyme ] GO chromatin [Amigo] chromatin GO regulation of cell growth [Amigo] regulation of cell growth GO chromatin binding [Amigo] chromatin binding GO transcription coactivator activity [Amigo] transcription coactivator activity GO histone acetyltransferase activity [Amigo] histone acetyltransferase activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO double-strand break repair [Amigo] double-strand break repair GO chromatin assembly or disassembly [Amigo] chromatin assembly or disassembly GO transcription [Amigo] transcription transcription from RNA polymerase II promoter [Amigo] transcription from RNA GO polymerase II promoter GO zinc ion binding [Amigo] zinc ion binding GO acyltransferase activity [Amigo] acyltransferase activity GO chromatin modification [Amigo] chromatin modification GO histone acetylation [Amigo] histone acetylation GO transferase activity [Amigo] transferase activity GO androgen receptor signaling pathway [Amigo] androgen receptor signaling pathway NuA4 histone acetyltransferase complex [Amigo] NuA4 histone acetyltransferase GO complex positive regulation of transcription, DNA-dependent [Amigo] positive regulation of GO transcription, DNA-dependent GO metal ion binding [Amigo] metal ion binding GO androgen receptor binding [Amigo] androgen receptor binding BIOCARTA Multi-step Regulation of Transcription by Pitx2 [Genes] PubGene HTATIP TreeFam HTATIP CTD 10524 [Comparative Genomics Database] Other databases Probes Probe HTATIP Related clones (RZPD - Berlin) PubMed PubMed 63 Pubmed reference(s) in LocusLink Bibliography Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G Virology. 1996 ; 216 (2) : 357-366. PMID 8607265

Tip60 is a nuclear hormone receptor coactivator. Brady ME, Ozanne DM, Gaughan L, Waite I, Cook S, Neal DE, Robson CN

Atlas Genet Cytogenet Oncol Haematol 2008; 3 401 The Journal of biological chemistry. 1999 ; 274 (25) : 17599-17604. PMID 10364196

Control of the histone-acetyltransferase activity of Tip60 by the HIV-1 transactivator protein, Tat. Creaven M, Hans F, Mutskov V, Col E, Caron C, Dimitrov S, Khochbin S Biochemistry. 1999 ; 38 (27) : 8826-8830. PMID 10393559

Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y Cell. 2000 ; 102 (4) : 463-473. PMID 10966108

Identification of an alternatively spliced form of the Tat interactive protein (Tip60), Tip60(beta). Ran Q, Pereira-Smith OM Gene. 2000 ; 258 (1-2) : 141-146. PMID 11111051

Tip60 is a co-activator specific for class I nuclear hormone receptors. Gaughan L, Brady ME, Cook S, Neal DE, Robson CN The Journal of biological chemistry. 2001 ; 276 (50) : 46841-46848. PMID 11591700

PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production. Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, Bonventre JV Molecular and cellular biology. 2001 ; 21 (14) : 4470-4481. PMID 11416127

Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. Gaughan L, Logan IR, Cook S, Neal DE, Robson CN The Journal of biological chemistry. 2002 ; 277 (29) : 25904-25913. PMID 11994312

The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. Kinoshita A, Whelan CM, Berezovska O, Hyman BT The Journal of biological chemistry. 2002 ; 277 (32) : 28530-28536. PMID 12032152

Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation. Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S, Trouche D The EMBO journal. 2002 ; 21 (7) : 1704-1712. PMID 11927554

Characterization and expression of the mouse tat interactive protein 60 kD (TIP60) gene. McAllister D, Merlo X, Lough J Gene. 2002 ; 289 (1-2) : 169-176. PMID 12036595

MYC recruits the TIP60 histone acetyltransferase complex to chromatin. Frank SR, Parisi T, Taubert S, Fernandez P, Fuchs M, Chan HM, Livingston DM, Amati B EMBO reports. 2003 ; 4 (6) : 575-580. PMID 12776177

Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 402 Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady ME, Cook S, Leung HY, Neal DE, Robson CN Oncogene. 2003 ; 22 (16) : 2466-2477. PMID 12717424

Identification of a larger form of the histone acetyl transferase Tip60. Legube G, Trouche D Gene. 2003 ; 310 : 161-168. PMID 12801643

Tip60 acetyltransferase activity is controlled by phosphorylation. Lemercier C, Legube G, Caron C, Louwagie M, Garin J, Trouche D, Khochbin S The Journal of biological chemistry. 2003 ; 278 (7) : 4713-4718. PMID 12468530

A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley PS, Beijersbergen RL, Bernards R Nature. 2004 ; 428 (6981) : 431-437. PMID 15042092

Role of the histone acetyl transferase Tip60 in the p53 pathway. Legube G, Linares LK, Tyteca S, Caron C, Scheffner M, Chevillard-Briet M, Trouche D The Journal of biological chemistry. 2004 ; 279 (43) : 44825-44833. PMID 15310756

E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Taubert S, Gorrini C, Frank SR, Parisi T, Fuchs M, Chan HM, Livingston DM, Amati B Molecular and cellular biology. 2004 ; 24 (10) : 4546-4556. PMID 15121871

A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions. Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers L, Motloch P, Takemoto S, Taguchi H, Cole MD, Lˆºscher B, Dittrich O, Tagami H, Nakatani Y, McGee M, Girard AM, Gaughan L, Robson CN, Monnat RJ Jr, Harrod R Molecular and cellular biology. 2005 ; 25 (14) : 6178-6198. PMID 15988028

HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses. Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S, Komatsu Y, Yoshida M, Benkirane M, Trouche D, Khochbin S The EMBO journal. 2005 ; 24 (14) : 2634-2645. PMID 16001085

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Sun Y, Jiang X, Chen S, Fernandes N, Price BD Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (37) : 13182-13187. PMID 16141325

Tip60 protein isoforms and altered function in skin and tumors that overexpress ornithine decarboxylase. Hobbs CA, Wei G, DeFeo K, Paul B, Hayes CS, Gilmour SK Cancer research. 2006 ; 66 (16) : 8116-8122. PMID 16912189

Co-activation of atrial natriuretic factor promoter by Tip60 and serum response factor.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 403 Kim MS, Merlo X, Wilson C, Lough J The Journal of biological chemistry. 2006 ; 281 (22) : 15082-15089. PMID 16597624

New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas. LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F, Cuatrecasas M, Lˆ„pez-Vicente L, Kondoh H, Blanco C, Carnero A, Ramˆ„n y Cajal S Oncology reports. 2006 ; 16 (3) : 603-608. PMID 16865262

Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z Nature cell biology. 2006 ; 8 (1) : 91-99. PMID 16341205

RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT Cell. 2006 ; 127 (4) : 697-708. PMID 17110330

Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB Molecular cell. 2006 ; 24 (6) : 841-851. PMID 17189187

Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Tang Y, Luo J, Zhang W, Gu W Molecular cell. 2006 ; 24 (6) : 827-839. PMID 17189186

Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression. Tyteca S, Vandromme M, Legube G, Chevillard-Briet M, Trouche D The EMBO journal. 2006 ; 25 (8) : 1680-1689. PMID 16601686

Functional characterization of TIP60 sumoylation in UV-irradiated DNA damage response. Cheng Z, Ke Y, Ding X, Wang F, Wang H, Ahmed K, Liu Z, Xu Y, Aikhionbare F, Yan H, Liu J, Xue Y, Powell M, Liang S, Reddy SE, Hu R, Huang H, Jin C, Yao X Oncogene. 2008 ; 27 (7) : 931-941. PMID 17704809

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Contributor(s) Written 10-2007 Lise Mattera Dr Trouche Team, LBCMCP, UMR 5088 CNRS, 118 route de Narbonne, 31062 Toulouse cedex 9, France Citation This paper should be referenced as such : Mattera L . HTATIP (HIV-1 Tat interacting protein, 60kDa). Atlas Genet Cytogenet Oncol Haematol.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 404 October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/HTATIPID40893ch11q13.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 405 Atlas of Genetics and Cytogenetics in Oncology and Haematology

GRN (Granulin)

Identity Other names GEP GP88 PCDGF PEPI PGRN acrogranin granulin-epithelin proepithelin progranulin Hugo GRN Location 17q21.32 DNA/RNA Description 13 exons, including 12 protein encoding exons and a further 5'non-coding exon. Transcription Major mRNA: 2323bp Protein Description Granulins are a family of secreted, glycosylated peptides; Granulins are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, and granulin C, etc. Expression Granulins are widely expressed. Normally, high levels of GRN expression on rapidly proliferating cells, such as skin cells, deep crypts of gastrointestinal tract, kidney, and immune cells; Low levels of GRN expression on muscle and liver cells. However, over- expressing on some kinds of tumor cells, such as breast cancer, prostate cancer, ovarian cancer. Localisation Nucleus Function Progranulin stimulates cell proliferation, migration and survival. It activates conventional growth factor signaling pathways including the p44/42 MAPkinase and phosphatidylinositol 3-kinase pathways and the Focal Adhesion Kinase pathway. Many experiments show that increasing the expression of progranulin can stimulate the tumor growth on immortalized but otherwise non-tumorigenic cells. SW13 cells overexpress progranulin (high PGRN), so, they produce large tumors in nude mice; cells that express less progranulin (basal PGRN), do not grow as tumors. However, progranulin is necessary for tumor growth. Attenuating progranulin (PCDGF) expression in mammary cancer cells MDA-MB-468 and human hepatocellular carcinoma cell lines (HepB3) leaded to a dramatic reduction (90% and 87%, respectively) in the size of tumors when the cells were grown in nude mice. Also, some experiments indicated that progranulin caused an increase of the motility and the invasiveness of tumor and played an important effect on apoptosis of tumor cells, reduced the rate of cell death. Mutations Note Mutations in the progranulin (PGRN) gene have been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. There are two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene, and PGRN mutations in familial cases recruited from a large population- based study of frontotemporal lobar degeneration carried out in the Netherlands. However, no mutation was found in the development of different cancers.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 406 Implicated in Entity Breast cancer Disease Progranulin has been shown to play a major role in breast tumorigenesis by stimulating proliferation, mediating survival and conferring resistance to some chemicals such as tamoxifen and doxorubicin, and its overexpression account for the resistance to therapeutic agents. PCDGF/GP88 has metastatic potential in breast cancer, and tumor cells (such as MCF-7 cells) with a PCDGF over-expression or treated exogenously with PCDGF both stimulated anchorage-independent cell growth and accelerated cell migration through matrigel. Furthermore, PCDGF/GP88 also can up-regulated the expression of matrix metalloprotease-9, and stimulated VEGF expression in some tumor cells. So, PCDGF/GP88 could act to promote metastasis and angiogenesis in human breast cancer cells in addition to stimulating their proliferation and survival. PCDGF/GP88 activated mitogen-activated protein kinase (MAP kinase Erk1/Erk2) as well as phosphatidylinositol 30-kinase (PI-3 kinase) pathways leading to the stimulation of several cyclins including Cyclin D1 and Cyclin B. In the adrenal carcinoma SW-13 cells, progranulin expression was also a major determinant of focal adhesion kinase signaling pathway in addition to MAP kinase and PI-3 kinase. Prognosis GRN might play an important role in deciding the behavior of node-positive breast cancer, so, GRN maybe provide valuable information for the prognosis of breast cancer patients. Since all the in vitro studies indicated the importance of PCDGF/GP88 in breast tumorigenesis. PCDGF/GP88 expression was then examined in pathological samples. Correlation studies between PCDGF expression and prognostic markers such as ER/PR expression, proliferation index Ki67, p53, and erbB2 were also conducted. Normally, PCDGF staining was observed in breast carcinoma, whereas it was not detected in benign breast epithelium. In breast carcinoma, PCDGF expression was more common in ductal carcinoma than in invasive lobular carcinoma. Moreover, PCDGF staining was almost never observed in lobular carcinoma in situ, whereas most of ductal carcinoma in situ (DCIS) expressed PCDGF. PCDGF expression in DCIS correlated strongly with nuclear grade in DCIS and histological grades in IDC. Both ER positive and ER negative tumors had moderate to strong PCDGF expression. Positive correlation was found between PCDGF staining and Ki 67 proliferation index. Similarly, a larger percentage of tumors with moderate/strong PCDGF expression were p53 positive. In contrast, PCDGF expression was independent of cerbB-2 overexpression. This study provides evidence of the high incidence of PCDGF expression in human breast cancer with positive correlation with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics the absence of expression in benign breast tissue suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer. Entity Prostate Cancer Disease Normal prostate tissue did not express, or expressed low levels of PCDGF. PCDGF expression could be detected in more than 50% of cells in all specimens of prostatic intraepithelial neoplasia(PIN) and invasive prostate cancer. The expression of PCDGF in normal prostate tissue was much less intense and in a smaller fraction of cells than in PIN and invasive adenocarcinoma (P less than 0.0001). There was no correlation of PCDGF expression with age, Gleason score, pathological stage, status of lymph node metastasis, extraprostatic extension, perineural invasion, surgical margins, and vascular invasion. So, the induction of PCDGF expression occurs during the development of PIN. PCDGF may be a new molecular target for the treatment and prevention of prostate cancer. Entity Ovarian Carcinoma Disease The GEP/PCDGF has been shown to be an important growth and survival factor induced by low-malignant-potential (LPA) and ET-1 and cAMP/EPAC through ERK1/2 for ovarian cancer cells, and its expression is a predictor of patient survival in metastatic ovarian cancer cells. The prosurvival function of GEP is important in ovarian cancer tumor progression and chemoresponse. Overexpression of GEP increased capacity to migrate and invade their substratum, and was associated with cisplatin chemoresistance. Meantime, GEP overexpression increased tumor formation and protected cells from tumor regression in response to cisplatin treatment in vivo. Prognosis Several experiments discovered and validated the differential expression of GEP

Atlas Genet Cytogenet Oncol Haematol 2008; 3 407 between noninvasive LPA tumors and invasive epithelial ovarian cancers in an effort to define a molecular basis for the pathologic differences between these epithelial tumor subtypes. Low malignant potential tumors share cytologic similarities with invasive ovarian cancers but have epithelial cells that lack the capacity to invade their underlying stroma. These tumors are slow growing and rarely metastasize and patients with LMP tumors present most often with disease limited to the ovary. This presentation translates into a marked improved clinical outcome over patients with invasive ovarian cancers, with over 95% of patients alive at 10 years. In contrast, patients with invasive ovarian cancers more commonly present with, and die of, disseminated disease and have a 40% overall 5-year survival. GEP expression also was observed in primary and metastatic epithelial ovarian carcinoma specimens, with down-regulated expression in tumor cells of malignant effusions. The poor outcome associated with stromal GEP expression suggests a prognostic role for this growth factor in ovarian carcinoma. Entity Endometrial cancer Disease The majority of endometrial cancers arise as a result of estrogen stimulation, the molecular targets of which remain incompletely defined. GEP may be one such target. GEP co-expression with ER was observed in most of cancers examined. A two to fivefold increase in GEP expression with estradiol and/or tamoxifen treatment was observed in KLE cells. Silencing of GEP in HEC-1-A cells using shRNA resulted in a decrease in proliferation among transfected cells. However, co-expression of GEP and ER in endometrial cancer cells, and the regulation of GEP by estrogen, suggests a role for GEP in steroid-mediated endometrial cancer cell growth. Further, characterization of GEP as a steroid-mediated growth factor in these cells may help me to understand endometrial cancer biology very well. Entity Teratoma Disease The PC cell line is a highly tumorigenic, insulin-independent, teratoma-derived cell line isolated from the nontumorigenic, insulin-dependent 1246 cell line. Studies of the PC cell growth properties have led to the purification of an 88-kDa secreted glycoprotein called PC cell-derived growth factor (PCDGF), which has been shown to stimulate the growth of PC cells as well as 3T3 fibroblasts. Since PCDGF was isolated from highly tumorigenic cells, its level of expression was examined in PC cells as well as in nontumorigenic and moderately tumorigenic cells from which PC cells were derived, and the levels of PCDGF mRNA and protein were very low in the nontumorigenic cells and increased in tumorigenic cell lines in a positive correlation with their tumorigenic properties. An inhibition of PCDGF expression resulted in a dramatic inhibition of tumorigenicity of the transfected cells when compared with empty-vector control cells. These data demonstrate the importance in tumor formation of overexpression of the novel growth factor PCDGF. Entity Brain tumor-glioblastoma multiforme Disease The 2.1-kb granulin mRNA was expressed predominantly in glial tumors, whereas expression was not detected in non-tumor brain tissues. Granulin may be a glial mitogen, as addition of synthetic granulin peptide to primary rat astrocytes and three different early-passage human glioblastoma cultures increased cell proliferation in vitro, whereas increasing concentrations of granulin antibody inhibited cell growth in a dose-dependent manner. The differential expression pattern, tissue distribution, and implication of this glioma-associated molecule in growth regulation suggest a potentially important role for granulin in the pathogenesis and/or malignant progression of primary brain neoplasms. Entity Multiple Myeloma Disease PCDGF mRNA and protein expression was detected in human MM cell lines such as ARP-1 and RPMI 8226, and PCDGF added exogenously stimulated cell growth and sustained cell survival of both ARP-1 and RPMI 8226 cells in a dose- and time- dependent fashion. When treated with neutralizing anti-PCDGF antibody, RPMI 8225 cells growth was inhibited. This indicated that PCDGF acts as an autocrine growth factor for MM cells. Studies of signal transduction pathways showed PCDGF stimulated mitogen-activated protein kinase and phosphatidylinositol 3'-kinase pathways but not the Janus-activated kinase-signal transducer and activator of transcription pathway. Immunohistochemical analysis of bone marrow smears obtained from MM patients indicated that PCDGF expression was associated with myeloma cells from MM patients

Atlas Genet Cytogenet Oncol Haematol 2008; 3 408 and correlated with the presence of MM disease. Entity Laryngeal carcinoma Disease The PC cell-derived growth factor protein levels and mRNA levels of the laryngeal squamous cell carcinomas were significantly higher than those of normal laryngeal tissues. Simultaneously, the difference in the levels of mRNA and protein between those of laryngeal precancerous lesions (papilloma/leukoplakia) and those of normal tissues was significant, whereas those of laryngeal precancerous lesions (papilloma/leukoplakia) were significantly lower than those of laryngeal squamous cell carcinomas. Strong PC cell-derived growth factor expression was associated with lymph node metastases in laryngeal squamous cell carcinoma. Functional studies on Hep-2 cell lines demonstrated that the attenuation of PC cell-derived growth factor expression levels led to diminished cell proliferation rates, anchorage-independent growth in vitro, tumor forming in vivo and resistance to apoptosis. PC cell-derived growth factor is a pivotal autocrine growth factor in the tumorigenesis of laryngeal squamous cell carcinoma. In the future, PC cell-derived growth factor may be a logical and potential target for early diagnosis, specific therapy and prognosis of laryngeal squamous cell carcinoma. Entity Bladder Cancer Disease Proepithelin is overexpressed in bladder cancer cell lines and clinical specimens of bladder cancer. Proepithelin did not appreciably affect cell growth, but it did promote migration of 5637 bladder cancer cells and stimulate in vitro wound closure and invasion. These effects required the activation of the mitogen-activated protein kinase pathway and paxillin, which upon proepithelin stimulation formed a complex with focal adhesion kinase and active extracellular signal-regulated kinase. However, proepithelin plays a role in stimulating migration, invasion of bladder cancer cells, and establishing of the invasive phenotype. Prognosis So far, it is unclear if proepithelin has an significant effect on the prognosis of patient with bladder cancer. Entity Renal epithelium Disease Acrogranin levels were low in benign renal tissue and increased in malignant renal tissue. In addition, high-grade RCC exhibited higher levels of expression than low-grade RCC and normal tissue. So, acrogranin may be a functional important growth factor in RCC and a potential molecular marker for high-grade RCC. Entity Hepatocellular carcinoma Disease In hepatocellular carcinoma, there is a closed relationship between p53 and GEP protein. Studies revealed an overall positive association between the two protein expression patterns, and the association of p53 and GEP protein expression was found to be highly significant only in HCCs with wild-type p53; there was no association in HCCs with p53 mutation. The GEP levels in the HepG2 hepatoma cell line with a wild- type p53 background were modulated by transfection experiments. Overexpression of the GEP protein resulted in an increased p53 protein level and suppression of the GEP protein resulted in a decreased p53 protein level in HepG2 cells. In summary, p53 wild- type protein nuclei accumulation is associated with GEP protein expression in human HCC specimens, and GEP modulates p53 wild-type protein levels in vitro. Entity Gastric cancer Disease Granulin was expressed in gastric cancer cells, and may be considered as a tumor associated antigen. External links Nomenclature Hugo GRN GDB GRN Entrez_Gene GRN 2896 granulin Cards Atlas GRNID40757ch17q21 GeneCards GRN Ensembl GRN [Search_View] ENSG00000030582 [Gene_View] Genatlas GRN GeneLynx GRN

