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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to , cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008.

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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics

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Editor

Jean-Loup Huret (Poitiers, France) Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumours Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Louis Dallaire (Montreal, Canada) Education Section Brigitte Debuire (Villejuif, France) Deep Insights Section François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 14, Number 3, March 2010

Table of contents

Gene Section

MAFA (v- musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) 235 Celio Pouponnot, Alain Eychène MAP3K7 (mitogen-activated kinase kinase kinase 7) 238 Hui Hui Tang, Kam C Yeung MCPH1 (microcephalin 1) 243 Yulong Liang, Shiaw-Yih Lin, Kaiyi Li NKX3-1 (NK3 1) 246 Liang-Nian Song, Edward P Gelmann PLXNB1 (plexin B1) 249 José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José Fernando Val-Bernal RUVBL1 (RuvB-like 1 (E. coli)) 254 Valérie Haurie, Aude Grigoletto, Jean Rosenbaum RUVBL2 (RuvB-like 2 (E. coli)) 257 Aude Grigoletto, Valérie Haurie, Jean Rosenbaum SH3GL2 (SH3-domain GRB2-like 2) 260 Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti TOPORS (topoisomerase I binding, arginine/serine-rich) 263 Jafar Sharif, Asami Tsuboi, Haruhiko Koseki TRPV6 (transient potential cation channel, subfamily V, member 6) 267 Yoshiro Suzuki, Matthias A Hediger ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) 270 Shian-Ying Sung CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) 275 Maria Norlin EPHA3 (EPH receptor A3) 279 Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd JAZF1 (JAZF 1) 286 Hui Li, Jeffrey Sklar LPAR1 (lysophosphatidic acid receptor 1) 289 Mandi M Murph, Harish Radhakrishna PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) 293 Montserrat Sanchez-Cespedes SFRP4 (Secreted Frizzled-Related Protein 4) 296 Kendra S Carmon, David S Loose SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) 301 Stephen Hiscox

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) Atlast(11;14)(q 13;q32)of Genetics in multiple myeloma and Cytogenetics Huret JL, Laï JL in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

TACC3 (transforming, acidic coiled-coil containing protein 3) 305 Melissa R Eslinger, Brenda Lauffart, Ivan H Still TP53INP1 (tumor protein inducible nuclear protein 1) 311 Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti

Leukaemia Section del(5q) in myeloid neoplasms 314 Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke t(11;11)(q13;q23) 317 Jean-Loup Huret t(11;19)(q23;p13.3) MLL/ACER1 319 Jean-Loup Huret t(2;5)(p21;q33) 320 Jean-Loup Huret

Solid Tumour Section

Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) 321 Rodney C Diaz Lymphangioleiomyoma 327 Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) Atlas of Genetics and Cytogenetics

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Gene Section Mini Review

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Celio Pouponnot, Alain Eychène Institut Curie, CNRS UMR 146, F-91405 Orsay, France (CP, AE) Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/MAFAID41235ch8q24.html DOI: 10.4267/2042/44698 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Pseudogene Unknown. Other names: RIPE3b1; KLRG1; Maf-A,: hMafA; L- Maf Protein HGNC (Hugo): MAFA Note Location: 8q24.3 Maf oncoproteins are b-ZIP transcription factors that Local order: C8orf51, RHPN1, MAFA, ZC3H3, belong to the AP-1 super-family, which notably GSDMD includes JUN and FOS. The Maf family contains seven members, which can be subdivided into two groups; the DNA/RNA large and small Maf . While the small Maf Note proteins, MAFF, MAFG and MAFK, are essentially composed of a b-Zip domain, the large Maf proteins, The MAFA open reading frame is encoded by a unique MAFA/L-MAF, MAFB, MAF/c-MAF and NRL exon. The entire genomic organization and the putative contain an additional amino-terminal transactivation existence of non-coding exons remain unknown. domain. MAFA was initially cloned in quail and Transcription chicken species and named MAFA and L-MAF, MAFA displays a restricted expression pattern. It is respectively. More recently, mammalian MAFA was notably expressed in pancreas (in beta-cells) and lens. cloned and identi-fied as an essential component of the RIPE3b1 complex, which binds the insulin promoter.

Schematic representation of the MAFA protein structure. Critical residues involved in post-translational modifications are indicated by the color code. The kinases responsible for S14 and S65 phosphorylation in MAFA remain to be identified. GSK-3 phosphorylates the transactivation domain of MAFA, thereby inducing its ubiquitination and proteasome-dependent degradation. This is linked to an increase in MAFA transactivation. These phosphorylations are required for MAFA transforming activity. In contrast, sumoylation of MAFA transactivation domain decreases its transactivation activity.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 235 MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A

Description Implicated in MAFA, like all large Maf proteins, contains an amino- terminal transactivation domain and a carboxy-terminal Multiple myeloma b-ZIP DNA binding domain. Large Maf proteins Hybrid/Mutated gene stimulate transcription of their target genes through Two cases reported translocations of MAFA to the their binding to two types of palindromic sequences immunoglobulin heavy-chain (IgH) locus, juxta-posing called TRE- or CRE- type MARE (Maf Responsive the MAFA gene with the strong enhancers of the IgH Element) (TGCTGAC(G) TCAGCA). The leucine locus (meeting report, accurate description lacking). zipper domain allows the formation of homo- or hetero- Oncogenesis dimers, an absolute pre-requisite for DNA binding. As Large Maf proteins, MAFA, MAFB, and MAF/c-MAF homodimers, these proteins recognize palindromic are bona fide oncogenes as demonstrated in tissue sequences, with the basic domain contacting DNA culture, animal models and in human cancers. MAFA directly. Among the AP-1 family, the Maf proteins are displays the strongest transforming activity, in vitro. In defined by the presence of an additional homolo-gous human, MAF/c-MAF, MAFB and MAFA genes are domain, called the Extended Homology Region (EHR) translocated to the immunoglo-bulin heavy chain (IgH) or ancillary domain, which also contacts DNA. locus in 8-10% of multiple myelomas. MAFA Consequently, they recognize a longer palindromic translocations are present in less than 1% of multiple sequence than other AP-1 family members. The MARE myelomas. MAF/C-MAF over-expression plays a sequence is composed of a TRE or CRE core contacted causative role in multiple myeloma by promoting by the basic domain and a TGC flanking sequence, proliferation and patholo-gical interactions with bone which is recognized by the EHR domain. While the