Atlas Genet Cytogenet Oncol Haematol 2008; 3 409 eGenome GRN euGene 2896 Genomic and cartography GRN - 17q21.32 chr17:39778017-39785996 + 17q21.32 [Description] (hg18- GoldenPath Mar_2006) Ensembl GRN - 17q21.32 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene GRN Gene and transcription Genbank AF055008 [ ENTREZ ] Genbank AK000607 [ ENTREZ ] Genbank AK023348 [ ENTREZ ] Genbank AK222522 [ ENTREZ ] Genbank AY124489 [ ENTREZ ] RefSeq NM_001012479 [ SRS ] NM_001012479 [ ENTREZ ] RefSeq NM_002087 [ SRS ] NM_002087 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010783 [ SRS ] NT_010783 [ ENTREZ ] RefSeq NW_926839 [ SRS ] NW_926839 [ ENTREZ ] AceView GRN AceView - NCBI Unigene Hs.514220 [ SRS ] Hs.514220 [ NCBI ] HS514220 [ spliceNest ] Fast-db 11371 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P28799 [ SRS] P28799 [ EXPASY ] P28799 [ INTERPRO ] Prosite PS00799 GRANULINS [ SRS ] PS00799 GRANULINS [ Expasy ] Interpro IPR015874 4-disulphide_core [ SRS ] IPR015874 4-disulphide_core [ EBI ] Interpro IPR006150 Cys_repeat_1 [ SRS ] IPR006150 Cys_repeat_1 [ EBI ] Interpro IPR000118 Granulin [ SRS ] IPR000118 Granulin [ EBI ] CluSTr P28799 Pfam PF00396 Granulin [ SRS ] PF00396 Granulin [ Sanger ] pfam00396 [ NCBI-CDD ] Smart SM00277 GRAN [EMBL] Smart SM00289 WR1 [EMBL] Blocks P28799 PDB 1G26 [ SRS ] 1G26 [ PdbSum ], 1G26 [ IMB ] 1G26 [ RSDB ] HPRD 00733 Protein Interaction databases DIP P28799 IntAct P28799 Polymorphism : SNP, mutations, diseases OMIM 138945;607485 [ map ] GENECLINICS 138945;607485 SNP GRN [dbSNP-NCBI] SNP NM_001012479 [SNP-NCI] SNP NM_002087 [SNP-NCI] SNP GRN [GeneSNPs - Utah] GRN] [HGBASE - SRS] HAPMAP GRN [HAPMAP] HGMD GRN General knowledge Family Browser GRN [UCSC Family Browser] SOURCE NM_001012479 SOURCE NM_002087

Atlas Genet Cytogenet Oncol Haematol 2008; 3 410 SMD Hs.514220 SAGE Hs.514220 GO phospholipase A2 activity [Amigo] phospholipase A2 activity GO cytokine activity [Amigo] cytokine activity GO extracellular region [Amigo] extracellular region GO extracellular space [Amigo] extracellular space GO phospholipid metabolic process [Amigo] phospholipid metabolic process GO signal transduction [Amigo] signal transduction GO cell-cell signaling [Amigo] cell-cell signaling GO growth factor activity [Amigo] growth factor activity GO cell proliferation [Amigo] cell proliferation GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO lipid catabolic process [Amigo] lipid catabolic process BIOCARTA Proepithelin Conversion to Epithelin and Wound Repair Control [Genes] PubGene GRN TreeFam GRN CTD 2896 [Comparative Genomics Database] Other databases Probes Probe GRN Related clones (RZPD - Berlin) PubMed PubMed 63 Pubmed reference(s) in LocusLink Bibliography Biochemical analysis of the epithelin receptor. Culouscou JM, Carlton GW, Shoyab M The Journal of biological chemistry. 1993 ; 268 (14) : 10458-10462. PMID 8387520

Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. Zhou J, Gao G, Crabb JW, Serrero G The Journal of biological chemistry. 1993 ; 268 (15) : 10863-10869. PMID 8496151

Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor). Zhang H, Serrero G Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (24) : 14202-14207. PMID 9826678

Stimulation of PC cell-derived growth factor (epithelin/granulin precursor) expression by estradiol in human breast cancer cells. Lu R, Serrero G Biochemical and biophysical research communications. 1999 ; 256 (1) : 204-207. PMID 10066447

Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. Liau LM, Lallone RL, Seitz RS, Buznikov A, Gregg JP, Kornblum HI, Nelson SF, Bronstein JM Cancer research. 2000 ; 60 (5) : 1353-1360. PMID 10728698

Inhibition of PC cell-derived growth factor (PCDGF, epithelin/granulin precursor) expression by antisense PCDGF cDNA transfection inhibits tumorigenicity of the human breast carcinoma cell line MDA-MB-468. Lu R, Serrero G

Atlas Genet Cytogenet Oncol Haematol 2008; 3 411 Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (8) : 3993-3998. PMID 10760271

Expression of progranulin and the epithelin/granulin precursor acrogranin correlates with neoplastic state in renal epithelium. Donald CD, Laddu A, Chandham P, Lim SD, Cohen C, Amin M, Gerton GL, Marshall FF, Petros JA Anticancer research. 2001 ; 21 (6A) : 3739-3742. PMID 11911241

Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Lu R, Serrero G Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (1) : 142-147. PMID 11134521

Differential gene expression profiling in human brain tumors. Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, Lee K, Gullans SR, Mapstone TB, Benos DJ Physiological genomics. 2001 ; 5 (1) : 21-33. PMID 11161003

Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis. Larramendy ML, Niini T, Elonen E, Nagy B, Ollila J, Vihinen M, Knuutila S Haematologica. 2002 ; 87 (6) : 569-577. PMID 12031912

Serological identification and expression analysis of gastric cancer-associated genes. LinŸì A, StengrŸìvics A, Slucka Z, Li G, Jankevics E, Rees RC British journal of cancer. 2002 ; 86 (11) : 1824-1830. PMID 12087473

The granulin-epithelin precursor/PC-cell-derived growth factor is a growth factor for epithelial ovarian cancer. Jones MB, Michener CM, Blanchette JO, Kuznetsov VA, Raffeld M, Serrero G, Emmert-Buck MR, Petricoin EF, Krizman DB, Liotta LA, Kohn EC Clinical cancer research : an official journal of the American Association for Cancer Research. 2003 ; 9 (1) : 44-51. PMID 12538450

The granulin-epithelin precursor: a putative new growth factor for ovarian cancer. Jones MB, Spooner M, Kohn EC Gynecologic oncology. 2003 ; 88 (1 Pt 2) : S136-S139. PMID 12586105

Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. He Z, Bateman A Journal of molecular medicine (Berlin, Germany). 2003 ; 81 (10) : 600-612. PMID 12928786

Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. Ong CH, Bateman A Histology and histopathology. 2003 ; 18 (4) : 1275-1288. PMID 12973694

Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player

Atlas Genet Cytogenet Oncol Haematol 2008; 3 412 in breast cancer tumorigenesis. Serrero G Biochemical and biophysical research communications. 2003 ; 308 (3) : 409-413. PMID 12914763

PC cell-derived growth factor (granulin precursor) expression and action in human multiple myeloma. Wang W, Hayashi J, Kim WE, Serrero G Clinical cancer research : an official journal of the American Association for Cancer Research. 2003 ; 9 (6) : 2221-2228. PMID 12796389

Molecular characterization of brain tumors. Boudreau CR, Liau LM Clinical neurosurgery. 2004 ; 51 : 81-90. PMID 15571131

Granulin-epithelin precursor overexpression promotes growth and invasion of hepatocellular carcinoma. Cheung ST, Wong SY, Leung KL, Chen X, So S, Ng IO, Fan ST Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (22) : 7629-7636. PMID 15569995

Granulin-epithelin precursor is a novel prognostic marker in epithelial ovarian carcinoma. Davidson B, Alejandro E, Flˆ½renes VA, Goderstad JM, Risberg B, Kristensen GB, Trope CG, Kohn EC Cancer. 2004 ; 100 (10) : 2139-2147. PMID 15139056

PC cell-derived growth factor expression in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Pan CX, Kinch MS, Kiener PA, Langermann S, Serrero G, Sun L, Corvera J, Sweeney CJ, Li L, Zhang S, Baldridge LA, Jones TD, Koch MO, Ulbright TM, Eble JN, Cheng L Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (4) : 1333-1337. PMID 14977833

PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Tangkeangsirisin W, Serrero G Carcinogenesis. 2004 ; 25 (9) : 1587-1592. PMID 15117809

Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. Kamrava M, Simpkins F, Alejandro E, Michener C, Meltzer E, Kohn EC Oncogene. 2005 ; 24 (47) : 7084-7093. PMID 16044162

Genetic prognostic index influences patient outcome for node-positive breast cancer. Asaka S, Fujimoto T, Akaishi J, Ogawa K, Onda M Surgery today. 2006 ; 36 (9) : 793-801. PMID 16937283

GEP associates with wild-type p53 in hepatocellular carcinoma. Cheung ST, Wong SY, Lee YT, Fan ST Oncology reports. 2006 ; 15 (6) : 1507-1511. PMID 16685387

Atlas Genet Cytogenet Oncol Haematol 2008; 3 413

The granulin-epithelin precursor is a steroid-regulated growth factor in endometrial cancer. Jones MB, Houwink AP, Freeman BK, Greenwood TM, Lafky JM, Lingle WL, Berchuck A, Maxwell GL, Podratz KC, Maihle NJ Journal of the Society for Gynecologic Investigation. 2006 ; 13 (4) : 304-311. PMID 16697948

Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1/2 and the formation of a paxillin/FAK/ERK complex. Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV, Morrione A Cancer research. 2006 ; 66 (14) : 7103-7110. PMID 16849556

PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma. Wang W, Hayashi J, Serrero G Clinical cancer research : an official journal of the American Association for Cancer Research. 2006 ; 12 (1) : 49-56. PMID 16397023

Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo. Klenke FM, Abdollahi A, Bertl E, Gebhard MM, Ewerbeck V, Huber PE, Sckell A BMC cancer. 2007 ; 7 : page 49. PMID 17367541

PC cell-derived growth factor overexpression promotes proliferation and survival of laryngeal carcinoma. Kong WJ, Zhang SL, Chen X, Zhang S, Wang YJ, Zhang D, Sun Y Anti-cancer drugs. 2007 ; 18 (1) : 29-40. PMID 17159500

Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression. Miyanishi M, Mandai M, Matsumura N, Yamaguchi K, Hamanishi J, Higuchi T, Takakura K, Fujii S Oncology reports. 2007 ; 17 (2) : 329-333. PMID 17203169

Prosurvival function of the granulin-epithelin precursor is important in tumor progression and chemoresponse. Pizarro GO, Zhou XC, Koch A, Gharib M, Raval S, Bible K, Jones MB International journal of cancer. Journal international du cancer. 2007 ; 120 (11) : 2339-2343. PMID 17266030

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Contributor(s) Written 10-2007 Hongyong Zhang, Chong-xian Pan, Liang Cheng UC Davis Cancer Center, 2700 Stockton Blvd, Oak Park Research Building, Ste 2301, Univ. of California at Davis, Sacramento, CA 95817, USA (HZ) ; Division of Hematology/Oncology, Univ. of California at Davis, 4501 X Street, Rm 3016, Sacramento, CA 95817, USA (CXP) ; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Clarian Pathology Laboratory Room 4010, 350 West 11th Street, Indianapolis, IN 46202, USA (LC) Citation

Atlas Genet Cytogenet Oncol Haematol 2008; 3 414 This paper should be referenced as such : Zhang H, Pan CX, Cheng L . GRN (Granulin). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/GRNID40757ch17q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 415 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CDH1 (cadherin 1, type 1, E-cadherin (epithelial))

Identity Other names Arc-1 CD324 CDHE Cadherin-1 E-cadherin ECAD LCAM UVO Uvomorulin Hugo CDH1 Location 16q22.1 DNA/RNA

DNA of CDH1 gene composed of 16 coding exons.

Description DNA contains 98250 bp composed of 16 coding exons. Transcription 4828 bp mRNA transcribed in centromeric to telomeric orientation; 2649 bp open reading frame. Pseudogene Yes, for example, the repeat sequence named c41-cad is a pseudogene of the cadherin family. c41-cad is localizated on 5q13 Protein

Three-dimensional structure of the beta-catenin arm repeat region in complex with the E-cadherin cytoplasmic domain (Huber and Weis, 2001). The arm repeats are formed by three helices, H1 and H2 (both gray) and H3 (blue). Residues 134-161, which include part of the alpha-catenin-binding site and a portion of the first arm repeat, form a single helix in this particular crystal structure (cyan). E-cadherin is divided into five regions of primary structure (1-5) that are indicated in distinct colors (Pokutta S and Weis WI, 2007). Description The cadherins are a family of calcium-dependent transmembrane linker proteins; the first three that were discovered were named according to their tissue origin (E-cadherin

Atlas Genet Cytogenet Oncol Haematol 2008; 3 416 from epithelium, N-cadherin from neural tissue and P-cadherin from placenta). The mature E-cadherin protein consists of three major domains: a large extracellular portion (exons 4-13), which mediates homophilic cellular interactions; and smaller transmembrane (exons 13-14) and cytoplasmic domains (exons 14-16), the latter providing a link to the actin cytoskeleton through an association with various catenins, such as B-catenin. The protein E-cadherin is a calcium-dependent cell-cell adhesion molecule expressed in adherents junctions between epithelial cells. It is a transmembrane glycoprotein with five extracellular domains that mediate intercellular adhesion through homophilic binding. The cytoplasmatic domain is bound to the actin cytoskeleton via intracellular attachment proteins, the catenins. The actin cytoskeleton forms a transcellular network mediating structural integrity, cellular polarity and epithelial morphogenesis. Expression Present tissue specificity for non-neural epithelial tissues and there are high levels in solid tissues. Localisation Cell junction; single-pass type I membrane protein. Anchored to actin microfilaments through association with alpha-catenin, beta -catenin and gamma-catenin. Sequential proteolysis induced by apoptosis or calcium influx, results in translocation from sites of cell-cell contact to the cytoplasm. Function One of the most important and ubiquitous types of adhesive interactions required for the maintenance of solid tissues is that mediated by the classic cadherin adhesion molecules. Cadherins are transmembrane Ca2+- dependent homophilic adhesion receptors that are well known to play important roles in cell recognition and cell sorting during development. However, they continue to be expressed at high levels in virtually all solid tissues. There are many members of the classic cadherin family (which is a subset of the larger cadherin superfamily), but E-cadherin in epithelial tissues has been the most studied in the context of stable adhesions. Continued expression and functional activity of E-cadherin are required for cells to remain tightly associated in the epithelium, and in its absence the many other cell adhesion and cell junction proteins expressed in epithelial cells (see below) are not capable of supporting intercellular adhesion. In its capacity to maintain the overall state of adhesion between epithelial cells, E-cadherin is thought to act as an important suppressor of epithelial tumor cell invasiveness and metastasis. Homology Pan troglodytes - CDH1; Canis lupus familiaris - CDH1; Mus musculus - Cdh1; Rattus norvegicus - Cdh1; Gallus gallus - LOC415860; Danio rerio - cdh1 Mutations

57 CDH1 mutations have been found to date. 50 of these are listed in Human Gene Mutation Database. Truncating (27) and splice site (7) mutations are found above the Schema (34/45, 76%), missense mutations below it (11/45, 24%). Two marked with an asterisk have been reported as somatic mutations in sporadic diffuse gastric cancer. No Polymorphisms. No Gross deletions/duplications, complex rearrangements, repeat variations been reported. They spread out all over CDH1 gene (Brooks-Wilson et al., 2004).

Germinal 30 CDH1 germline mutations have been described in hereditary diffuse gastric cancer families. 25 have been inactivating (frameshift, nonsense, and splice-site), the remainders are missense. The mutations are distributed equally throughout the gene. Somatic Somatically acquired mutations in CDH1 were found in about 56% of lobular breast

Atlas Genet Cytogenet Oncol Haematol 2008; 3 417 tumors, generally (>90%) in combination with loss of the wild-type allele, while no mutations were found in ductal primary breast carcinomas. Most of these somatic mutations result in premature stop codons as a consequence of insertions, deletions and nonsense mutations. As the majority of these frameshift and nonsense mutations is predicted to generate secreted E-cadherin fragments, the functionality of this major cell-cell adhesion protein is lost. Other cancer-confined E-cadherin mutations also result in crippled proteins. The distinctive invasive growth pattern, which is typical for lobular breast cancers, is fully compatible with this functional inactivation. 472 human tumors and 15 different cancer cell lines derived from 10 different tissues have been screened for CDH1 mutation. So far, frequent somatic mutations (50%) have been identified only in sporadic diffuse gastric cancer (DGC), Lobular Breast Cancer. For sporadic DGC, most somatic mutations are missense (exons 8, 9) or exon skipping. For sporadic Lobular Breast Cancer, most somatic mutations are truncating. 472 human tumors and 15 different cancer cell lines derived from 10 different tissues have been screened for CDH1 mutation. So far, frequent somatic mutations (50%) have been identified only in sporadic Diffuse Gastric Cancer, Lobular Breast Cancer. Interestingly, there is a major difference between the mutation types identified in these two carcinoma types. In diffuse gastric carcinomas, the predominant mutations are exon skippings causing in-frame deletions. By contrast, most mutations identified in lobular breast cancer result in premature stop codons. In the case of the diffuse gastric carcinomas, a mutation cluster region is suggested as more than 60% of mutations cause exon skipping of exon 8 and 9. Preliminary in vitro studies using transfected cell lines suggest that tumor-associated E-cadherin mutations reduce cell adhesion, increase cell motility, and change cell morphology possibly by dominant negative mechanisms. On the contrary, the truncating mutations present in lobular breast cancers are obviously scattered over the entire E-cadherin gene. In line with this finding is the observation that the expression of E-cadherin protein is lost in lobular breast cancers, in contrast to the retention of expression of the mutant E-cadherin proteins in diffuse gastric carcinomas. Surprisingly, so far almost no E-cadherin mutations have been found to be located in the highly conserved cytoplasmic domain. In most cases, E-cadherin mutations are found in combination with loss of the wild-type allele. Implicated in Entity Non-small cell lung cancer Prognosis Reduced E-cadherin correlates with lymph node metastasis. The rate of vascular invasion was statistically high in cases with the reduced expression of E-cadherin. Reduction of E-cadherin is associated with the degree of differentiation. Bohm et al. found a correlation between differentiation and E-cadherin expression in lung squamous cell carcinoma, and Bongiorno et al. found that well-differentiated lung cancers express E-cadherin, in a preserved fashion, and that poorly differentiated tumors exhibited a reduced or disorganized staining pattern. Sulzer et al. also found that E-cadherin expression significantly correlated with increasing tumor differentiation. In general, undifferentiated or poorly differentiated cancer cells tend to have a strong potential to invade tissues. These results suggest that reduction of E-cadherin correlates with tumor invasion. Oncogenesis Reduced E-cadherin expression weakens cell-to-cell attachment, and tumor cells detach from the primary tumor, invade vessels, and migrate to lymph nodes. Once tumor cells reattach to lymph nodes, E-cadherin is strongly expressed, and lymph nodes are subject to metastases. Entity Melanoma Oncogenesis The major adhesion mediator between keratinocytes and normal melanocytes is E- cadherin, which disappears during melanoma progression. While normal melanocytes express E-cadherin, this molecule is not found on nevus or melanoma cells. The loss of E-cadherin likely plays a crucial role in tumor progression. Cells that have lost epithelial differentiation, as manifested by the loss of functional E-cadherin, show increased mobility and invasiveness. Keratinocytes can no longer control melanoma cells that have lost E-cadherin. When melanoma cells are forced to express E-cadherin and are cocultured with keratinocytes, they dramatically change: melanomas adhere to keratinocytes, no longer express invasion-related molecules, and lose their invasive capacities

Atlas Genet Cytogenet Oncol Haematol 2008; 3 418 Entity Oesophageal adenocarcinoma Prognosis Reduction in the expression of E-cadherin in patients with OSCC was shown to be strongly associated with postoperative blood borne recurrence, resulting in a poorer prognosis than in those patients with tumours showing normal expression before surgery. This finding suggested that in patients with reduced E-cadherin immunoreactivity, the metastatic potential of the oesophageal cancer cells may be increased. Therefore, the evaluation of E-cadherin immunoreactivity may be useful in predicting haematogenous spread and hence recurrence, thus serving as an aid for planning adjuvant treatment after surgery in patients with OSCC. It has also been reported that E-cadherin might be an independent predictor of micrometastasis in lymph nodes that are classified as N0 by routine histopathological analysis. External links Nomenclature Hugo CDH1 GDB CDH1 Entrez_Gene CDH1 999 cadherin 1, type 1, E-cadherin (epithelial) Cards Atlas CDH1ID166ch16q22 GeneCards CDH1 Ensembl CDH1 [Search_View] ENSG00000039068 [Gene_View] Genatlas CDH1 GeneLynx CDH1 eGenome CDH1 euGene 999 Genomic and cartography CDH1 - 16q22.1 chr16:67328696-67426945 + 16q22.1 [Description] (hg18- GoldenPath Mar_2006) Ensembl CDH1 - 16q22.1 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CDH1 Gene and transcription Genbank AB025105 [ ENTREZ ] Genbank AB025106 [ ENTREZ ] Genbank AI890107 [ ENTREZ ] Genbank AK290012 [ ENTREZ ] Genbank BC013851 [ ENTREZ ] RefSeq NM_004360 [ SRS ] NM_004360 [ ENTREZ ] RefSeq AC_000059 [ SRS ] AC_000059 [ ENTREZ ] RefSeq NC_000016 [ SRS ] NC_000016 [ ENTREZ ] RefSeq NT_010498 [ SRS ] NT_010498 [ ENTREZ ] RefSeq NW_926462 [ SRS ] NW_926462 [ ENTREZ ] AceView CDH1 AceView - NCBI Unigene Hs.461086 [ SRS ] Hs.461086 [ NCBI ] HS461086 [ spliceNest ] Fast-db 10552 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P12830 [ SRS] P12830 [ EXPASY ] P12830 [ INTERPRO ] Prosite PS00232 CADHERIN_1 [ SRS ] PS00232 CADHERIN_1 [ Expasy ] Prosite PS50268 CADHERIN_2 [ SRS ] PS50268 CADHERIN_2 [ Expasy ] Interpro IPR002126 Cadherin [ SRS ] IPR002126 Cadherin [ EBI ] Interpro IPR000233 Cadherin_C_term [ SRS ] IPR000233 Cadherin_C_term [ EBI ] Interpro IPR014868 Cadherin_pro [ SRS ] IPR014868 Cadherin_pro [ EBI ] CluSTr P12830 Pfam PF00028 Cadherin [ SRS ] PF00028 Cadherin [ Sanger ] pfam00028 [ NCBI-CDD ] Pfam PF01049 Cadherin_C [ SRS ] PF01049 Cadherin_C [ Sanger ] pfam01049 [ NCBI-

Atlas Genet Cytogenet Oncol Haematol 2008; 3 419 CDD ] PF08758 Cadherin_pro [ SRS ] PF08758 Cadherin_pro [ Sanger ] pfam08758 Pfam [ NCBI-CDD ] Smart SM00112 CA [EMBL] Blocks P12830 PDB 1O6S [ SRS ] 1O6S [ PdbSum ], 1O6S [ IMB ] 1O6S [ RSDB ] PDB 2O72 [ SRS ] 2O72 [ PdbSum ], 2O72 [ IMB ] 2O72 [ RSDB ] PDB 2OMT [ SRS ] 2OMT [ PdbSum ], 2OMT [ IMB ] 2OMT [ RSDB ] PDB 2OMU [ SRS ] 2OMU [ PdbSum ], 2OMU [ IMB ] 2OMU [ RSDB ] PDB 2OMV [ SRS ] 2OMV [ PdbSum ], 2OMV [ IMB ] 2OMV [ RSDB ] PDB 2OMX [ SRS ] 2OMX [ PdbSum ], 2OMX [ IMB ] 2OMX [ RSDB ] PDB 2OMY [ SRS ] 2OMY [ PdbSum ], 2OMY [ IMB ] 2OMY [ RSDB ] PDB 2OMZ [ SRS ] 2OMZ [ PdbSum ], 2OMZ [ IMB ] 2OMZ [ RSDB ] HPRD 01885 Protein Interaction databases DIP P12830 IntAct P12830 Polymorphism : SNP, mutations, diseases OMIM 137215;192090 [ map ] GENECLINICS 137215;192090 SNP CDH1 [dbSNP-NCBI] SNP NM_004360 [SNP-NCI] SNP CDH1 [GeneSNPs - Utah] CDH1] [HGBASE - SRS] HAPMAP CDH1 [HAPMAP] COSMIC CDH1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD CDH1 General knowledge Family Browser CDH1 [UCSC Family Browser] SOURCE NM_004360 SMD Hs.461086 SAGE Hs.461086 GO calcium ion binding [Amigo] calcium ion binding GO protein binding [Amigo] protein binding GO plasma membrane [Amigo] plasma membrane GO cell-cell adherens junction [Amigo] cell-cell adherens junction GO cell adhesion [Amigo] cell adhesion GO homophilic cell adhesion [Amigo] homophilic cell adhesion GO homophilic cell adhesion [Amigo] homophilic cell adhesion GO actin cytoskeleton [Amigo] actin cytoskeleton GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO lateral plasma membrane [Amigo] lateral plasma membrane GO transcription activator activity [Amigo] transcription activator activity GO cell junction [Amigo] cell junction positive regulation of transcription factor import into nucleus [Amigo] positive GO regulation of transcription factor import into nucleus GO perinuclear region of cytoplasm [Amigo] perinuclear region of cytoplasm GO cell adhesion molecule binding [Amigo] cell adhesion molecule binding SUMOylation as a mechanism to modulate CtBP-dependent gene BIOCARTA responses [Genes] BIOCARTA Downregulated of MTA-3 in ER-negative Breast Tumors [Genes] BIOCARTA TGF beta signaling pathway [Genes] KEGG Cell adhesion molecules (CAMs) KEGG Adherens junction

Atlas Genet Cytogenet Oncol Haematol 2008; 3 420 PubGene CDH1 TreeFam CDH1 CTD 999 [Comparative Genomics Database] Other databases Probes Probe CDH1 Related clones (RZPD - Berlin) PubMed PubMed 425 Pubmed reference(s) in LocusLink Bibliography Differences of E-cadherin expression levels and patterns in primary and metastatic human lung cancer. Bˆ ﾏ hm M, Totzeck B, Birchmeier W, Wieland I Clinical & experimental metastasis. 1994 ; 12 (1) : 55-62. PMID 8287621

E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F The EMBO journal. 1995 ; 14 (24) : 6107-6115. PMID 8557030

Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1). Berx G, Staes K, van Hengel J, Molemans F, Bussemakers MJ, van Bokhoven A, van Roy F Genomics. 1995 ; 26 (2) : 281-289. PMID 7601454

E-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus. Bongiorno PF, al-Kasspooles M, Lee SW, Rachwal WJ, Moore JH, Whyte RI, Orringer MB, Beer DG British journal of cancer. 1995 ; 71 (1) : 166-172. PMID 7819034

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene. Selig S, Bruno S, Scharf JM, Wang CH, Vitale E, Gilliam TC, Kunkel LM Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (9) : 3702-3706. PMID 7731968

E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C Oncogene. 1996 ; 13 (9) : 1919-1925. PMID 8934538

Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Gumbiner BM Cell. 1996 ; 84 (3) : 345-357. PMID 8608588

An efficient and reliable multiplex PCR-SSCP mutation analysis test applied to the human E- cadherin gene. Berx G, Nollet F, Strumane K, van Roy F Human mutation. 1997 ; 9 (6) : 567-574. PMID 9195232

Mutations of the human E-cadherin (CDH1) gene. Berx G, Becker KF, Hˆ ﾏ fler H, van Roy F Human mutation. 1998 ; 12 (4) : 226-237. PMID 9744472

Atlas Genet Cytogenet Oncol Haematol 2008; 3 421

Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Sulzer MA, Leers MP, van Noord JA, Bollen EC, Theunissen PH American journal of respiratory and critical care medicine. 1998 ; 157 (4 Pt 1) : 1319-1323. PMID 9563756

Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance. Kase S, Sugio K, Yamazaki K, Okamoto T, Yano T, Sugimachi K Clinical cancer research : an official journal of the American Association for Cancer Research. 2000 ; 6 (12) : 4789-4796. PMID 11156236

The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Berx G, Van Roy F Breast cancer research : BCR. 2001 ; 3 (5) : 289-293. PMID 11597316

E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Cleton-Jansen AM Breast cancer research : BCR. 2002 ; 4 (1) : 5-8. PMID 11879552

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, Gilchrist D, Hughes R, Jackson CE, Monaghan KG, Oliveira MJ, Seruca R, Gallinger S, Caldas C, Huntsman D Journal of medical genetics. 2004 ; 41 (7) : 508-517. PMID 15235021

Recent advances in melanoma biology. Perlis C, Herlyn M The oncologist. 2004 ; 9 (2) : 182-187. PMID 15047922

Genetic aetiology of diffuse gastric cancer: so near, yet so far. Sweet KM, Lynch HT Journal of medical genetics. 2004 ; 41 (7) : 481-483. PMID 15235018

Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. Nair KS, Naidoo R, Chetty R Journal of clinical pathology. 2005 ; 58 (4) : 343-351. PMID 15790695

Structure and mechanism of cadherins and catenins in cell-cell contacts. Pokutta S, Weis WI Annual review of cell and developmental biology. 2007 ; 23 : 237-261. PMID 17539752

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Atlas Genet Cytogenet Oncol Haematol 2008; 3 422 Contributor(s) Written 10-2007 Marilia de Freitas Calmon, Paula Rahal Laboratory of Genomics studies, São Paulo State University, Departament of Biology, São José do Rio Preto, SP, Brasil Citation This paper should be referenced as such : Calmon MF, Rahal P . CDH1 (cadherin 1, type 1, E-cadherin (epithelial)). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CDH1ID166ch16q22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 423 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CD97 (CD97 molecule)

Identity Other names TM7LN1 Hugo CD97 Location 19p13 DNA/RNA

Genomic organization of CD97 (drawn to scale), boxes represent exons.

Description DNA contains 27.322 kb composed of 20 coding exons. Exons 1-2 encode the 5' untranslated region and the signal peptide, exons 3-7 the five EGF domains, exons 8-13 the extracellular stalk, exons 14-18 the seven-span transmembrane (TM7) domains and exons 19-20 the intracellular part and the 3' untranslated region. Transcription 3247 bp mRNA transcribed in telomeric to centromeric orientation; 2508 bp open reading frame. Human CD97 exists in three isoforms that result from alternative splicing of exons 5 and 6 and thus contain different numbers of EGF domains in the extracellular part of the molecule. The isoforms are designated as CD97(EGF1,2,5), CD97(EGF1,2,3,5) and CD97(EGF1-5) in human. Pseudogene No pseudogenes reported. Protein

Structure of CD97. Three isoforms containing 3, 4, or 5 EGF domains exist. N-glycosylation sites in the EGF domains are indicated. Description CD97 belongs to the B family of G protein-coupled receptors (GCPRs). Subfamily B2 contains cell surface molecules with long extracellular N-termini (LNB-TM7) known also as adhesion class of heptahelical receptors. CD97 is the founding member of a small subfamily within the adhesion class called EGF-TM7 family. All EGF-TM7 receptors (CD97, EMR1, EMR2, EMR3, EMR4) consist of extracellular tandemly arranged EGF domains, a stalk, the seven-span transmembrane (TM7) und a short intracellular part. They are expressed as

Atlas Genet Cytogenet Oncol Haematol 2008; 3 424 heterodimers of a non-covalently bound alpha- and beta-chain resulting from intracellular autocatalytic cleavage at a conserved GCPR proteolytic site (GPS). The alpha-chain represents the extracellular region with the varying numbers of EGF domains and the main part of the stalk and the beta-chain consists of the stalk residue, the TM7 and intracellular part. Three CD97 isoforms containing 3, 4 or 5 EGF domains are described. The mature full length proteins contain either 722, 766 or 815 amino acids (aa). After cleavage the (secretory) alpha-chains contain 420, 464, or 513 aa. The beta-chain theoretically contains 305 aa with a molecular weight of 34.3 kDa. However, immunoprecipitation of the beta-chain yielded a molecular weight of approximately 28 kDa. The discrepancy between the theoretical and actual molecular weight of the beta-chain is not yet clarified. Depending on the cell type and transformation status of the cell, CD97 is completely or partly N-glycosylated or naked. In normal muscle cells CD97 is not or only slightly N- glycosylated. The molecular weights for the respective naked alpha-chain of the various CD97 isoforms are 45.6, 50.5 and 55.8 kDa. In hematopoetic cells CD97 is N- glycosylated at the EGF domains resulting in molecular weights of 74-78, 80-82, and 86-89 kDa for the alpha-chains of the respective isoform. During tumor transformation CD97 may get N-glycosylated. Although the CD97 stalk contains many Ser or Thr residues the molecule seems not to be O-glycosylated. Expression Broad, not cell-type specific.  Hematopoetic system: strong in peripheral blood myeloid cells and activated lymphocytes, moderately in subsets of tissue-derived leukocytes;  Strong in smooth muscle cells (except for arterial vascular smooth muscle cells), skeletal muscle cells (stronger in slow-twitch fibers), heart muscle cells;  Fat cells;  Low in normal intestinal, thyroidal epithelial cells, moderately in duct cells of the pancreas, parotis gland and in bile duct cells of the liver. Localisation Usually at the cell membrane; soluble CD97 (sCD97) representing the CD97 alpha- chain in body fluids; Skeletal muscle cells: at the sarcolemm and intracellularly in the sacroendoplasmatic reticulum (SR). Function CD97 has the ability to bind cellular and extracellular matrix ligands. The first two EGF domains of CD97 bind CD55 (decay accelerating factor). The fourth EGF domain of CD97 and thus only the longest CD97 isoform interacts with the glycosaminoglycan chondroitin sulfate B. CD97 binds to alpha5beta1 and alphavbeta3 integrins through interaction with the CD97 stalk region.  Hematopoetic cells: Functional studies indicate a role of CD97 in leukocyte trafficking. CD97 antibodies block tissue localization of immune cells in vivo leading to impaired protection against bacteria and amelioration of autoimmune pathology.  Tumor cells: In vitro CD97 increases single cell random motility and directed migration and invasion of tumor cells in 2D and 3D matrices. CD97 enhances proteolytic activity of matrix metalloproteinases (MMPs) and secretion of chemokines in an isoform-specific manner. CD97 (EGF 1, 2, 5) overexpression promotes tumor growth in scid mice. The alpha-chain of the longest CD97 (EGF1-5) isoform (sCD97) enhances angiogenesis in in vivo tumor models.  Muscle, fat, duct cells: function unknown. Homology H. sapiens: CD97 P. troglodytes: CD97 B. taurus: CD97 S. scrofa: CD97 C. lupus: CD97 M. musculus: CD97 R. norvegicus: CD97 Exists only in mammals. Mutations Note unknown Implicated in

Atlas Genet Cytogenet Oncol Haematol 2008; 3 425 Note Note for all tumors: Antibodies to various epitopes of CD97 vary strongly in their staining pattern and cross- reactivity to other EGF-TM7 molecules. The first group of monoclonal antibodies, which includes BL-Ac/F2, VIM-3b and CLB-CD97/1, binds to the EGF domains of CD97 (CD97EGF antibodies). These antibodies also detect EMR2, another member of the EGF- TM7 family. In most cases, this cross-reactivity will not influence the results obtained for CD97 staining in tumors since EMR2 is strongly restricted to myeloid cells. CD97 antibodies MEM-180 and CLB-CD97/3 bind to the stalk region of CD97 (CD97stalk) and do not bind EMR2. CD97EGF epitope accessibility depends on cell type-specific N-glycosylation (see above). CD97EGF antibodies detect only N-glycosylated CD97. During tumor transformation, not only the CD97 protein expression level but also the degree of CD97 N-glycosylation varies. Thus, the selection of the CD97 antibody strongly influences the result in immunohistological studies focused on the correlation between CD97 and histopathological subtypes, diagnosis, progression, or prognosis of tumors. CD97 in tumors is strongly regulated at the post-trancriptional level. Entity Thyroid cancer Note In normal thyroid tissue, no or low immunoreactivity of CD97 is found. In differentiated follicular thyroid carcinoma or papillary thyroid carcinoma, CD97 expression is also either lacking or low. Most undifferentiated anaplastic carcinomas reveal high CD97 presentation. CD97 is absent or only weakly present in patients with postoperative T1 tumors but increased greatly with the progression to postoperative T4 tumors. Until now, only antibodies against CD97 EGF domains (CD97EGF antibodies, see above) have been used in studies of thyroid carcinomas. Prognosis not determined Cytogenetics not determined Oncogenesis Overexpression of CD97 might be important for the progression of thyroid cancer. Entity Colorectal cancer Note Normal human colorectal epithelium is slightly CD97-positive. Most colorectal carcinomas express CD97. The strongest staining for CD97 occurs in scattered tumor cells at the invasion front compared to cells located within solid tumor formations of the same tumor. Carcinomas with more strongly CD97-stained scattered tumor cells show a poorer clinical stage as well as increased lymph vessel invasion compared to cases with uniform CD97 staining. Prognosis not determined Cytogenetics not determined Oncogenesis Overexpression of CD97 might be important for invasion and metastasis of colorectal cancer. Entity Gastric cancer Note CD97 is present in normal parietal cells of gastric mucosa. It is stronger expressed by most gastric carcinomas. Half of the tumors show scattered tumor cells at the invasion front with stronger CD97 expression than tumor cells located in solid tumor formations. Prognosis not determined Cytogenetics not determined Entity Leiomyosarcoma Note Normal smooth muscle cells are CD97-positive. In this cell type CD97 is not N- glycosylated. Thus, monoclonal antibodies that detect an N-glycosylation dependent epitop of CD97 do not react with normal smooth muscle cells (CD97EGF antibodies). During transformation CD97 get partly N-glyocosylated in most uterine leiomyoma and or completely N-glyocosylated in nearly 25% of the leiomyosarcomas. These tumors are now positive for CD97EGF antibodies. However, one third of leiomyosarcomas are completely devoid of CD97. Prognosis not determined Cytogenetics not determined External links Nomenclature Hugo CD97

Atlas Genet Cytogenet Oncol Haematol 2008; 3 426 GDB CD97 Entrez_Gene CD97 976 CD97 molecule Cards Atlas CD97ID996ch19p13 GeneCards CD97 Ensembl CD97 [Search_View] ENSG00000123146 [Gene_View] Genatlas CD97 GeneLynx CD97 eGenome CD97 euGene 976 Genomic and cartography CD97 - 19p13 chr19:14353213-14380533 + 19p13 [Description] (hg18- GoldenPath Mar_2006) Ensembl CD97 - 19p13 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene CD97 Gene and transcription Genbank AK097264 [ ENTREZ ] Genbank AK225655 [ ENTREZ ] Genbank AK225677 [ ENTREZ ] Genbank AK292159 [ ENTREZ ] Genbank AU117846 [ ENTREZ ] RefSeq NM_001025160 [ SRS ] NM_001025160 [ ENTREZ ] RefSeq NM_001784 [ SRS ] NM_001784 [ ENTREZ ] RefSeq NM_078481 [ SRS ] NM_078481 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView CD97 AceView - NCBI Unigene Hs.466039 [ SRS ] Hs.466039 [ NCBI ] HS466039 [ spliceNest ] Fast-db 7720 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P48960 [ SRS] P48960 [ EXPASY ] P48960 [ INTERPRO ] Prosite PS00010 ASX_HYDROXYL [ SRS ] PS00010 ASX_HYDROXYL [ Expasy ] Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ] Prosite PS01187 EGF_CA [ SRS ] PS01187 EGF_CA [ Expasy ] PS00650 G_PROTEIN_RECEP_F2_2 [ SRS ] PS00650 Prosite G_PROTEIN_RECEP_F2_2 [ Expasy ] PS50261 G_PROTEIN_RECEP_F2_4 [ SRS ] PS50261 Prosite G_PROTEIN_RECEP_F2_4 [ Expasy ] Prosite PS50221 GPS [ SRS ] PS50221 GPS [ Expasy ] Interpro IPR000152 Asx_hydroxyl_S [ SRS ] IPR000152 Asx_hydroxyl_S [ EBI ] Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ] Interpro IPR001881 EGF_Ca_bd [ SRS ] IPR001881 EGF_Ca_bd [ EBI ] Interpro IPR013091 EGF_Ca_bd_2 [ SRS ] IPR013091 EGF_Ca_bd_2 [ EBI ] Interpro IPR003056 GPCR_2_CD97 [ SRS ] IPR003056 GPCR_2_CD97 [ EBI ] Interpro IPR000832 GPCR_2_secretin-like [ SRS ] IPR000832 GPCR_2_secretin-like [ EBI ] Interpro IPR000203 PKD_cys_rich [ SRS ] IPR000203 PKD_cys_rich [ EBI ] CluSTr P48960 Pfam PF00002 7tm_2 [ SRS ] PF00002 7tm_2 [ Sanger ] pfam00002 [ NCBI-CDD ] Pfam PF07645 EGF_CA [ SRS ] PF07645 EGF_CA [ Sanger ] pfam07645 [ NCBI-CDD ] Pfam PF01825 GPS [ SRS ] PF01825 GPS [ Sanger ] pfam01825 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 427 Smart SM00179 EGF_CA [EMBL] Smart SM00303 GPS [EMBL] Blocks P48960 HPRD 03130 Protein Interaction databases DIP P48960 IntAct P48960 Polymorphism : SNP, mutations, diseases OMIM 601211 [ map ] GENECLINICS 601211 SNP CD97 [dbSNP-NCBI]

SNP NM_001025160 [SNP-NCI] SNP NM_001784 [SNP-NCI] SNP NM_078481 [SNP-NCI] SNP CD97 [GeneSNPs - Utah] CD97] [HGBASE - SRS] HAPMAP CD97 [HAPMAP] HGMD CD97 General knowledge Family Browser CD97 [UCSC Family Browser] SOURCE NM_001025160 SOURCE NM_001784 SOURCE NM_078481 SMD Hs.466039 SAGE Hs.466039 GO G-protein coupled receptor activity [Amigo] G-protein coupled receptor activity GO calcium ion binding [Amigo] calcium ion binding GO protein binding [Amigo] protein binding GO protein binding [Amigo] protein binding GO extracellular region [Amigo] extracellular region GO plasma membrane [Amigo] plasma membrane GO integral to plasma membrane [Amigo] integral to plasma membrane GO cell motility [Amigo] cell motility GO inflammatory response [Amigo] inflammatory response GO immune response [Amigo] immune response GO cell adhesion [Amigo] cell adhesion GO neuropeptide signaling pathway [Amigo] neuropeptide signaling pathway GO cell-cell signaling [Amigo] cell-cell signaling PubGene CD97 TreeFam CD97 CTD 976 [Comparative Genomics Database] Other databases HREF="http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=63891">Family 2 or Other database B of the G-protein-coupled receptors (GCPRs) Probes Probe CD97 Related clones (RZPD - Berlin) PubMed PubMed 26 Pubmed reference(s) in LocusLink Bibliography CD97: a dedifferentiation marker in human thyroid carcinomas. Aust G, Eichler W, Laue S, Lehmann I, Heldin NE, Lotz O, Scherbaum WA, Dralle H, Hoang-Vu C Cancer research. 1997 ; 57 (9) : 1798-1806. PMID 9135025

Atlas Genet Cytogenet Oncol Haematol 2008; 3 428 CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas. Aust G, Steinert M, Schˆºtz A, Boltze C, Wahlbuhl M, Hamann J, Wobus M American journal of clinical pathology. 2002 ; 118 (5) : 699-707. PMID 12428789

Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues. Steinert M, Wobus M, Boltze C, Schˆºtz A, Wahlbuhl M, Hamann J, Aust G The American journal of pathology. 2002 ; 161 (5) : 1657-1667. PMID 12414513

CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Wang T, Ward Y, Tian L, Lake R, Guedez L, Stetler-Stevenson WG, Kelly K Blood. 2005 ; 105 (7) : 2836-2844. PMID 15576472

Comparative study of gill neuroepithelial cells and their innervation in teleosts and Xenopus tadpoles. Saltys HA, Jonz MG, Nurse CA Cell and tissue research. 2006 ; 323 (1) : 1-10. PMID 16163489

Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion. Galle J, Sittig D, Hanisch I, Wobus M, Wandel E, Loeffler M, Aust G The American journal of pathology. 2006 ; 169 (5) : 1802-1811. PMID 17071601

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Contributor(s) Written 10-2007 Gabriela Aust University of Leipzig, Faculty of Medicine, Research Laboratories, Center of Surgery, Liebigstr. 20, Leipzig, D-04103, Germany Citation This paper should be referenced as such : Aust G . CD97 (CD97 molecule). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CD97ID996ch19p13.html

Atlas Genet Cytogenet Oncol Haematol 2008; 3 429 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BRCA1 (breast cancer 1, early onset)

Identity Other names BRCAI BRCC1 IRIS PSCP RNF53 Hugo BRCA1 Location 17q21.31 According to NCBI Map Viewer, genes flanking BRCA1 in centromere to telomere direction on 17q21 are: VAT1 17q21 (vesicle amine transport protein 1 homolog (T californica)); RND2 17q21 Rho family GTPase 2; RPL21P4 17q21 ribosomal protein Local_order L21 pseudogene 4; BRCA1 17q21 breast cancer 1, early onset; NBR2 17q21 neighbour of BRCA1 gene; BRCA1P1 17q21 BRCA1 pseudogene 1; NBR1 17q21.31 neighbour of BRCA1 gene. Note BRCA1 is a tumour suppressor phosphoprotein that combines with other tumour suppressors, DNA damage and repair proteins, and signal transducers to form a large multi-subunit protein complex known as BRCA1-associated genome surveillance complex (BASC). Truncating mutations and missence mutations in the BRCA1 gene are found in a large number of familial breast cancer cases. Individuals who inherit a germline mutation of BRCA1 or BRCA2 have a significantly increased lifetime risk for the development of breast and/or ovarian cancer. DNA/RNA Note The subcellular localization and physiological function of this gene is greatly modulated by the several alternately splices isoforms that are found. Several of these alternatively spliced transcript variants have been described, however, not all have had their full- length natures identified. Description According to Entrez-Gene, BRCA1 gene maps to NC_000017.9 in the region between 38449840 and 38530994 on the minus strand and spans across 81.1 kilo bases. According to Spidey (mRNA to genomic sequence alignment tool, http://www.ncbi.nlm.nih.gov/spidey), BRCA1 has 24 exons, the sizes being 181, 99, 54, 78, 89, 140, 105, 47, 77, 89, 172, 127, 191, 311, 88, 78, 41, 84, 55, 74, 61, 1506. Transcription BRCA1 mRNA NM_007302.3 has 7388bps. The BRCA1 gene contains two separate promoters that induce transcription of mRNAs with different 5' UTRs, a shorter 5'UTRa and a longer 5'UTRb. The downregulation of BRCA1 gene expression in certain breast cancers is caused by a switch from expression of a 5'UTRa, which enables efficient translation, to expression of 5' UTRb, which contains secondary structure and upstream open reading frames that strongly inhibit translation. Pseudogene According to Entrez Gene the BRCA1 pseudogene 1 (BRCA1P1) is located on 17q21. Protein

The BRCA1 protein showing the RING finger domain, the Nuclear Localisation Signal domain and the BRCT domains. AA- amino acids. Note BRCA1 sequence is not well conserved between mammals, however, two domains, the C terminal BRCT (BRCA1 C Terminal) motifs and the N-terminal RING domain are highly conserved.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 430 Description BRCA1 is an 1863 amino acid 220kDa protein with an E3 ubiquitin ligase activity as well as a phospho-peptide binding activity. It has several domains that are essential for its function as depicted in the figure. The RING finger domain of BRCA1, commonly found in many DNA repair proteins, consists of a conserved core of approximately 50 amino acids in a pattern of seven cysteine residues and one histidine residue to form a structure that can bind to two Zn++ ions. This motif aids in mediating protein-protein interaction, as exemplified by the interaction of BRCA1 with BARD1 (BRCA1 associated RING domain). This interaction is critical since mutations in the Zn++ binding regions, crucial for heterodimerization with BARD1, have been found in tumours. BRCA1 accumulates in distinct foci in the nucleus during S phase and this transfer is aided by its Nuclear Localisation Signal (NLS) domain. A further role of BARD1 is also implicated whereby its association with the RING finger domain of BRCA1 is necessary for the transfer of BRCA1 to the nucleus. BRCA1 interacts with Rad50 of the MRN complex through the region AA 341-748 and can directly bind to branched, flap and four way DNA structures through a central domain spanning residues 452-1079. The protein inhibits the nucleolytic activities of the Mre11/Rad50/Nbs1 complex as a result of this direct DNA binding. The C terminus of BRCA1, which can function as a transcriptional activation domain, consists of two tandemly arranged elements called BRCT (BRCA1 C- terminal). This motif specifically binds to phosphorylated proteins, an event that is commonly associated with DNA damage response. BRCA1 is capable of interacting directly with BRCA2 and with Rad51 via BRCA2 through this motif. Another protein that interacts with BRCA1 via BRCT is the BRCA1 associated C-terminal helicase (BACH1). BACH1 is said to aid BRCA1 in the DNA damage response and maintain the protein at the nuclear foci formed after DNA damage response. Other proteins that can interact with BRCA1 through the BRCT domains are C terminal Interacting protein /CtIP), RNA Polymerase II, BACH 1 (a member of DEAH helicase family) and p53 . Expression BRCA1 is ubiquitously expressed in humans with the highest levels observed in the ovaries, testis and thymus. It is a tumour suppressor and a reduced expression is correlated with the transformation procedure and aetiology of sporadic breast cancer. This reduction is expression is said to be transcriptionally regulated with implications of aberrant promoter methylation at CpG dinucleotides as well as CREB binding sites. Localisation Located in the nucleus. Function Role of BRCA1 in DNA repair: BRCA1 is a part of a large complex of proteins, the BASC, which monitors the genome for damage and signals downstream effectors. BRCA1 has been implicated in two pathways of DNA double strand break repair: homologous recombination (HR) and non homologous end joining (NHEJ). Upon exposure to DNA damaging agents, BRCA1 becomes hyperphosphorylated and is rapidly relocated, along with Rad51, to sites of DNA synthesis marked by proliferating cell nuclear antigen (PCNA). Rad51, a homolog of the bacterial RecA, is a central player in HR, catalyzing the invasion of the single stranded DNA in a homologous duplex and facilitating the homology search during the establishment of joint molecules. A recent study, however, has indicated that BRCA1 deficient breast cancer cells compensate for this deficiency by upregulating Rad51. The resultant HR may be erroneous and thereby lead to tumorigenesis. In addition, BRCA1 is said to inhibit the MRN complex which is is implicated in bringing together two DNA strands together for the error prone NHEJ. BRCA1-deficient cells are sensitive to ionizing radiation and DNA damaging drugs, such as mitomycin C. Transcriptional regulation: BRCA1 is capable of transcriptional regulation and chromatin remodelling when tethered to promoters of genes important in the DNA repair process and breast cancer markers. It is a member of the core RNA polymerase II transcriptional machinery, a feature exploited by the DNA damage recognition process. In addition, BRCA1 interacts with p300/CBP, transcriptional coactivators for CREB. p300/CBP are inhibited by the viral oncoprotein E1A and the functionality of E1A as an oncogene could be in part caused by an obstruction of BRCA1:p300/CBP cooperation resulting in the loss of the tumour-suppressing function of BRCA1. BRCA1 can act as a transcriptional coactivator or co repressor of proteins implicated in chromatin remodelling, such as the histone deacetylase complexes or components of the SWI/SNF-related chromatin-remodelling complex. Cell Cycle Regulation by BRCA1: BRCA1, based on its phosphorylation status, elicits

Atlas Genet Cytogenet Oncol Haematol 2008; 3 431 DNA damage induced cell cycle arrest at several stages through modulation of specific downstream target genes. BRCA1 transactivates p21cip1/WAF1, which contributes to an arrest at the G1/S boundary. ATM phosphorylation of BRCA1 appears to be important for its role in the intra S phase checkpoint activation. BRCA1 is also implicated in the transcriptional regulation of several genes such as cyclinB, 14-3-3sigma, GADD45, wee-1 kinase and PLK1 associated with the G2/M checkpoint. p53-dependent apoptosis: The BRCA1 protein is capable of physically interacting with the p53 tumour suppressor gene, and can stimulate p53-dependent transcription from the p21WAF1/CIP1 mdm2 and promoters. In addition, the BRCA1-BARD1 complex is required for the phosphorylation of p53 at Ser15 by ATM/ATR following DNA damage by IR or UV radiation. The phosphorylation of p53 at Ser-15 is essential for the G(1)/S cell cycle arrest via transcriptional induction of the cyclin-dependent kinase inhibitor p21 after DNA damage. Ubiquitination: BRCA1 and BARD1 interact together to form an E3 ubiquitin ligase. RNA polII stalled at sites of DNA damage is a target for this ubiquitin ligase mediated degradation following DNA damage, thereby allowing access to the repair machinery. BRCA1 ubiquitinates the transcriptional preinitiation complex, not for proteasomal degradation, but to prevent a stable association of TFIIE and TFIIH; thereby blocking the initiation of mRNA synthesis. Homology Dog (Canis familiaris): BRCA1 Chimpanzee (Pan troglodytes): BRCA1 Rat (Rattus norvegicus): Brca1 Mouse (Mus musculus): Brca1 Chicken (Gallus gallus): BRCA1 Mutations Note BRCA1 germline mutations contribute significantly to the development of familial/hereditary breast and ovarian cancer. However, each gene carries as many as 1000 different disease associated mutations, many of which are rare. These mutations are distributed uniformly along the entire coding region and intronic sequences flanking each exon. The mutations are at a high penetrance therefore women who carry these mutations have a lifetime risk of 80-90% to develop breast cancer. Founder mutations such as the BRCA1-185delAG and 5382insC are found among Ashkenazi Jews. Larger and complex genomic rearrangements in the exons 21 and 22 of the BRCA1 gene, resulting in a lack of the BRCT motif have been reported. Implicated in Entity Breast Cancer Disease Heterozygous carriers of high-risk mutations in the general Caucasian population have been estimated to be about one in 1000 for the BRCA1 gene. The lifetime risk of the development of hereditary breast cancer with the presence of BRCA1 mutations is very high. In addition, for sporadic breast cancer, a reduction in the expression of BRCA1 rather than the presence of mutations has been observed. The lack of a functional BRCA1 leads to impaired repair of DNA double strand breaks, cell cycle progression and transcriptional regulation, thereby causing the development of neoplasms. Entity Ovarian Cancer Disease Mutations of the BRCA1 gene are the major cause for familial breast and ovarian cancer incidence. The lifetime risks of ovarian cancer associated with a BRCA1 gene mutation carrier has been estimated as 40 to 50%. The most common mutations are frameshift and nonsense mutations that are predicted to cause premature truncation of the BRCA1 protein. In addition, mutations that are predicted to affect splice-site consensus sequences as well as missense mutation have also been seen in ovarian cancer. Large genomic alterations, such as the gains in copy number of exon 13 as well as deletion of exons in the BRCA1 gene is also associated with the development of ovarian cancer. Entity Other cancers Disease An increased relative risk to the development of cancer of the colon, cervix, uterus, pancreas and prostate has been suggested in BRCA1-mutation carriers. External links Nomenclature Hugo BRCA1

Atlas Genet Cytogenet Oncol Haematol 2008; 3 432 GDB BRCA1 Entrez_Gene BRCA1 672 breast cancer 1, early onset Cards Atlas BRCA1ID163ch17q21 GeneCards BRCA1 Ensembl BRCA1 [Search_View] ENSG00000012048 [Gene_View] Genatlas BRCA1 GeneLynx BRCA1 eGenome BRCA1 euGene 672 Genomic and cartography BRCA1 - 17q21.31 chr17:38449840-38530657 - 17q21 [Description] (hg18- GoldenPath Mar_2006) Ensembl BRCA1 - 17q21 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BRCA1 Gene and transcription Genbank AF005068 [ ENTREZ ] Genbank AF274503 [ ENTREZ ] Genbank AL701927 [ ENTREZ ] Genbank AY354539 [ ENTREZ ] Genbank AY751490 [ ENTREZ ] RefSeq NM_007294 [ SRS ] NM_007294 [ ENTREZ ] RefSeq NM_007295 [ SRS ] NM_007295 [ ENTREZ ] RefSeq NM_007296 [ SRS ] NM_007296 [ ENTREZ ] RefSeq NM_007297 [ SRS ] NM_007297 [ ENTREZ ] RefSeq NM_007298 [ SRS ] NM_007298 [ ENTREZ ] RefSeq NM_007299 [ SRS ] NM_007299 [ ENTREZ ] RefSeq NM_007300 [ SRS ] NM_007300 [ ENTREZ ] RefSeq NM_007302 [ SRS ] NM_007302 [ ENTREZ ] RefSeq NM_007303 [ SRS ] NM_007303 [ ENTREZ ] RefSeq NM_007304 [ SRS ] NM_007304 [ ENTREZ ] RefSeq NM_007305 [ SRS ] NM_007305 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NG_005905 [ SRS ] NG_005905 [ ENTREZ ] RefSeq NT_010755 [ SRS ] NT_010755 [ ENTREZ ] RefSeq NW_926828 [ SRS ] NW_926828 [ ENTREZ ] AceView BRCA1 AceView - NCBI Unigene Hs.194143 [ SRS ] Hs.194143 [ NCBI ] HS194143 [ spliceNest ] Fast-db 10956 (alternative variants) Protein : pattern, domain, 3D structure SwissProt P38398 [ SRS] P38398 [ EXPASY ] P38398 [ INTERPRO ] Prosite PS50172 BRCT [ SRS ] PS50172 BRCT [ Expasy ] Prosite PS00518 ZF_RING_1 [ SRS ] PS00518 ZF_RING_1 [ Expasy ] Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ] Interpro IPR011364 BRCA1 [ SRS ] IPR011364 BRCA1 [ EBI ] Interpro IPR001357 BRCT [ SRS ] IPR001357 BRCT [ EBI ] Interpro IPR002378 Brst_cancerI [ SRS ] IPR002378 Brst_cancerI [ EBI ] Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] Interpro IPR013083 Znf_RING/FYVE/PHD [ SRS ] IPR013083 Znf_RING/FYVE/PHD [ EBI ] CluSTr P38398

Atlas Genet Cytogenet Oncol Haematol 2008; 3 433 Pfam PF00533 BRCT [ SRS ] PF00533 BRCT [ Sanger ] pfam00533 [ NCBI-CDD ] PF00097 zf-C3HC4 [ SRS ] PF00097 zf-C3HC4 [ Sanger ] pfam00097 [ NCBI-CDD Pfam ] Smart SM00292 BRCT [EMBL] Smart SM00184 RING [EMBL] Blocks P38398 PDB 1JM7 [ SRS ] 1JM7 [ PdbSum ], 1JM7 [ IMB ] 1JM7 [ RSDB ] PDB 1JNX [ SRS ] 1JNX [ PdbSum ], 1JNX [ IMB ] 1JNX [ RSDB ] PDB 1N5O [ SRS ] 1N5O [ PdbSum ], 1N5O [ IMB ] 1N5O [ RSDB ] PDB 1OQA [ SRS ] 1OQA [ PdbSum ], 1OQA [ IMB ] 1OQA [ RSDB ] PDB 1T15 [ SRS ] 1T15 [ PdbSum ], 1T15 [ IMB ] 1T15 [ RSDB ] PDB 1T29 [ SRS ] 1T29 [ PdbSum ], 1T29 [ IMB ] 1T29 [ RSDB ] PDB 1T2U [ SRS ] 1T2U [ PdbSum ], 1T2U [ IMB ] 1T2U [ RSDB ] PDB 1T2V [ SRS ] 1T2V [ PdbSum ], 1T2V [ IMB ] 1T2V [ RSDB ] PDB 1Y98 [ SRS ] 1Y98 [ PdbSum ], 1Y98 [ IMB ] 1Y98 [ RSDB ] PDB 2ING [ SRS ] 2ING [ PdbSum ], 2ING [ IMB ] 2ING [ RSDB ] HPRD 00218 Protein Interaction databases DIP P38398 IntAct P38398 Polymorphism : SNP, mutations, diseases OMIM 113705 [ map ] GENECLINICS 113705 SNP BRCA1 [dbSNP-NCBI] SNP NM_007294 [SNP-NCI] SNP NM_007295 [SNP-NCI] SNP NM_007296 [SNP-NCI] SNP NM_007297 [SNP-NCI] SNP NM_007298 [SNP-NCI] SNP NM_007299 [SNP-NCI] SNP NM_007300 [SNP-NCI] SNP NM_007302 [SNP-NCI] SNP NM_007303 [SNP-NCI] SNP NM_007304 [SNP-NCI] SNP NM_007305 [SNP-NCI] SNP BRCA1 [GeneSNPs - Utah] BRCA1] [HGBASE - SRS] HAPMAP BRCA1 [HAPMAP] COSMIC BRCA1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD BRCA1 General knowledge Family Browser BRCA1 [UCSC Family Browser] SOURCE NM_007294 SOURCE NM_007295 SOURCE NM_007296 SOURCE NM_007297 SOURCE NM_007298 SOURCE NM_007299 SOURCE NM_007300 SOURCE NM_007302 SOURCE NM_007303 SOURCE NM_007304 SOURCE NM_007305 SMD Hs.194143

Atlas Genet Cytogenet Oncol Haematol 2008; 3 434 SAGE Hs.194143 GO cell cycle checkpoint [Amigo] cell cycle checkpoint GO ubiquitin ligase complex [Amigo] ubiquitin ligase complex double-strand break repair via homologous recombination [Amigo] double-strand GO break repair via homologous recombination GO molecular_function [Amigo] molecular_function GO DNA binding [Amigo] DNA binding GO DNA binding [Amigo] DNA binding GO transcription coactivator activity [Amigo] transcription coactivator activity GO ubiquitin-protein ligase activity [Amigo] ubiquitin-protein ligase activity GO protein binding [Amigo] protein binding GO cellular_component [Amigo] cellular_component GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO DNA repair [Amigo] DNA repair GO postreplication repair [Amigo] postreplication repair regulation of transcription from RNA polymerase II promoter [Amigo] regulation of GO transcription from RNA polymerase II promoter regulation of transcription from RNA polymerase III promoter [Amigo] regulation of GO transcription from RNA polymerase III promoter GO fatty acid biosynthetic process [Amigo] fatty acid biosynthetic process DNA damage response, signal transduction by p53 class mediator resulting in GO transcription of p21 class mediator [Amigo] DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator GO cell cycle [Amigo] cell cycle GO zinc ion binding [Amigo] zinc ion binding GO zinc ion binding [Amigo] zinc ion binding GO gamma-tubulin ring complex [Amigo] gamma-tubulin ring complex DNA damage response, signal transduction resulting in induction of apoptosis GO [Amigo] DNA damage response, signal transduction resulting in induction of apoptosis GO tubulin binding [Amigo] tubulin binding GO negative regulation of transcription [Amigo] negative regulation of transcription GO protein ubiquitination [Amigo] protein ubiquitination GO enzyme binding [Amigo] enzyme binding GO androgen receptor signaling pathway [Amigo] androgen receptor signaling pathway positive regulation of protein ubiquitination [Amigo] positive regulation of protein GO ubiquitination GO BRCA1-BARD1 complex [Amigo] BRCA1-BARD1 complex GO regulation of cell proliferation [Amigo] regulation of cell proliferation GO regulation of apoptosis [Amigo] regulation of apoptosis GO response to estrogen stimulus [Amigo] response to estrogen stimulus negative regulation of fatty acid biosynthetic process [Amigo] negative regulation of GO fatty acid biosynthetic process GO positive regulation of DNA repair [Amigo] positive regulation of DNA repair GO negative regulation of cell cycle [Amigo] negative regulation of cell cycle positive regulation of transcription, DNA-dependent [Amigo] positive regulation of GO transcription, DNA-dependent negative regulation of centriole replication [Amigo] negative regulation of centriole GO replication GO metal ion binding [Amigo] metal ion binding GO androgen receptor binding [Amigo] androgen receptor binding BIOCARTA ATM Signaling Pathway [Genes] BIOCARTA Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes] BIOCARTA BRCA1-dependent Ub-ligase activity [Genes]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 435 BIOCARTA CARM1 and Regulation of the Estrogen Receptor [Genes] BIOCARTA Cell Cycle: G2/M Checkpoint [Genes] PubGene BRCA1 TreeFam BRCA1 CTD 672 [Comparative Genomics Database] Other databases Probes Probe BRCA1 Related clones (RZPD - Berlin) PubMed PubMed 499 Pubmed reference(s) in LocusLink Bibliography A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W Science (New York, N.Y.). 1994 ; 266 (5182) : 66-71. PMID 7545954

Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Baumann P, Benson FE, West SC Cell. 1996 ; 87 (4) : 757-766. PMID 8929543

Transcriptional activation by BRCA1. Chapman MS, Verma IM Nature. 1996 ; 382 (6593) : 678-679. PMID 8751436

BRCA1 is a cell cycle-regulated nuclear phosphoprotein. Ruffner H, Verma IM Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (14) : 7138-7143. PMID 9207057

BRCA1 is a component of the RNA polymerase II holoenzyme. Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (11) : 5605-5610. PMID 9159119

Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM Cell. 1997 ; 90 (3) : 425-435. PMID 9267023

Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R Molecular cell. 1998 ; 2 (3) : 317-328. PMID 9774970

BRCA1 regulates p53-dependent gene expression. Ouchi T, Monteiro AN, August A, Aaronson SA, Hanafusa H Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (5) : 2302-2306. PMID 9482880

Atlas Genet Cytogenet Oncol Haematol 2008; 3 436 Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Rice JC, Massey-Brown KS, Futscher BW Oncogene. 1998 ; 17 (14) : 1807-1812. PMID 9778046

The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter. Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN Oncogene. 1999 ; 18 (1) : 263-268. PMID 9926942

Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH Science (New York, N.Y.). 1999 ; 285 (5428) : 747-750. PMID 10426999

CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (3) : 1020-1025. PMID 10655477

BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J Genes & development. 2000 ; 14 (8) : 927-939. PMID 10783165

A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element. Atlas E, Stramwasser M, Mueller CR Oncogene. 2001 ; 20 (48) : 7110-7114. PMID 11704836

The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer- derived mutation. Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T The Journal of biological chemistry. 2001 ; 276 (18) : 14537-14540. PMID 11278247

Direct DNA binding by Brca1. Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (11) : 6086-6091. PMID 11353843

BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. Fabbro M, Rodriguez JA, Baer R, Henderson BR The Journal of biological chemistry. 2002 ; 277 (24) : 21315-21324. PMID 11925436

Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Jasin M Oncogene. 2002 ; 21 (58) : 8981-8993. PMID 12483514

Structural determinants of BRCA1 translational regulation. Sobczak K, Krzyzosiak WJ The Journal of biological chemistry. 2002 ; 277 (19) : 17349-17358.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 437 PMID 11877386

BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA, Khanna KK The Journal of biological chemistry. 2004 ; 279 (30) : 31251-31258. PMID 15159397

Molecular functions of BRCA1 in the DNA damage response. Scully R, Xie A, Nagaraju G Cancer biology & therapy. 2004 ; 3 (6) : 521-527. PMID 15280660

Good timing in the cell cycle for precise DNA repair by BRCA1. Durant ST, Nickoloff JA Cell cycle (Georgetown, Tex.). 2005 ; 4 (9) : 1216-1222. PMID 16103751

Cellular functions of the BRCA tumour-suppressor proteins. Boulton SJ Biochemical Society transactions. 2006 ; 34 (Pt 5) : 633-645. PMID 17052168

Assessing the link between BACH1 and BRCA1 in the FA pathway. Cantor SB, Andreassen PR Cell cycle (Georgetown, Tex.). 2006 ; 5 (2) : 164-167. PMID 16357529

The role of BRCA1 in transcriptional regulation and cell cycle control. Mullan PB, Quinn JE, Harkin DP Oncogene. 2006 ; 25 (43) : 5854-5863. PMID 16998500

BACH1 is a DNA repair protein supporting BRCA1 damage response. Peng M, Litman R, Jin Z, Fong G, Cantor SB Oncogene. 2006 ; 25 (15) : 2245-2253. PMID 16462773

Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC JAMA : the journal of the American Medical Association. 2006 ; 295 (12) : 1379-1388. PMID 16551709

Founder mutations in BRCA1 and BRCA2 genes. Ferla R, Calˆ¾ V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2007 ; 18 Suppl 6 : vi93-vi98. PMID 17591843

A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase. Horwitz AA, Affar el B, Heine GF, Shi Y, Parvin JD Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (16) : 6614-6619. PMID 17420471

RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 438 Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK Cancer research. 2007 ; 67 (20) : 9658-9665. PMID 17942895

Genetic susceptibility for breast cancer: how many more genes to be found? Oldenburg RA, Meijers-Heijboer H, Cornelisse CJ, Devilee P Critical reviews in oncology/hematology. 2007 ; 63 (2) : 125-149. PMID 17498966

Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Ramus SJ, Harrington PA, Pye C, DiCioccio RA, Cox MJ, Garlinghouse-Jones K, Oakley-Girvan I, Jacobs IJ, Hardy RM, Whittemore AS, Ponder BA, Piver MS, Pharoah PD, Gayther SA Human mutation. 2007 ; 28 (12) : 1207-1215. PMID 17688236

Novel complex genomic rearrangement of the BRCA1 gene. Zikan M, Pohlreich P, Stribrna J, Kleibl Z, Cibula D Mutation research. 2008 ; 637 (1-2) : 205-208. PMID 17868747

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Contributor(s) Written 10-2007 Sreeparna Banerjee Department of Biology, Middle East Technical University, Ankara 06531, Turkey Citation This paper should be referenced as such : Banerjee S . BRCA1 (breast cancer 1, early onset). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BRCA1ID163ch17q21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 439 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3)

Identity Other names NIP3 Hugo BNIP3 Location 10q26.3 DNA/RNA

Description 14.23 kb on reverse strand; 6 exons Transcription mRNA in MCF-7 cells are 1.7kb (major) and 1.5 kb (minor) and 1.3 kb (minor). Protein

Domain map of BNIP3 protein; BH3 domain (Bcl-2 holomogy 3 domain); TM domain (transmembrane domain) Description 194 amino acids; 1 BH3 domain and 1 TM domain; BH3 only Bcl2 family member. The TM domain and C-terminal tail are essential for mitochondrial membrane localization and proapoptotic function. The predicted molecular weight is 21.5 kDa. BNIP3 migrates as 30 kDa monomeric form and 60 kDa dimeric form on SDS-PAGE. Expression BNIP3 is detected in mouse oviduct, uterus, spleen, lung, stomach, brain, seminal, lacrimal, submaxillary, heart, kidney, liver. It can be detected in cell lines such as HeLa, 293T, RAW264.7 and K562 cells. Its expression can be induced in both normal and cancer tissues that experience hypoxia or hypoxia-like conditions. Other stimuli, such as nitric oxide or arsenic trioxide, are also reported to induce BNIP3 expression. Localisation Outer mitochondrial membrane Function Proapoptotic protein; BNIP3 leads to opening of the mitochondrial permeability transition pore (PTP) thereby abolishing the proton electrochemical gradient and this is followed by chromatin condensation and DNA fragmentation. BNIP3 leads necrosis-like apoptosis. Unusually to the other Bcl-2 family proteins, the BNIP3-induced cell death depends not on BH3 domain but on C-terminal TM domain. BNIP3-induced cell death is known to be independent the nuclear translocation of AIF. However, whether caspase activation and cytochrome c release are involved in the cell death remains controversial. BNIP3 can induce autophagy. However whether the consequence of the autophagy is the cell death or survival remains to be established. Homology The close homologue: BNIP3L/ BNIP3a/ Nix/ B5 (8q21) The BH3-only Bcl2 family members: BBC3/PUMA (19q13), BCL2L11/BIM/BOD (2Q13), BID (22q11), BIK/NBK/BBC1 (22q13), BLK (8q23), BMF (15Q14), HRK/DP5/BID3 (12q24), PMAIP1/NOXA (18q21) Implicated in Entity Pancreatic cancer Prognosis Pancreatic adenocarcinoma is highly resistant to chemical and radiation therapy, and has an extremely poor prognosis. Reduced expression of BNIP3 increased resistance

Atlas Genet Cytogenet Oncol Haematol 2008; 3 440 to gemcitabine and 5-fluoro-uracil (5-FU) and showed a good correlation with reduced patient survival. Oncogenesis In most cases of pancreatic adenocarcinoma, BNIP3 expression was not detected even in response to hypoxia. The promoter of BNIP3 is located within a CpG island and is methylated in most pancreatic cancer cell lines. Restoration of BNIP3 expression by the methyltransferase inhibitor, 5-aza-deoxycytidine, induced death of pancreatic cancer cells in response to hypoxia. Entity Colorectal cancer Oncogenesis Methylation of BNIP3 in 66% of primary colorectal cancer External links Nomenclature Hugo BNIP3 GDB BNIP3 Entrez_Gene BNIP3 664 BCL2/adenovirus E1B 19kDa interacting protein 3 Cards Atlas BNIP3ID822ch10q26 GeneCards BNIP3 Ensembl BNIP3 [Search_View] ENSG00000176171 [Gene_View] Genatlas BNIP3 GeneLynx BNIP3 eGenome BNIP3 euGene 664 Genomic and cartography BNIP3 - 10q26.3 chr10:133631194-133645425 - 10q26.3 [Description] (hg18- GoldenPath Mar_2006) Ensembl BNIP3 - 10q26.3 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene BNIP3 Gene and transcription Genbank AF002697 [ ENTREZ ] Genbank AK222626 [ ENTREZ ] Genbank BC009342 [ ENTREZ ] Genbank BC021989 [ ENTREZ ] Genbank BC067818 [ ENTREZ ] RefSeq NM_004052 [ SRS ] NM_004052 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_017795 [ SRS ] NT_017795 [ ENTREZ ] RefSeq NW_924884 [ SRS ] NW_924884 [ ENTREZ ] AceView BNIP3 AceView - NCBI Unigene Hs.144873 [ SRS ] Hs.144873 [ NCBI ] HS144873 [ spliceNest ] Fast-db 17100 (alternative variants) Protein : pattern, domain, 3D structure SwissProt Q12983 [ SRS] Q12983 [ EXPASY ] Q12983 [ INTERPRO ] Interpro IPR010548 BNIP3 [ SRS ] IPR010548 BNIP3 [ EBI ] CluSTr Q12983 Pfam PF06553 BNIP3 [ SRS ] PF06553 BNIP3 [ Sanger ] pfam06553 [ NCBI-CDD ] Blocks Q12983 PDB 2J5D [ SRS ] 2J5D [ PdbSum ], 2J5D [ IMB ] 2J5D [ RSDB ] HPRD 04482 Protein Interaction databases DIP Q12983 IntAct Q12983

Atlas Genet Cytogenet Oncol Haematol 2008; 3 441 Polymorphism : SNP, mutations, diseases OMIM 603293 [ map ] GENECLINICS 603293 SNP BNIP3 [dbSNP-NCBI] SNP NM_004052 [SNP-NCI] SNP BNIP3 [GeneSNPs - Utah] BNIP3] [HGBASE - SRS] HAPMAP BNIP3 [HAPMAP] COSMIC BNIP3 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD BNIP3 General knowledge Family Browser BNIP3 [UCSC Family Browser] SOURCE NM_004052 SMD Hs.144873 SAGE Hs.144873 GO response to hypoxia [Amigo] response to hypoxia GO nucleus [Amigo] nucleus GO nuclear envelope [Amigo] nuclear envelope GO nucleoplasm [Amigo] nucleoplasm GO cytoplasm [Amigo] cytoplasm GO mitochondrion [Amigo] mitochondrion GO mitochondrion [Amigo] mitochondrion GO DNA fragmentation during apoptosis [Amigo] DNA fragmentation during apoptosis GO chromatin remodeling [Amigo] chromatin remodeling oxygen and reactive oxygen species metabolic process [Amigo] oxygen and reactive GO oxygen species metabolic process GO anti-apoptosis [Amigo] anti-apoptosis GO induction of apoptosis [Amigo] induction of apoptosis GO cell death [Amigo] cell death GO cell death [Amigo] cell death negative regulation of survival gene product activity [Amigo] negative regulation of GO survival gene product activity GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO dendrite [Amigo] dendrite integral to mitochondrial outer membrane [Amigo] integral to mitochondrial outer GO membrane GO mitochondrial membrane [Amigo] mitochondrial membrane GO mitochondrial membrane [Amigo] mitochondrial membrane GO protein homodimerization activity [Amigo] protein homodimerization activity negative regulation of membrane potential [Amigo] negative regulation of membrane GO potential regulation of mitochondrial membrane permeability [Amigo] regulation of mitochondrial GO membrane permeability GO protein heterodimerization activity [Amigo] protein heterodimerization activity GO neuron apoptosis [Amigo] neuron apoptosis GO defense response to virus [Amigo] defense response to virus PubGene BNIP3 TreeFam BNIP3 CTD 664 [Comparative Genomics Database] Other databases Probes Probe BNIP3 Related clones (RZPD - Berlin) PubMed PubMed 40 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2008; 3 442 Bibliography Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G Cell. 1994 ; 79 (2) : 341-351. PMID 7954800

The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, Saxena S, Gietz RD, Greenberg AH The Journal of experimental medicine. 1997 ; 186 (12) : 1975-1983. PMID 9396766

Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence. Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G The Journal of biological chemistry. 1998 ; 273 (20) : 12415-12421. PMID 9575197

Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Bruick RK Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (16) : 9082-9087. PMID 10922063

BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH The Journal of biological chemistry. 2000 ; 275 (2) : 1439-1448. PMID 10625696

BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH Molecular and cellular biology. 2000 ; 20 (15) : 5454-5468. PMID 10891486

The carboxy terminal C-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondria. Kim JY, Cho JJ, Ha J, Park JH Archives of biochemistry and biophysics. 2002 ; 398 (2) : 147-152. PMID 11831844

Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (20) : 12825-12830. PMID 12226479

Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Okami J, Simeone DM, Logsdon CD Cancer research. 2004 ; 64 (15) : 5338-5346. PMID 15289340

Nitric oxide induces BNIP3 expression that causes cell death in macrophages. Yook YH, Kang KH, Maeng O, Kim TR, Lee JO, Kang KI, Kim YS, Paik SG, Lee H Biochemical and biophysical research communications. 2004 ; 321 (2) : 298-305. PMID 15358175

Upregulation of BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-

Atlas Genet Cytogenet Oncol Haematol 2008; 3 443 mediated cell death. Abe T, Toyota M, Suzuki H, Murai M, Akino K, Ueno M, Nojima M, Yawata A, Miyakawa H, Suga T, Ito H, Endo T, Tokino T, Hinoda Y, Imai K Journal of gastroenterology. 2005 ; 40 (5) : 504-510. PMID 15942716

Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer. Akada M, Crnogorac-Jurcevic T, Lattimore S, Mahon P, Lopes R, Sunamura M, Matsuno S, Lemoine NR Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (8) : 3094-3101. PMID 15837765

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Erkan M, Kleeff J, Esposito I, Giese T, Ketterer K, Bˆºchler MW, Giese NA, Friess H Oncogene. 2005 ; 24 (27) : 4421-4432. PMID 15856026

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours. Murai M, Toyota M, Satoh A, Suzuki H, Akino K, Mita H, Sasaki Y, Ishida T, Shen L, Garcia-Manero G, Issa JP, Hinoda Y, Tokino T, Imai K British journal of cancer. 2005 ; 92 (6) : 1165-1172. PMID 15756280

Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. Murai M, Toyota M, Suzuki H, Satoh A, Sasaki Y, Akino K, Ueno M, Takahashi F, Kusano M, Mita H, Yanagihara K, Endo T, Hinoda Y, Tokino T, Imai K Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (3) : 1021-1027. PMID 15709167

BNip3 and signal-specific programmed death in the heart. Webster KA, Graham RM, Bishopric NH Journal of molecular and cellular cardiology. 2005 ; 38 (1) : 35-45. PMID 15623420

Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric oxide-induced cell death. An HJ, Maeng O, Kang KH, Lee JO, Kim YS, Paik SG, Lee H The Journal of biological chemistry. 2006 ; 281 (45) : 33939-33948. PMID 16954213

Regulation of BNIP3 in normal and cancer cells. Lee H, Paik SG Molecules and cells. 2006 ; 21 (1) : 1-6. PMID 16511341

Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer. Bacon AL, Fox S, Turley H, Harris AL Oncogene. 2007 ; 26 (1) : 132-141. PMID 16799636

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Atlas Genet Cytogenet Oncol Haematol 2008; 3 444 Contributor(s) Written 10-2007 Sang-Gi Paik, Hayyoung Lee Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon 305-764, Korea. Citation This paper should be referenced as such : Paik SG, Lee H . BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/BNIP3ID822ch10q26.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 445 Atlas of Genetics and Cytogenetics in Oncology and Haematology

AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1)

Identity Other names AIF PDCD8 MGC111425 Hugo AIFM1 Location Xq25 Centromere (59,500 Kbp)- ARHGEF9 - (Š) - RAB33A- AIFM1 - ELF4 - (Š) - IL9R Local_order -telomere (154,914 Kbp). DNA/RNA Note AIF (Apoptosis-Inducing Factor). Total gene size 36.471 Kb with a transcribed region of 2.215 Kb which codes for 613 amino acids. To date, five isoforms from AIF gene have been described (AIF, AIFexB, AIFsh, AIFsh2, and AIFsh3).

AIF gene structure and known isoforms. Genomic organization of AIF and resulting AIF, AIF-exB, AIFsh, AIFsh2, and AIFsh3 mRNA transcripts (schemas in the left). Translation start (ATG, in green) and stop (TGA/ TAA, in red) codons are indicated, and the predicted protein product is shown at the right. Numbers in AIF designate exons (in mRNA transcripts) and amino acids (in the predicted proteins). Mitochondria localization signal (MLS), Pyridoxin-redox (Pyr-Redox), nuclear localization sequence (NLS), and C-terminal domains are indicated. I9 (in green) indicates intron 9. The inclusion of the 203-bp exon 9b (lettering in red) produces AIFsh2 and AIFsh3, which encodes 324- and 237-amino acid proteins, respectively. AIFsh2 contains the MLS and the Pyr-Redox domain, but lacks the C-terminal portion of AIF. AIFsh3 has a similar structure as AIFsh2 with the splicing of exon 2, leading to the loss of MLS. Blue lines indicate the splicing of the different isoforms.

Description 16 exons spanning 36.471 Kb. Transcription 2,215 bp mRNA. Pseudogene Not known. Protein

Atlas Genet Cytogenet Oncol Haematol 2008; 3 446

Figure 1: Schematic model representing the three different AIF forms: precursor, mature, and truncated. AIF is a flavoprotein (with an oxidoreductase enzymatic activity) containing a FAD-bipartite domain (yellow, amino-acids 128-262 and 401-480), a NADH-binding motif (violet, amino-acids 263-400), and a C-terminal domain (red, amino-acids 481-608) where the proapoptotic activity of the protein resides. In addition, it has a Mitochondria Localization Sequence (MLS, in green, amino-acids 1-41) placed in its N-terminal region. Between the first-N-terminal FAD motif and the MLS, AIF possesses a potential Transmembrane Domain (TM, in green, amino-acids 67-83). This TM is flanked by two peptidase-processing positions: a Mitochondrial Processing Peptidase (MPP)-cleavage site (in blue, amino-acid 54) and a calpains- and/or cathepsins- cleavage site (in red, amino-acid 103). Hsp70 (Heat Shock Protein-70) and CypA (Cyclophilin A) bind AIF in amino-acids 150-228 and 367-369, respectively. AIF also possesses two DNA-binding sites, which are located in amino-acids 255-265 and 510-518, respectively. AIF precursor protein has 613 amino-acids. The MPP-mediated cleavage generates the mitochondrial mature AIF (amino-acids 55-613). After an apoptotic insult, calpains or cathepsins cleave AIF to produce truncated-AIF (tAIF), which is released from mitochondria

Atlas Genet Cytogenet Oncol Haematol 2008; 3 447 to cytosol (amino-acids 104-613). Figure 2: Ribbon structure of mouse AIF in its mature form (pdb id: 1GV4). As depicted here, three domains are present in the protein. The FAD-binding domain and the NAD-binding domain (yellow) are both similar to oxidoreductase domains from members of the glutathione reductase family. In contrast, the C-terminal domain (blue) displays a particular folding with a specific insertion, which includes residues 580 to 610. This picture also includes the AIF cofactor Flavin Adenine Dinucleotide (FAD; magenta). Figure 3: Phylogenetic tree representing the relationship between AIF and other oxidoreductases from different species. Note the proximity of the AIF family (red branch) to the NADH-oxidase family from Archaea. The PIR accession codes are enumerated following the abbreviation of each specie: AA: Aquifex aeolicus; AC: Acinetobacter calcoaceticus; AF: Archaeoglobus fulgidus; AT: Arabidopsis thaliana; BC: Burkholderia cepacia; BS: Bacillus subtilis; CE: Caenorhabditis elegans; DD: Dictyostelium discoideum; DM: Drosophila melanogaster; EC: Escherichia coli; HS: Homo sapiens; LS: Lycopersicon esculentum; MJ: Methanocaldococcus jannaschii; MM: Mus musculus; MTH: Methanobacterium thermoautotrophicum; N A: Novosphingobium aromaticivorans; PF: Pseudomonas fluorescens; PH: Pyrococcus horikoshii; PO: Pseudomonas oleovorans; PP: Pseudomonas putida; PS: Pseudomonas sp.; PSA: Pisum sativum; SP: Schizosaccharomyces pombe; SS: Sphingomonas sp.; RE: Rhodococcus erythropolis; RG: Rhodococcus globerulus; XL: Xenopus laevis. Note 613 amino acids long protein whose structure may be divided into three domains: a FAD- binding domain (residues 128-262 and 401-480), a NADH-binding domain (residues 263-400), and a C-terminal domain (residues 481-608). Description AIF was initially identified as a protein released from the mitochondrial intermembrane space during the apoptotic process. First studies showed that upon an apoptotic stimulus AIF translocates from mitochondria to cytosol and further to the nucleus where it triggers caspase-independent programmed cell death. AIF, expressed as a precursor of 67 kDa, is addressed to mitochondria by the two MLS placed within the N-terminal prodomain of the protein. Once in mitochondria, this precursor is processed to a mature form of 62 kDa by a first proteolytic cleavage. In this configuration, AIF is an inner-membrane-anchored protein in which the N-terminus is exposed to the mitochondrial matrix and the C-terminal portion to the mitochondrial intermembrane space. AIF is here required for maintenance or maturation of the mitochondrial respiratory chain complex I. After a cell death insult, the 62 kDa AIF- mitochondrial form is cleaved by activated calpains and/or cathepsins to yield a soluble proapoptotic protein with an apparent molecular weight of 57 kDa tAIF (truncated AIF). tAIF is released from mitochondria to cytosol and nucleus to generate two typical hallmarks of caspase-independent programmed cell death: chromatin condensation and large-scale approximatively 50 kb DNA fragmentation. Expression Ubiquitously expressed. Localisation Mitochondrion. Function AIF has a double life/death function. In its vital role, AIF is required to maintain and/or organize the mitochondrial respiratory complex I, and displays NADH oxidoreductase and peroxide scavenging activities. In addition to this vital function, AIF has been shown to be implicated in programmed cell death (PCD) induction in several experimental models (see bibliography section). In the two most studied AIF-dependent PCD models, AIF death activity is associated with the increase of intracellular Ca2+ (e.g., ischemia/reperfusion injury), or relates with extensive DNA-damage (e.g., treatment with alkylating agents). In the first model, increased intracellular Ca2+ levels trigger depolarization of mitochondrial membrane, subsequent loss of membrane potential, generation of reactive oxygen species (ROS), and AIF mitochondrial release. In the second model, extensive DNA damage, provoked by high doses of alkylating agents such as MNNG or MNU, triggers poly(ADP-ribose) polymerase-1 (PARP-1) over-activation and AIF release from the mitochondrial intermembrane space. This cell death pathway sequentially involves PARP-1, calpains, Bax, and AIF. Homology AIF is a highly conserved protein ubiquitously present in all primary kingdoms, Bacteria, Archaea and Eucaryota. The aif gene is inherited from the last universal common ancestor and follows the tree topology with the primary radiation of the archaeo-eukaryotic and bacterial clades. AIF also has a highly significant homology with different families of oxidoreductases, including NADH oxydases, Ascorbate reductases, Glutathione reductases and many NADH-dependent ferredoxin reductases from Archaea and Bacteria to invertebrates and vertebrates. (See Figure 3). Mouse, Rat homology: (http://www.ncbi.nlm.nih.gov/mapview/maps.cgi? taxid=9606&chr=X&MAPS=genes-r-org/rat-chr/human%3AX,genes-r-org/mouse-chr/human %3AX,genes-r-org/human-chrX&query=e%3A9131[egene_id]+AND +gene[obj_type]&QSTR=aifm1&cmd=focus&fill=10) Mutations

Atlas Genet Cytogenet Oncol Haematol 2008; 3 448 Note Several polymorphisms have been identified but none of them has shown any association with a disease. Implicated in Entity Various cancers Note Upregulated in cancers (colorectal carcinoma, gastric carcinoma, breast carcinoma and hepatocellular carcinoma, glioblastoma). AIF expression may play a role in tumor formation and could maintain a transformed state of colon cancer cells involving mitochondrial complex I function. Entity Cell death Disease AIF has been directly designed as main mediator of cell death in ischemic injuries after overproduction of reactive oxygen species. Indeed, blocking the mitochondrial release of AIF to cytosol and its further nuclear translocation provides protection against neuronal and cardiomyocites cell death. AIF-deficient harlequin mutant mouse presents a significant reduction of neuronal cell death in brain trauma and cerebral ischemia. A similar protective effect was observed in AIF siRNA-treated neurons. Entity Degenerative disorders Disease AIF is involved in several degenerative disorders. The elevated production of ROS generated in Amyotrophic Lateral Sclerosis, Alzheimer's, or Parkinson diseases concludes in the translocation of AIF. Likewise, AIF release triggered by calpains and cathepsins was observed on in vitro models of Epilepsy and Huntington's disease. AIF- mediated cell death is involved in the pathogenesis of different retinal affections such as retinal detachment, retinitis pigmentosa, or in models of retinal hypoxia. Moreover, an increase of AIF expression has been reported in patients affected with diabetic retinopathy. External links Nomenclature Hugo AIFM1 GDB AIFM1 Entrez_Gene AIFM1 9131 apoptosis-inducing factor, mitochondrion-associated, 1 Cards Atlas AIFM1ID44053chXq25.txt GeneCards AIFM1 Ensembl AIFM1 [Search_View] ENSG00000156709 [Gene_View] Genatlas AIFM1 GeneLynx AIFM1 eGenome AIFM1 euGene 9131 Genomic and cartography AIFM1 - Xq25 chrX:129091020-129127489 - Xq25-q26 [Description] (hg18- GoldenPath Mar_2006) Ensembl AIFM1 - Xq25-q26 [CytoView] NCBI Mapview OMIM Disease map [OMIM] HomoloGene AIFM1 Gene and transcription Genbank AF100928 [ ENTREZ ] Genbank AF131759 [ ENTREZ ] Genbank AK000775 [ ENTREZ ] Genbank AL049703 [ ENTREZ ] Genbank AL049704 [ ENTREZ ] RefSeq NM_004208 [ SRS ] NM_004208 [ ENTREZ ] RefSeq NM_145812 [ SRS ] NM_145812 [ ENTREZ ] RefSeq NM_145813 [ SRS ] NM_145813 [ ENTREZ ] RefSeq AC_000066 [ SRS ] AC_000066 [ ENTREZ ] RefSeq NC_000023 [ SRS ] NC_000023 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2008; 3 449 RefSeq NT_011786 [ SRS ] NT_011786 [ ENTREZ ] RefSeq NW_927721 [ SRS ] NW_927721 [ ENTREZ ] AceView AIFM1 AceView - NCBI Unigene Hs.424932 [ SRS ] Hs.424932 [ NCBI ] HS424932 [ spliceNest ] Fast-db 14752 (alternative variants) Protein : pattern, domain, 3D structure SwissProt O95831 [ SRS] O95831 [ EXPASY ] O95831 [ INTERPRO ] IPR013027 FAD_pyr_nucl-diS_OxRdtase [ SRS ] IPR013027 FAD_pyr_nucl- Interpro diS_OxRdtase [ EBI ] IPR001100 Pyr_nuc-diS_OxRdtase [ SRS ] IPR001100 Pyr_nuc-diS_OxRdtase [ EBI Interpro ] IPR004099 Pyr_nucl-diS_OxRdtase_dimer [ SRS ] IPR004099 Pyr_nucl- Interpro diS_OxRdtase_dimer [ EBI ] IPR001327 Pyr_OxRdtase_NAD_bd [ SRS ] IPR001327 Pyr_OxRdtase_NAD_bd Interpro [ EBI ] CluSTr O95831 PF00070 Pyr_redox [ SRS ] PF00070 Pyr_redox [ Sanger ] pfam00070 [ NCBI- Pfam CDD ] PF07992 Pyr_redox_2 [ SRS ] PF07992 Pyr_redox_2 [ Sanger ] pfam07992 Pfam [ NCBI-CDD ] Prodom PD000139 FAD_pyr_redox[INRA-Toulouse]

O95831 AIFM1_HUMAN [ Domain structure ] O95831 AIFM1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks O95831 PDB 1M6I [ SRS ] 1M6I [ PdbSum ], 1M6I [ IMB ] 1M6I [ RSDB ] HPRD 02161 Protein Interaction databases DIP O95831 IntAct O95831 Polymorphism : SNP, mutations, diseases OMIM 300169 [ map ] GENECLINICS 300169 SNP AIFM1 [dbSNP-NCBI] SNP NM_004208 [SNP-NCI] SNP NM_145812 [SNP-NCI] SNP NM_145813 [SNP-NCI] SNP AIFM1 [GeneSNPs - Utah] AIFM1] [HGBASE - SRS] HAPMAP AIFM1 [HAPMAP] COSMIC AIFM1 [Somatic mutation (COSMIC-CGP-Sanger)] HGMD AIFM1 General knowledge Family Browser AIFM1 [UCSC Family Browser] SOURCE NM_004208 SOURCE NM_145812 SOURCE NM_145813 SMD Hs.424932 SAGE Hs.424932 Enzyme 1.-.-.- [ Enzyme-SRS ] 1.-.-.- [ Brenda-SRS ] 1.-.-.- [ KEGG ] 1.-.-.- [ WIT ] GO DNA binding [Amigo] DNA binding GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO mitochondrion [Amigo] mitochondrion

Atlas Genet Cytogenet Oncol Haematol 2008; 3 450 GO mitochondrial intermembrane space [Amigo] mitochondrial intermembrane space GO electron transport [Amigo] electron transport GO DNA fragmentation during apoptosis [Amigo] DNA fragmentation during apoptosis GO apoptosis [Amigo] apoptosis DNA damage response, signal transduction resulting in induction of apoptosis GO [Amigo] DNA damage response, signal transduction resulting in induction of apoptosis GO electron carrier activity [Amigo] electron carrier activity GO cell redox homeostasis [Amigo] cell redox homeostasis GO FAD binding [Amigo] FAD binding BIOCARTA Opposing roles of AIF in Apoptosis and Cell Survival [Genes] BIOCARTA Ceramide Signaling Pathway [Genes] BIOCARTA Role of Mitochondria in Apoptotic Signaling [Genes] KEGG Apoptosis PubGene AIFM1 TreeFam AIFM1 CTD 9131 [Comparative Genomics Database] Other databases Probes Probe AIFM1 Related clones (RZPD - Berlin) PubMed PubMed 47 Pubmed reference(s) in LocusLink Bibliography Molecular characterization of mitochondrial apoptosis-inducing factor. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G Nature. 1999 ; 397 (6718) : 441-446. PMID 9989411

Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zˆ†ˆ±iga-Pflˆºcker JC, Kroemer G, Penninger JM Nature. 2001 ; 410 (6828) : 549-554. PMID 11279485

NADH oxidase activity of mitochondrial apoptosis-inducing factor. Miramar MD, Costantini P, Ravagnan L, Saraiva LM, Haouzi D, Brothers G, Penninger JM, Peleato ML, Kroemer G, Susin SA The Journal of biological chemistry. 2001 ; 276 (19) : 16391-16398. PMID 11278689

Heat-shock protein 70 antagonizes apoptosis-inducing factor. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jˆ§ˆ§ttelˆ§ M, Penninger JM, Garrido C, Kroemer G Nature cell biology. 2001 ; 3 (9) : 839-843. PMID 11533664

The harlequin mouse mutation downregulates apoptosis-inducing factor. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL Nature. 2002 ; 419 (6905) : 367-374. PMID 12353028

The crystal structure of the mouse apoptosis-inducing factor AIF. Matˆ© MJ, Ortiz-Lombardˆ‚a M, Boitel B, Haouz A, Tello D, Susin SA, Penninger J, Kroemer G, Alzari PM Nature structural biology. 2002 ; 9 (6) : 442-446. PMID 11967568

Atlas Genet Cytogenet Oncol Haematol 2008; 3 451

DNA binding is required for the apoptogenic action of apoptosis inducing factor. Ye H, Cande C, Stephanou NC, Jiang S, Gurbuxani S, Larochette N, Daugas E, Garrido C, Kroemer G, Wu H Nature structural biology. 2002 ; 9 (9) : 680-684. PMID 12198487

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL Science (New York, N.Y.). 2002 ; 297 (5579) : 259-263. PMID 12114629

Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. Bidˆ®re N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, Senik A The Journal of biological chemistry. 2003 ; 278 (33) : 31401-31411. PMID 12782632

Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Gurbuxani S, Schmitt E, Cande C, Parcellier A, Hammann A, Daugas E, Kouranti I, Spahr C, Pance A, Kroemer G, Garrido C Oncogene. 2003 ; 22 (43) : 6669-6678. PMID 14555980

Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Yu SW, Wang H, Dawson TM, Dawson VL Neurobiology of disease. 2003 ; 14 (3) : 303-317. PMID 14678748

AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Candˆ© C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger JM, Kroemer G Oncogene. 2004 ; 23 (8) : 1514-1521. PMID 14716299

Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas. Gallego MA, Joseph B, Hemstrˆ ﾏ m TH, Tamiji S, Mortier L, Kroemer G, Formstecher P, Zhivotovsky B, Marchetti P Oncogene. 2004 ; 23 (37) : 6282-6291. PMID 15286713

AIF deficiency compromises oxidative phosphorylation. Vahsen N, Candˆ© C, Briˆ®re JJ, Bˆ©nit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schˆ§gger H, Rustin P, Kroemer G The EMBO journal. 2004 ; 23 (23) : 4679-4689. PMID 15526035

Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space. Otera H, Ohsakaya S, Nagaura Z, Ishihara N, Mihara K The EMBO journal. 2005 ; 24 (7) : 1375-1386. PMID 15775970

Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. Polster BM, Basaˆ±ez G, Etxebarria A, Hardwick JM, Nicholls DG The Journal of biological chemistry. 2005 ; 280 (8) : 6447-6454.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 452 PMID 15590628

AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells. Urbano A, Lakshmanan U, Choo PH, Kwan JC, Ng PY, Guo K, Dhakshinamoorthy S, Porter A The EMBO journal. 2005 ; 24 (15) : 2815-2826. PMID 16001080

Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, d'Alayer J, Susin SA Cell death and differentiation. 2005 ; 12 (11) : 1445-1448. PMID 15933737

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells. Artus C, Maquarre E, Moubarak RS, Delettre C, Jasmin C, Susin SA, Robert-Lˆ©zˆ©nˆ®s J Oncogene. 2006 ; 25 (42) : 5741-5751. PMID 16636662

Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. Cheung EC, Joza N, Steenaart NA, McClellan KA, Neuspiel M, McNamara S, MacLaurin JG, Rippstein P, Park DS, Shore GC, McBride HM, Penninger JM, Slack RS The EMBO journal. 2006 ; 25 (17) : 4061-4073. PMID 16917506

AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer. Delettre C, Yuste VJ, Moubarak RS, Bras M, Lesbordes-Brion JC, Petres S, Bellalou J, Susin SA The Journal of biological chemistry. 2006 ; 281 (10) : 6413-6427. PMID 16365034

Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity. Delettre C, Yuste VJ, Moubarak RS, Bras M, Robert N, Susin SA The Journal of biological chemistry. 2006 ; 281 (27) : 18507-18518. PMID 16644725

Immunohistochemical and mutational analysis of apoptosis-inducing factor (AIF) in colorectal carcinomas. Jeong EG, Lee JW, Soung YH, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2006 ; 114 (12) : 867-873. PMID 17207087

Apoptosis-inducing factor: vital and lethal. Modjtahedi N, Giordanetto F, Madeo F, Kroemer G Trends in cell biology. 2006 ; 16 (5) : 264-272. PMID 16621561

Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. Ruchalski K, Mao H, Li Z, Wang Z, Gillers S, Wang Y, Mosser DD, Gabai V, Schwartz JH, Borkan SC The Journal of biological chemistry. 2006 ; 281 (12) : 7873-7880. PMID 16407317

Regulation of AIF expression by p53. Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M, Rotter V Cell death and differentiation. 2006 ; 13 (12) : 2140-2149. PMID 16729031

Physical interaction of apoptosis-inducing factor with DNA and RNA.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 453 Vahsen N, Candˆ© C, Dupaigne P, Giordanetto F, Kroemer RT, Herker E, Scholz S, Modjtahedi N, Madeo F, Le Cam E, Kroemer G Oncogene. 2006 ; 25 (12) : 1763-1774. PMID 16278674

Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (48) : 18314-18319. PMID 17116881

AIF-mediated programmed necrosis: a highly regulated way to die. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA Cell cycle (Georgetown, Tex.). 2007 ; 6 (21) : 2612-2619. PMID 17912035

Therapeutic potential of AIF-mediated caspase-independent programmed cell death. Lorenzo HK, Susin SA Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2007 ; 10 (6) : 235-255. PMID 18180198

Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J, Susin SA Molecular and cellular biology. 2007 ; 27 (13) : 4844-4862. PMID 17470554

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Contributor(s) Written 10-2007 Victor J Yuste, Hans K Lorenzo, Santos A Susin Cell Death, Senescence and Survival Research Group, Institut de Neurociencies, Universitat Autonoma de Barcelona (UAB), Edifici M, Campus de Bellaterra, 08193 Bellaterra (Cerdanyola del Valles), Spain (VJY); University of Paris XI, School of Medicine, Hospital Paul Brousse, INSERM U542, 14, av. Paul Vaillant Couturier, 94807 Villejuif, France (HKL); Apoptosis and Immune System, Institut Pasteur, URA 1961-CNRS, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France (SAS) Citation This paper should be referenced as such : Yuste VJ, Lorenzo HK, Susin SA . AIFM1 (apoptosis-inducing factor, mitochondrion-associated, 1). Atlas Genet Cytogenet Oncol Haematol. October 2007 . URL : http://AtlasGeneticsOncology.org/Genes/AIFM1ID44053chXq25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 454 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(6;7)(q23;q34)

Identity

R-band analysis. Partial karyotype showing t(6;7)(q23;q34) Clinics and Pathology Disease T cell acute lymphoblastic leukemia (T-ALL). Phenotype / T cell precursor. cell stem origin Epidemiology Less than 5% among a series of non selected adult and pediatric T-ALLs (n = 3 out of 92). Six cases were described, all of them children, and 5 out of 6 being under 3 years old (1.1, 1.3, 1.8, 2.5, and 2.9 years old, respectively), which is very young for T-cell leukemia. The t(6;7) translocation could therefore be relatively common in this very low range of age. Cytology Lymphoblasts Prognosis The prognosis is yet to be evaluated. Cytogenetics Cytogenetics t(6;7)(q23;q34) may be barely detectable by chromosome banding techniques alone. Morphological

Left: Whole chromosome painting of chromosomes 6 (green) and 7 (red). Right: Locus-specific break-apart FISH using 6q23 probes RP11-184J4 (red) and RP11-845K5 (green) showing translocation involving the 6q23 locus.

Cytogenetics Involvement of the TCRB locus and the MYB locus can be demonstrated using flanking Molecular FISH probes. Genes involved and Proteins Gene Name TRB Location 7q34 Protein T-cell receptor beta chain Gene Name C-MYB Location 6q23.3 Dna / Rna Spans over 38 kb, 15 exons (and additionnal alternative exons), mRNA 3.3 kb. Protein v-myb myeloblastosis viral oncogene homolog. Transcription factor. 640 amino acids. Gene Name AHI-1 Location 6q23.3

Atlas Genet Cytogenet Oncol Haematol 2008; 3 455 Dna / Rna Spans over 214 kb, 28 exons (and additional alternative exons), mRNA 5.5 kb. Protein Jouberin (Abelson helper integration site 1 protein homolog) (AHI-1). 1196 amino acids including one SH3 domain and WD repeats. Result of the chromosomal anomaly

Hybrid gene

Note No fusion gene The t(6;7)(q23.3;q34) translocation results in juxtaposition of TRB regulatory sequences to the MYB-AHI1 locus. It results in deregulated expression of C-MYB, as demonstrated by skewed allelic expression.

Fusion Protein

Oncogenesis C-MYB is a transcription factor involved in hematopoiesis. In T-cell differenciation, discrete threshold levels of MYB activity regulate transition through distinct stages, suggesting that a deregulated expression could disturb the maturation process and play a role in oncogenesis. A potential role of AHI1 deregulation as a cofactor has to be evaluated. Of note, the same locus at 6q23.3 is also involved in short tandem duplications of a about 230 kb genomic region which includes the C-MYB gene (about 10% T-ALL in children and adults). This somatic abnormality can be detected by array-CGH, genomic Q-PCR or fiber-FISH, but not or hardly by standard metaphasic or interphasic FISH. External links Other t(6;7)(q23;q34) Mitelman database (CGAP - NCBI) database Other t(6;7)(q23;q34) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Analysis of balanced rearrangements of chromosome 6 in acute leukemia: clustered breakpoints in q22-q23 and possible involvement of c-MYB in a new recurrent translocation, t(6;7)(q23;q32 through 36). Sinclair P, Harrison CJ, Jarosovˆ° M, Foroni L Haematologica. 2005 ; 90 (5) : 602-611. PMID 15921375

The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, Langerak AW, Montpellier B, Nadel B, Walrafen P, Delattre O, Aurias A, Leblanc T, Dombret H, Gewirtz AM, Baruchel A, Sigaux F, Soulier J Blood. 2007 ; 110 (4) : 1251-1261. PMID 17452517

Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C, Cauwelier B, Lambert F, Mentens N, Beverloo HB, Pieters R, Speleman F, Odero MD, Bauters M, Froyen G, Marynen P, Vandenberghe P, Wlodarska I, Meijerink JP, Cools J Nature genetics. 2007 ; 39 (5) : 593-595. PMID 17435759

Contributor(s) Written 07-2007 Emmanuelle Clappier, Jean Soulier

Atlas Genet Cytogenet Oncol Haematol 2008; 3 456 Group "Genome Rearrangements and Cancer", Hematology Laboratory APHP, INSERM U728 and Paris 7 University, Institut Universitaire d¹Hématologie, Hôpital Saint-Louis, Paris, France Citation This paper should be referenced as such : Clappier E, Soulier J . t(6;7)(q23;q34). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0607q23q34ID1465.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 457 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;9)(q26;p23)

Clinics and Pathology Disease T-cell non Hodgkin lymphoma (T-cell NHL) Note This is one of the very rare cases of EVI1 involvement in lymphoid malignancies Epidemiology Only one case to date, a 11 year old boy Prognosis No data Cytogenetics Cytogenetics Sole anomaly Morphological Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include: GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell-type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Other t(3;9)(q26;p23) Mitelman database (CGAP - NCBI) database Other t(3;9)(q26;p23) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F Genes, chromosomes & cancer. 2006 ; 45 (4) : 349-356. PMID 16342172

The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R Gene. 2007 ; 396 (2) : 346-357. PMID 17507183

Contributor(s) Written 07-2007 Jean-Loup Huret Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(3;9)(q26;p23). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0309q26p23ID1279.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 458 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;5)(q26;q34)

Clinics and Pathology Disease Acute myeloid leukaemia (AML) Epidemiology Only two cases to date, a 48 year old female patient and a male patient of unknown age, both with M2 AML Prognosis No data Cytogenetics Cytogenetics Sole anomaly in both cases Morphological Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include: GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell-type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Other t(3;5)(q26;q34) Mitelman database (CGAP - NCBI) database Other t(3;5)(q26;q34) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Cytogenetic analysis in 139 Tunisian patients with de novo acute myeloid leukemia. Sendi HS, Elghezal H, Temmi H, Hichri H, Gribaa M, Elomri H, Meddeb B, Ben Othmane T, Elloumi M, Saad A Annales de genetique. 2002 ; 45 (1) : 29-32. PMID 11934387

EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements. Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F Genes, chromosomes & cancer. 2006 ; 45 (4) : 349-356. PMID 16342172

The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R Gene. 2007 ; 396 (2) : 346-357. PMID 17507183

Contributor(s) Written 07-2007 Jean-Loup Huret Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation

Atlas Genet Cytogenet Oncol Haematol 2008; 3 459 This paper should be referenced as such : Huret JL . t(3;5)(q26;q34). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0305q26q34ID1278.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 460 Atlas of Genetics and Cytogenetics in Oncology and Haematology t(3;17)(q26;q22)

Clinics and Pathology Disease Chronic myelogenous leukaemia with t(9;22)(q34;q11) and blast crisis of CML (BC- CML) (4 cases altogether), other myeloproliferative syndromes, Acute myeloid leukaemia (AML) Epidemiology At least 9 cases to date, aged 62 years (medain, range: 49-78); sex ration was 5M/3F. Prognosis No data Cytogenetics Cytogenetics Sole anomaly in 3 cases, with t(9;22)(q34;q11) in 4 cases (one of which was a complex Morphological translocation), with del(5q) (1 case), and with del(7q), and +21 in 1 case. Genes involved and Proteins Note The partner of EVI1 is yet unknown. Gene Name EVI1 Location 3q26.2 Protein Transcrition factor; EVI1 targets include: GATA2, ZBTB16 /PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell-type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differsntiation External links Other t(3;17)(q26;q22) Mitelman database (CGAP - NCBI) database Other t(3;17)(q26;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 Translocation t(3;17)(q26;q22): a marker of acute disease in myeloproliferative disorders? Mecucci C, Michaux JL, Broeckaert-Van Orshoven A, Symann M, Boogaerts M, Kulling G, Van den Berghe H Cancer genetics and cytogenetics. 1984 ; 12 (2) : 111-119. PMID 6722753

New case of t(3;17)(q26;q22) as an additional change in a Philadelphia-positive chronic myelogenous leukemia in acceleration. Mugneret F, Solary E, Favre B, Caillot D, Sidaner I, Guy H Cancer genetics and cytogenetics. 1992 ; 60 (1) : 90-92. PMID 1591713

Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P Blood. 1995 ; 86 (9) : 3542-3552. PMID 7579462

Structural rearrangements of chromosome 3 in 57 patients with acute myeloid leukemia: clinical, hematological and cytogenetic features. Charrin C, Belhabri A, Treille-Ritouet D, Theuil G, Magaud JP, Fiere D, Thomas X The hematology journal : the official journal of the European Haematology Association / EHA. 2002 ; 3 (1) : 21-31. PMID 11960392

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High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel- van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lˆ ﾏ wenberg B, Delwel R Blood. 2003 ; 101 (3) : 837-845. PMID 12393383

The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Wieser R Gene. 2007 ; 396 (2) : 346-357. PMID 17507183

Contributor(s) Written 07-2007 Jean-Loup Huret Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . t(3;17)(q26;q22). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0317q26q22ID1282.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 462 Atlas of Genetics and Cytogenetics in Oncology and Haematology del(11)(p12p13)

Clinics and Pathology Disease T-cell acute lymphoblastic leukemia (T-ALL). Epidemiology About 5% of T-ALL patients. Prognosis Currenlty, no relation between the cryptic deletion, del(11)(p12p13), and prognosis could be established. This could be due to the limited patient numbers in the study. Genetics The cryptic deletion, del(11)(p12p13) was identified using microarray-based comparative genome hybridisation (array-CGH). The deleted region is about 3 Mb in size and the telomeric breakpoint of these deletions is situated in or near the LMO2 oncogene. Variances in the centromeric breakpoints is detected. Cytogenetics Variants One of the T-ALL patients showed a cryptic deletion, del(11)(p12p13), that did not target the LMO2 oncogene. Indeed, this case showed no ectopic LMO2 expression. Therefore, this genomic region could potentially contain a tumor supressor gene that also contributes to T-ALL pathogenesis. Genes involved and Proteins Gene Name RBTN2/LMO2 Location 11p13 Protein LMO2 encodes a protein that participates in the transcription factor complex, which includes E2A, TAL1, GATA1, and LDB1 in erythroid cells. Within this transcription complex, LMO2 mediates the protein-protein interactions by recruiting LDB1, whereas TAL1, GATA1, and E2A regulate the binding to specific DNA target sites. This complex regulates the expression of several genes in various cellular backgrounds including C- KIT, EKLF, and RALDH. In normal T-cell development, LMO2 is expressed in immature CD4/CD8 double-negative thymocytes, and is down-regulated during T-cell maturation. Result of the chromosomal anomaly

Hybrid gene

Note Ectopic expression of the LMO2 oncogene due to the removal of a negative regulatory element situated upstream of the LMO2 gene, leading to activation of the proximal LMO2 promoter. In one T-ALL case, this recurrent deletion resulted in a RAG2-LMO2 fusion gene, bringing the LMO2 gene under the control of RAG2 promoter sequences. However, it was shown that promoter substitution was not the main activational mechanism as none of the other del(11)(p12p13) positive cases showed a similar RAG2-LMO2 fusion gene. In addition, RQ-PCR analysis revealed that the expression of the RAG2-LMO2 fusion is much lower than the wildtype LMO2 expression from the proximal LMO2 gene promoter. External links Other del(11)(p12p13) Mitelman database (CGAP - NCBI) database Bibliography The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J, Passier M, van Wering ER, Veerman AJ, Kamps WA, Meijerink JP, Pieters R Blood. 2006 ; 108 (10) : 3520-3529. PMID 16873670

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Contributor(s) Written 07-2007 Pieter Van Vlierberghe, Jules PP Meijerink ErasmusMC/Sophia Children’s Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands Citation This paper should be referenced as such : Van Vlierberghe P, Meijerink JPP . del(11)(p12p13). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Anomalies/del11p12p13ID1351.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 464 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Subungual exostosis with t(X;6)(q13;q22)

Identity Other names Dupuytren's exostosis Classification Note Benign bone-producing neoplasm of unknown cellular origin. Clinics and Pathology Disease Subungual exostosis. Phenotype / Unknown. cell stem origin Embryonic Unknown. origin Etiology Unknown. Epidemiology Affects children and young adults. Clinics Subungual exostosis usually presents as a slowly growing, painful mass localized dorsomedially in the distal phalanx, and in contrast to osteochondroma, there is usually no continuity with the underlying cortex. Treatment Surgical excision, but local recurrences are not uncommon. Prognosis Excellent. Cytogenetics Cytogenetics t(X;6)(q22;q13-14). Morphological

Partial G-banding karyotype showing chromosomes 6 and X in a case of subungual exostosis. The arrows indicate the breakpoints.

Cytogenetics A Probe specific for COL12A1 (RP11-815E21) identified the breakpoint in 6q14.1, as it Molecular showed splitting signals on der(X) and der(6). On the same chromosomes, these signals colocalized with the signals of RP11-815E21, encompassing the COL4A5 and IRS4 genes in band Xq22.3.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 465 FISH experiment revealing the breakpoint regions on both chromosomes 6 and X on a case of subungual exostosis.

Probes RP11-815E21 (COL4A5 and IRS4); RP11-1072D13 (COL12A1). Variants The breakpoint on chromosome 6 could be centromeric to COL4A5, in an unknown location. Genes involved and Proteins Gene Name COL4A5 (alpha 5 type IV collagen) Location Xq22.3 Note It is currently unknown whether any of these two genes is involved in the pathogenesis of subungual exostosis. Dna / Rna Genomic (chrX: 107,569,810-107,827,431). Three transcript variants: isoform 1 (NM_000495), isoform 2 (NM_033380), isoform 3 (NM_03338). Protein Three proteins, respectively encoded by the isoform 1 (695 aa), isoform 2 (1691 aa), and isoform 3 (1688 aa).

Gene Name COL12A1 (collagen, type XII, alpha 1) Location 6q13 Dna / Rna Genomic (chr6:75,850,762-75,972,343). Two transcript variants, a long (NM_004370) and a short isoform (NM_080645). Protein Two proteins: 1899 amino acids (aa) and 3063 aa, respectively encoded by the short and long transcript isoforms.

Result of the chromosomal anomaly Hybrid Gene Note No detected fusion gene. To be noted To elucidate how the transcription of these genes is affected by the translocation, further fresh or fresh frozen samples need to be studied. Bibliography Clonal chromosome abnormalities in a so-called Dupuytren's subungual exostosis. Dal Cin P, Pauwels P, Poldermans LJ, Sciot R, Van den Berghe H. Genes Chromosomes Cancer 1999; 24: 162-164. PMID 9885985

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Imaging of osteochondroma: variants and complications with radiologic-pathologic correlation. Murphey MD, Choi JJ, Kransdorf MJ, Flemming DJ, Gannon FH. Radiographics 2000; 20: 1407-1434. Review. PMID 10992031

Subungual exostosis of the third toe. Ilyas W, Geskin L, Joseph AK, Seraly MP. J Am Acad Dermatol 2001; 45: S200-S201. PMID 11712058

Distinct chromosomal rearrangements in subungual (Dupuytren) exostosis and bizarre parosteal osteochondromatous proliferation (Nora lesion). Zambrano E, Nose V, Perez-Atayde AR, Gebhardt M, Hresko MT, Kleinman P, Richkind KE, Kozakewich HP. Am J Surg Pathol 2004; 28: 1033-1039. PMID 15252309

Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic delineation of the tumor-specific translocation t(X;6)(q13-14;q22). Storlazzi CT, Wozniak A, Panagopoulos I, Sciot R, Mandahl N, Mertens F, Debiec-Rychter M. Int J Cancer 2006; 118: 1972-1976. PMID 16284948

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 07-2007 Clelia Tiziana Storlazzi, Fredrik Mertens Department of Genetics and Microbiology, University of Bari, Bari, Italy (CTS); Department of Clinical Genetics, Lund University Hospital, Lund, Sweden (FM) Citation This paper should be referenced as such : Storlazzi CT, Mertens F . Subungual exostosis with t(X;6)(q13;q22). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Tumors/SubungExosttX6ID5526.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2008; 3 467 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Soft tissue tumors: Alveolar soft part sarcoma

Identity Other names Malignant nonchromaffin paraganglioma Malignant organoid granular cell myoblastoma Clinics and Pathology Embryonic The histogenesis of this tumour is still unknown, despite immunohistochemestry origin studies and electron microscopy. It may have a myogenic origin, and might be a variant of rhabdomyosarcoma. Epidemiology Rare tumour: represents less than 1% of soft tissues sarcomas of adults and 1-2% of soft tissues sarcomas in children. Occurs most often in the young adult, less frequently in children. Median age is 20 yrs in female patients, and 30 yrs in male patients. More frequently, patients are females (ratio M/F is 2/3). Clinics Involve the muscles and soft tissues, in particular those of the lower extremities (buttocks, thighs and legs). This represents more than half cases in the adults. It may also arise in the upper extremities, in the head and neck regions, especially in the child, but it can also have extra muscular localizations, such as the female genital tract, the trunk, the mediastinum, or the retroperitoneum. Metastases are frequent. They occur mainly in lungs, bones, and brain. Symptoms at diagnosis may be pain and/or swelling. Diagnosis is often retarded. Pathology Well circumscribed tumours with a multinodular pattern, haemorrhagic and necrotic. Microcopically, exhibits an alveoloar structure, the center of the alveolar space being formed by detachment of necrotic cells, and with surronding capillaries (there is a more solid pattern in children). Cells are large, with abundant cytoplasm. Mitoses are rare. Secretory process with the formation of cytoplasmic membrane-bound crystals (PAS+, diastase resistant) can often be seen with electron microscopy, a feature of great diagnostic value (they are pathognomic). These granules contain monocarboxylate transporter 1 (MCT1)-CD147 complexes. Immunochemistry: in general, alveolar soft part sarcomas are negative for neuroendocrin and epithelial markers, and often positive for vimentin, muscle-specific actin, and desmin. The strong nuclear staining of an anti C-term TFE3 can be used for diagnosis (although cytogenetics and/or molecular genetics are the most relevant tools for diagnosis). To be noted is that a subset of renal cell carcinomas, the primary renal ASPSCR1- TFE3 tumour, share some morphological features with the alveolar soft part sarcoma (it may be a differential diagnosis); they also share a common genetic substratum. Treatment Primary tumours: large surgical excision (a complete resection is of great importance) and radiation. Metastases: chemotherapy, with or without radiation or surgery, depending on the number of metastases. Evolution Slow growing tumour, but highly angiogenic, which favours metastases dissemination. Metastases appear in more than half of the patients who presented without metastases at diagnosis (up to 70 % in one study); however, there is a long disease-free interval before appearence of metastases (median 6 yrs) in these patients. Prognosis Relatively indolent clinical course. In one study, overall survival of adult patients without metastases reached 87% at 5 yrs, but that of adult patients with metastases at diagnosis was only 20% at 5 yrs, with a median survival of 40 mths. Pediatric cases had a better prognosis, with a 5 yrs survival of 80% for all cases included, reaching 91% in cases without metastases. Median survival in patients without metastases at diagnosis was noted above 10 yrs in a large -but old (period 1923-1986) - study, and it may be expected that progress has been made. Due to the rarity of the disease and its long course, survival data are

Atlas Genet Cytogenet Oncol Haematol 2008; 3 468 outdated. Cytogenetics Cytogenetics t(X;17)(p11;q25) is found in all alveolar soft part sarcomas so far studied, but also in Morphological primary renal ASPSCR1-TFE3 tumours. In the case of alveolar soft part sarcoma, the chromosome rearrangement is found in an unbalanced form, as a der(17)t(X;17) (p11;q25), in 80% of cases; the unbalanced form implicates: 1- the formation of a hybrid gene at the breakpoint, but also, 2- gain in Xp11-pter sequences, and loss of heterozygocity in 17q25-qter, with possible implications, although no clinical (including prognostic) nor pathological differences have so far been noted between balanced and unbalanced cases... but, again, the disease is rare, and cases with cytogenetic studies even rarer (about 25 cases). Note: the t(X;17)(p11;q25) in primary renal ASPSCR1-TFE3 tumours is balanced in all known cases. Genes involved and Proteins Note Retention of heterozygocity in the tumours of female patients (i.e. a normal maternal X and a normal paternal X are present, in addition to the Xp11-pter involved in the translocation) has been noted in all (n=7) female cases studied, showing that the translocation occurred in G2 phase. Gene Name TFE3 Location Xp11 Dna / Rna 8 exons Protein Transcription factor; member of the basic helix-loop-helix family (b-HLH) of transcription factors primarily found to bind to the immunoglobulin enchancer muE3 motif.

Gene Name ASPSCR1 Location 17q25 Protein Contains an UBX domain, ASPSCR1 binds SLC2A4 (solute carrier family 2 (facilitated glucose transporter), member 4, also called GLUT4) endocytosed from the plasma membrane into vesicles. SLC2A4 is retained in the cell by ASPSCR1 in the absence of insulin. Insulin stimulates the release of retained SLC2A4 to exocytosis, allowing the rapid mobilization of glucose transporters to the cell surface.

Result of the chromosomal anomaly Hybrid Gene Description 5' ASPSCR1-3' TFE3; the reciprocal 5' TFE3 - 3' ASPSCR1 is most often absent. ASPSCR1 is fused in frame either to TFE3 exon 3 or to exon 4 (type 1 and type 2 fusions respectively). Fusion Protein Description 234 NH2 term amino acids from ASPSCR1, fused to the 280 or 315 C term amino acids from TFE3, including the activation domain, the helix-loop-helix, and the leucine zipper from TFE3. External links Other The Alliance against ASP Sarcoma database Other Cure Alveolar Soft Part Sarcoma International database Bibliography Alveolar soft-part sarcoma. A clinico-pathologic study of half a century. Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY. Cancer 1989; 63: 1-13. PMID 89089484

Atlas Genet Cytogenet Oncol Haematol 2008; 3 469 Molecular genetic, cytogenetic, and immunohistochemical characterization of alveolar soft-part sarcoma. Implications for cell of origin. Cullinane C, Thorner PS, Greenberg ML, Kwan Y, Kumar M, Squire J. Cancer 1992; 70(10): 2444-2450. PMID 1423174

An important role for chromosome 17, band q25, in the histogenesis of alveolar soft part sarcoma. van Echten J, van den Berg E, van Baarlen J, van Noort G, Vermey A, Dam A, Molenaar WM. Cancer Genet Cytogenet 1995; 82(1): 57-61. PMID 7627936

Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25. Heimann P, Devalck C, Debusscher C, Sariban E, Vamos E. Genes Chromosomes Cancer 1998; 23(2): 194-197. PMID 9739024

Alveolar soft-part sarcoma: a review of the pathology and histogenesis. Ordonez NG, Mackay B. Ultrastruct Pathol 1998; 22: 275-292. PMID 99022169

Chromosome rearrangement at 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature. Joyama S, Ueda T, Shimizu K, Kudawara I, Mano M, Funai H, Takemura K, Yoshikawa H. Cancer 1999; 86: 1246-1250. PMID 99438425

Alveolar soft part sarcoma: a review and update. Ordonez NG. Adv Anat Pathol 1999; 6: 125-139. PMID 99273556

Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group. Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, De Bernardi B, Indolfi P, Fossati Bellani F, Carli M. Ann Oncol 2000; 11: 1445-1449. PMID 21022094

Cytogenetic analysis of rare orbital tumors: further evidence for diagnostic implication. Lasudry J, Heimann P. Orbit 2000; 19(2): 87-95. PMID 12045953

Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez- Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. Am J Pathol 2001; 159(1): 179-192. PMID 11438465

The der(17)t(X.17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PHB, Mertens F, Mandahl N, van den Berghe H, Sciot R, dal Cin P, Bridge J. Oncogene 2001; 20: 48-57.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 470 PMID 21140288

Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Portera CA Jr, Ho V, Patel SR, Hunt KK, Feig BW, Respondek PM, Yasko AW, Benjamin RS, Pollock RE, Pisters PW. Cancer 2001; 91: 585-591. PMID 21097518

The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147. Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY, Golde DW, Cordon-Cardo C. Am J Pathol 2002; 160(4): 1215-1221. PMID 11943706

Alveolar soft part sarcoma. a report of 15 cases. van Ruth S, van Coevorden F, Peterse JL, Kroon BB. Eur J Cancer 2002; 38(10): 1324-1328. PMID 12091061

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: alveolar soft part sarcoma. Sandberg A, Bridge J. Cancer Genet Cytogenet 2002; 136(1): 1-9. PMID 12165444

Alveolar soft part sarcoma--reciprocal translocation between chromosome 17q25 and Xp11. Report of a case with metastases at presentation and review of the literature. Uppal S, Aviv H, Patterson F, Cohen S, Benevenia J, Aisner S, Hameed M. Acta Orthop Belg 2003; 69(2): 182-187. PMID 12769020

Alveolar soft part sarcoma: a rare and enigmatic entity. Anderson ME, Hornicek FJ, Gebhardt MC, Raskin KA, Mankin HJ. Clin Orthop Relat Res 2005; 438: 144-148. PMID 16131883

Nonrandom cell-cycle timing of a somatic chromosomal translocation: The t(X;17) of alveolar soft-part sarcoma occurs in G2. Huang HY, Lui MY, Ladanyi M. Genes Chromosomes Cancer 2005; 44(2): 170-176. PMID 15952162

Alveolar soft-part sarcoma: a review and update. Folpe AL, Deyrup AT. J Clin Pathol 2006; 59(11): 1127-1132. PMID 17071801

Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia MP. J Pediatr Surg 2006; 41(1): 187-193. PMID 16410131

Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG. Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME. Protein Sci 2006; 15(3): 498-508. PMID 16501224

Atlas Genet Cytogenet Oncol Haematol 2008; 3 471 Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas. Aulmann S, Longerich T, Schirmacher P, Mechtersheimer G, Penzel R. Histopathology 2007; 50(7): 881-886. PMID 17543078

Alveolar soft part sarcoma. Zarrin-Khameh N, Kaye KS. Arch Pathol Lab Med 2007; 131(3): 488-491. PMID 17516754

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 08-2001 Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, CHU Poitiers Hospital, F-86021 Poitiers, France Updated 07-2007 Jean-Loup Huret Genetics, Dept Medical Information, CHU Poitiers Hospital, F-86021 Poitiers, France Citation This paper should be referenced as such : Huret JL . Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html Huret JL . Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Glomuvenous malformation (GVM)

Identity Note Glomuvenous malformation (GVM) is a localized bluish-purple cutaneous vascular lesion, histologically consisting of distended venous channels with flattened endothelium surrounded by variable number of maldifferentiated smooth muscle-like "glomus cells" in the wall. GVM account for 5% of venous anomalies referred to centers for vascular anomalies. Previously, these lesions have been called "multiple glomus tumors" or "glomangioma". Other names venous malformation with glomus cells (VMGLOM) glomangioma multiple glomus tumor Inheritance GVM is often, if not always, hereditary (64%), and transmitted as an autosomal dominant disorder. Expressivity varies, as does penetrance, which is age dependent and maximal (93%) by 20 years of age. Clinics Phenotype and There is a wide phenotypic variation between GVM patients, even within the same clinics family (with the same germline mutation). An individual can have an extensive lesion, affecting for example a whole extremity or most of the trunk, while others have minor, scattered papulonodular lesions of a few millimetres in diameter. The lesions are often multiple, and they can affect any body part. Seven features characterize GVM lesions : (1) Colour: GVMs can be pink in infants, the most are bluish-purple (2) Affected tissues: the lesions are localized to the skin and subcutis, and they are rarely mucosal and never extend deeply into muscles (3) Localization: lesions are more often located on the extremities, although they can be found all over the body (4) Appearance : lesions are usually nodular and multifocal, raised with a cobblestone- like appearance, except for the rare plaque-like variant. They are often hyperkeratotic (5) The lesions are not compressible (6) The lesions are painful on palpation (7) New lesions can appear with time, likely after trauma At the histological level, the mural glomus cells are positive for smooth muscle alpha- actin and vimentin, but negative for desmin, Von Willebrand factor and S-100. Under electron microscopy, glomus cells show smooth muscle myofibrils and "dense bodies", characteristics of vascular smooth muscle cells (vSMCs). Thus, these cells are most likely incompletely or improperly differentiated vSMCs.

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Examples of GVMs: (A) Extended GVM on leg. (B) Small GVM on knee.

Neoplastic risk GVM has no neoplastic histological characteristics and never becomes malignant. Treatment The gold-standard treatment for GVM consists of surgical resection, as lesions are superficial and rarely affect deeply the underlying muscle, and sometimes sclerotherapy. In contrast to venous malformations, the use of elastic compressive garments often aggravates pain and should thus be avoided. Evolution GVM is a developmental lesion that grows proportionally with the child. After partial resection, recurrence is frequent. New small lesions can appear with time. The red plaque-like lesions of the young darken with age. Cytogenetics Note No cytogenetic abnormally has been reported for GVM Genes involved and Proteins

Gene Name Glomulin Location 1p22.1 DNA/RNA Description The glomulin gene spans about 55 kbp and contains 19 exons coding for 1785 bp. Protein Note Glomulin was identified by reverse genetics, and its function is currently unknown. Description Glomulin gene encodes a protein of 594 amino acids (68 kDa). Expression The high level of glomulin expression in the murine vasculature indicates that glomulin may have an important role in blood vessel development and/or maintenance. Localisation Glomulin is likely an intracellular protein. Function The exact function of glomulin is unknown. Glomulin has been described to interact with FKBP12, an immunophilin that binds the immunosuppressive drugs FK506 and rapamycin. FKBP12 interacts with the TGFbeta type I receptor, and prevents its phosphorylation. Thus, FKBP12 safeguards against the ligand-independent activation of this pathway. Glomulin, through its interaction with FKBP12, could act as a repressor of this inhibition. Glomulin has also been described to interact with c-MET. Glomulin interacts with the inactive, non phosphorylated form of c-MET. When c-MET is activated by HGF, glomulin is released in a phosphorylated form. This leads to p70 S6 protein kinase (p70S6K) phosphorylation. It is not known whether glomulin activates p70S6K directly or indirectly. The p70S6K is a key regulator of protein synthesis. Glomulin could thereby control cellular events such as migration and cell division.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 474 The third reported glomulin partner is Cul7. This places glomulin in an SCF-like complex, which is implicated in protein ubiquitination and degradation. Mutations Note There is no phenotype-genotype correlation in GVM.

Schematic representation of glomulin: The two stars indicate the start and the stop codons, in exon 2 and 19 respectively. All known mutations are shown. Somatic second hit is in blue.

Germinal To date, 29 different inherited mutations (deletions, insertions and nonsense substitutions) have been identified. The most 5' mutation are located in the first coding exon. The majority of them cause premature truncation of the protein and likely result in loss-of-function. One mutation deletes 3 nucleotides resulting in the deletion of an asparagine at position 394 of the protein. More than 70% of GVMs are caused by eight different mutations in glomulin: 157delAAGAA (40,7%), 108C to A (9,3%), 1179delCAA (8,1%), 421insT and 738insT (4,65% each), 554delA+556delCCT (3,5%), 107insG and IVS5-1(G to A) (2,3% each). Somatic The phenotypic variability observed in GVM could be explained by the need of a somatic second-hit mutation. Such a mechanism was discovered in one GVM (somatic mutation 980delCAGAA), suggesting that the lesion is due to a complete localized loss-of-function of glomulin. This concept can explain why some patients have bigger lesions than others, why new lesions appear, and why they are multifocal. This could also explain why some mutation carriers are unaffected.

Bibliography Multiple glomus tumors. A clinical and electron microscopic study. Goodman TF, Abele DC Archives of dermatology. 1971 ; 103 (1) : 11-23. PMID 4321799

FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin. Chambraud B, Radanyi C, Camonis JH, Shazand K, Rajkowski K, Baulieu EE The Journal of biological chemistry. 1996 ; 271 (51) : 32923-32929. PMID 8955134

Mechanism of TGFbeta receptor inhibition by FKBP12. Chen YG, Liu F, Massague J The EMBO journal. 1997 ; 16 (13) : 3866-3876. PMID 9233797

A gene for inherited cutaneous venous anomalies (glomangiomas) localizes to chromosome 1p21-22.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 475 Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, Rudolph R, Mulliken JB, Olsen BR, Vikkula M American journal of human genetics. 1999 ; 65 (1) : 125-133. PMID 10364524

High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Brouillard P, Olsen BR, Vikkula M Genomics. 2000 ; 67 (1) : 96-101. PMID 10945476

Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor. Grisendi S, Chambraud B, Gout I, Comoglio PM, Crepaldi T The Journal of biological chemistry. 2001 ; 276 (49) : 46632-46638. PMID 11571281

Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC. Irrthum A, Brouillard P, Enjolras O, Gibbs NF, Eichenfield LF, Olsen BR, Mulliken JB, Boon LM, Vikkula M European journal of human genetics : EJHG. 2001 ; 9 (1) : 34-38. PMID 11175297

Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (glomangiomas). Brouillard P, Boon LM, Mulliken JB, Enjolras O, Ghassibˆ© M, Warman ML, Tan OT, Olsen BR, Vikkula M American journal of human genetics. 2002 ; 70 (4) : 866-874. PMID 11845407

Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Arai T, Kasper JS, Skaar JR, Ali SH, Takahashi C, DeCaprio JA Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (17) : 9855-9860. PMID 12904573

Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Boon LM, Mulliken JB, Enjolras O, Vikkula M Archives of dermatology. 2004 ; 140 (8) : 971-976. PMID 15313813

Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse. McIntyre BA, Brouillard P, Aerts V, Gutierrez-Roelens I, Vikkula M Gene expression patterns : GEP. 2004 ; 4 (3) : 351-358. PMID 15053987

Four common glomulin mutations cause two thirds of glomuvenous malformations (familial glomangiomas): evidence for a founder effect. Brouillard P, Ghassibˆ© M, Penington A, Boon LM, Dompmartin A, Temple IK, Cordisco M, Adams D, Piette F, Harper JI, Syed S, Boralevi F, TaˆØeb A, Danda S, Baselga E, Enjolras O, Mulliken JB, Vikkula M Journal of medical genetics. 2005 ; 42 (2) : page e13. PMID 15689436

[Medical and surgical treatment of venous malformations] Boon LM, Vanwijck R Annales de chirurgie plastique et esthetique. 2006 ; 51 (4-5) : 403-411. PMID 17005307

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Congenital plaque-type glomuvenous malformations presenting in childhood. Mallory SB, Enjolras O, Boon LM, Rogers E, Berk DR, Blei F, Baselga E, Ros AM, Vikkula M Archives of dermatology. 2006 ; 142 (7) : 892-896. PMID 16847206

GLMN and Glomuvenous Malformation. Brouillard P, Enjolras O, Boon LM, Vikkula M Inborn Errors of Development 2e, edited by Charles Epstein, Robert Erickson and Anthony Wynshaw..

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 07-2007 Virginie Aerts, Pascal Brouillard, Laurence M. Boon, Miikka Vikkula Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium Citation This paper should be referenced as such : Aerts V, Brouillard P, Boon LM, Vikkula M . Glomuvenous malformation (GVM). Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Kprones/GlomuvenousID10120.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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do you wish to send a case report ? CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

Translocation t(1;6)(p35;p25) in B-cell lymphoproliferative disorder with evolution to Diffuse Large B-cell Lymphoma

Elvira D Rodrigues Pereira Velloso, Cristina Ratis, Sérgio A B Brasil, João Carlos Guerra, Nydia Bacal; Cristóvão P Mangueira LM Pitangueira Clinics Age and sex : 75 year(s) old female patient. Previous History : B- cell Lymphoproliferative disorder for 8 years Organomegaly : hepatomegaly ; splenomegaly ; enlarged lymph nodes ; no central nervous system involvement Blood WBC : 5,4 x 109/l; Hb : 13,6 g/dl; platelets : 169 x 109/l; blasts : 3,35% (x 109/l (lymphoid cells)) Bone marrow : 28% ( of lymphoid mature cells) Cyto pathology classification Cytology : B-cell Lymphoproliferative disorder (Atypical CLL) with evolution to diffuse large B-cell Lymphoma. Atypical CLL. Immunophenotype : 25% of total bone marrow cells are positive : CD20++, CD22+, CD25+, CD38, CD79b++, HLA-DR, sIgM, sIgD e sKappa ++. Rearranged Ig Tcr : not done Pathology : Inguinal Lymph node biopsy (August, 2005): Diffuse large B-cell Lymphoma, Ki-67: 70%, ciclina D1 -, CD20 +, BCL2 +. Electron microscopy : not done Precise diagnosis : B-cell Lymphoproliferative disorder (Atypical CLL) with evolution to diffuse large B- cell Lymphoma. Survival Date of diagnosis: (07-2007) Treatment : wide previous history (long previous history of chemotherapy), no chemotherapy after July, 2007 Complete remission : None Treatment related death : - Relapse : - Status : Alive 09-2007 Survival : 2 month(s) Karyotype Sample : bone marrow cells ; culture time : 72 h, ours with and without TPA (o-tetradecanoyl phorbol-13-acetate) ; banding : G Results : 47, XX, t(1;6) (p35;p25),+12[13]/46,XX[7] Karyotype at relapse : not done Other molecular cytogenetics technics : not done Other molecular studies technics : not done

Atlas Genet Cytogenet Oncol Haematol 2008; 3 478 Partial karyotype, G- band Comments In 2005, the Belgian group described the t(1;6)(p35.3;p25.2) in 8 patients with unmutated B-CLL. As in this case, this rare cytogenetic entity has been described in typical or atypical CLL (8/8 cases), with evolution to diffuse large B-cell Lymphoma (3/8 cases); trisomy 12 been a common additional abnormality (3/8 cases). Internal links Atlas Card t(1;6)(p35;p25) Bibliography Translocation t(1;6)(p35.3;p25.2): a new recurrent aberration in "unmutated" B-CLL. Michaux L, Wlodarska I, Rack K, Stul M, Criel A, Maerevoet M, Marichal S, Demuynck H, Mineur P, Kargar Samani K, Van Hoof A, Ferrant A, Marynen P, Hagemeijer A. Leukemia 2005; 19: 77-82. PMID 15510210

Contributor(s) Written Elvira D Rodrigues Pereira Velloso, Cristina Ratis, Sérgio A B Brasil, João 07-2007 Carlos Guerra, Nydia Bacal; Cristóvão P Mangueira LM Pitangueira Citation This paper should be referenced as such : Rodrigues Pereira Velloso ED, Ratis . Translocation t(1;6)(p35;p25) in B-cell lymphoproliferative disorder with evolution to Diffuse Large B-cell Lymphoma. Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0106RodriguesID100030.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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How human chromosome aberrations are formed

by Albert Schinzel Institute of Medical Genetics, CH-8603 Schwerzenbach, Switzerland Oral presentation at the 6th European Cytogenetic Conference (ECC), Istanbul, July 2007, organized by the European Cytogeneticists Association.

I- Introduction II- Origin and mechanisms of formation of chromosome aberrations III- Chromosome aberrations, classification IV- Modes of determination of the mechanisms of formation of chromosome pdf version aberrations V- Microsatellite marker analysis VI- Summary of parental origin of chromosome aberrations VII- Origin of Ullrich-Turner syndrome 45,X VIII- Origin of recurrent free trisomy 21 IX- Interchromosal effect (ICE) X- Origin of mosaic trisomy XI- Origin of interstitial (micro-)deletions, interchromosomal versus intrachromosomal XII- Frequent interstitial microdeletions (15q12, 7q11.23, 22q11.2) XIII- Origin of mosaic duplications (de novo) XIV- Origin of additional isochromosomes and isodicentric chromosomes XV- Chaotic chromosome aberrations XVI- Origin of multipe structural chromosome aberrations XVII- Primary and secondary chromosome aberrations XVIII- Conclusion

I- Introduction

- Characteristics of the species Homo sapiens: - Many! - Among others: excessively high incidence of reproductive failure and chromosome aberrations. - Determination of origin and mechanisms of formation of chromosome aberrations: Each newly developed technique, from Q banding over FISH and microsatellite marker analysis to CGH, has brought additional information as to the origin of chromosomal imbalance in man.

II- Origin and mechanisms of formation of chromosome aberrations

Origin maybe:

- maternal - paternal - combined

Formation:

 Nondisjunction:

Atlas Genet Cytogenet Oncol Haematol 2008; 3 480 - meiotic - pre-meiotic - post-meiotic  Rearrangement: - meiotic - pre-meiotic - post-meiotic

Any combination

Incorporation of 2 sperms or of a polar body into the oocyte.

III- Chromosome aberrations, classification

 Numerical aberrations: - Monosomy (X/Y) - Trisomy - Sex chromosome aneuploidy - Double/triple aneuploidy - Uniparental disomy  Ploidy aberrations: - Haploidy - Triploidy - Tetraploidy  Structural aberrations: - Deletions - Rings - Duplications - Balanced rearrangements - Combined duplication-deletion - Complex rearrangements  Mosaic and chimeras Combinations: - Numerical and structural - Numerical and ploidy, etc...

IV- Modes of determination of the mechanisms of formation of chromosome aberrations

 1. Aberration per se: - free trisomy: nondisjunction - mosaicism: either postzygotic origin or two steps - triploidy  2. Cytogenetic markers.  3. Molecular marker analysis in proband and parents.  4. Molecular marker analysis in grandparents of proband.  5. CGH.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 481 Legend: Paternal (P) and maternal (M) chromosomes 14, the free 14 and the 14/21 translocation from the Down's offspring, Q-banded. The free 14 is of paternal origin, therefore the 14/21 is of maternal origin (from Chamberlin 1980; Hum Genet 53: 343).

V- Microsatellite marker analysis

- Almost always able to determine the origin of deletions. - Often not successful for duplications, especially direct or inverted duplications stemming from chromatid interchanges (no third allele, often no clear intensity differences).

Atlas Genet Cytogenet Oncol Haematol 2008; 3 482 Atlas Genet Cytogenet Oncol Haematol 2008; 3 483 VI- Summary of parental origin of chromosome aberrations

 Numerical, autosomes: predominantly mat.  Numerical, X chromosomes: idem.  Numerical, X and Y: overwhelming paternal origin.  Structural, terminal deletions and rings: predominantly pat.  Structural, extra rearranged chromosomes isochromosomes, inv dup chromosomes: predominantly mat from initial nondisjunction.  Structural, intrachromosomal rearrangements: equal distribution.  Structural, interchromosomal rearrangements: idem.  Uniparental disomy: - Heterodisomy: predominantly mat from initial trisomy. - Isodisomy: predominantly pat.  Mosaics: mostly starting with maternal trisomy - Triploidy: Predominantly (80%) mat, incorporation of a polar body into the oocyte; rarer (20%) fertilization of the oocyte by 2 different sperms.

VII- Origin of Ullrich-Turner syndrome 45, X

Xg studies: predominant maternal origin of the remaining X-chromosome.

Expected distribution (as 45,Y is none-viable) if 66 vs 33% mat = pat: Distribution found: 80 vs 20% (statistically significant)

Parental Xg information about 306 females with 45,X Ullrich-Turner syndrome (Sanger et al. 1971).

Xg groups of Source of normal X Number Father Mother T + + + unknown 150 + + - maternal 31

Atlas Genet Cytogenet Oncol Haematol 2008; 3 484 + - + paternal 5 + - - maternal 10 - + + maternal 60 - + - unknown 35 - - - unknown 15 Total 306

+ = Xg(a+); - = Xg(a-)

VIII- Origin of recurrent free trisomy 21

Results of molecular marker studies:

 1. In siblings: - 60% by chance - 40% parental gonadal mosaicism  2. In more remote relatives: - 100% by chance

Atlas Genet Cytogenet Oncol Haematol 2008; 3 485 IX- Interchromosal effect (ICE)

- Definition: A balanced chromosome aberration increases the risk of non-disjunction for other chromosomes. - Consequence: Prenatal cytogenetic diagnosis is indicated if one parent carries a balanced rearrangement even if unbalanced segregation cannot lead to viable offspring. - Evidence for ICE: More familial balanced translocations found in Down syndrome patients than expected by chance. - Evidence against an ICE: In haploid sperms of male carriers of balanced translocations there is no increase of disomies over controls.

Number of Origin of the supernumerary 21

families mat pat mat. 2 2 0 rearrangement pat. 11 11 0 rearrangement

X- Origin of mosaic trisomy

- Mostly first trisomy: secondary somatic loss of the third homologue. - Not infrequently: mosaicism between (maternal) trisomy and (maternal) uniparental disomy.

XI- Origin of interstitial (micro-) deletions, interchromosomal versus intrachromosomal

 Principle: Investigation of grandparents of the side of origin with markers flanking the deleted segment.  Williams-Beuren syndrome: - Deletion of 7q11.22 including the Elastin locus. - Supravalvular aortic stenosis. - Peripheral pulmonary stenosis. - Growth retardation. - Moderate mental retardation. - Outgoing pleasant personality. - Full lips, cheeks and lids. - Deep voice

Atlas Genet Cytogenet Oncol Haematol 2008; 3 486 Legend: Representative examples of microsatellite analysis at 7q11.2 carried out. The deleted region of chromosome 7 is indicated with a black bar beside the chromosome 7 ideogram. Marker D7S1870, located within the deleted region, illustrates the maternal origin of the deletion. Grandparental origin of the regions flanking the deletion are shown with markers D7S672 (proximal region) and D7S524 (distal region).

 Result: - Switch from grandpaternal to grandmaternal origin on either side: - interchromosomal rearrangement. - meiotic origin. - low recurrence risk. - No switch, markers on either side from grandparent: - intrachromosomal rearrangement (between 2 chromatids). - meiotic or pre- or post-meiotic origin. - not necessarily low recurrence risk.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 487 XII- Frequent interstitial microdeletions (15q12, 7q11.23, 22q11.2)

- Reason for their high incidence: similar short tandem repeats. - Frequent paracentric inversions of this segment. - Tend to pair at meiosis. - Cutting out of the segment forming an inversion loop.

XIII- Origin of mosaic duplications (de novo)

Not infrequently:

Atlas Genet Cytogenet Oncol Haematol 2008; 3 488 - First trisomy; - Second rearrangement; - Third uniparental disomy.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 489 Atlas Genet Cytogenet Oncol Haematol 2008; 3 490 Atlas Genet Cytogenet Oncol Haematol 2008; 3 491 XIV- Origin of additional isochromosomes and isodicentric chromosomes

 Molecular marker analysis: - Postmeiotic: one normal, one strong allele. - Meiotic: M1: proximal heterozygosity / M2: vice versa. - Results: mostly M2 maternal.  Mechanism: - first meiotic nondisjunction, - second isochromosome formation. Examples: i(8p), i(9p), i(12p), i(18p).

Atlas Genet Cytogenet Oncol Haematol 2008; 3 492 Atlas Genet Cytogenet Oncol Haematol 2008; 3 493 XV- Chaotic chromosome aberrations

- Found especially at investigation of early spontaneous abortions. Multiple deletions, combined deletions and duplications, etc... Complex balanced and unbalanced aberrations often following irradiation.

XVI- Origin of multipe structural chromosome aberrations

CGH re-investigations of visible structural chromosome aberrations not infrequently detect further submicroscopic imbalances, mostly small deletions, rarer duplications.These point towards a much more complex mechanism of origin of structural aberrations than seen on the first glance and parallels the complex origin of mosaics, especially for structural and combined numerical - structural chromosome aberrations.

Atlas Genet Cytogenet Oncol Haematol 2008; 3 494 Atlas Genet Cytogenet Oncol Haematol 2008; 3 495 XVII- Primary and secondary chromosome aberrations

Secondary aberrations may enable survival of an otherwise lethal unbalanced product.

 Examples: - Additional isochromosomes deriving from a trisomy. - Correction of trisomy through uniparental disomy. - Secondary structural aberrations with loss of a chromosomal segment following a trisomy. - Reduction of a complex rearrangement with multiple breaks to a simpler one through recombination - balanced and unbalanced.

XVIII- Conclusion

A distinct feature of Homo sapiens is the excessively high incidence of unbalanced chromosome aberrations, especially trisomy and triploidy. Nature has an incredible phantasy and many different mechanisms to correct such unbalanced aberrations. This may happen because of a high proneness to early postzygotic numerical and structural aberrations combined with a high selection pressure. It is unknown whether primary aberrations may lead with preference to secondary imbalance. Anyway, these visible aberrations constitute the tip of an iceberg, and under the water surface are the many spontaneous miscarriages due to chromosomal imbalance.

Acknowledgements

Atlas Genet Cytogenet Oncol Haematol 2008; 3 496 IMG Zurich Alessandra Baumer and Collaborators. Mariluce Riegel and Collaborators. Europe Collegues from many countries, especially Turkey (Seher Basaran), Poland, Hungary, Ukraine, Spain, and the ECARUCA project . Contributor(s) Written 07-2007 Albert Schinzel Institute of Medical Genetics, CH-8603 Schwerzenbach, Switzerland Citation This paper should be referenced as such : Schinzel A . How human chromosome aberrations are formed. Atlas Genet Cytogenet Oncol Haematol. July 2007 . URL : http://AtlasGeneticsOncology.org/Educ/ChromAberFormedID30065ES.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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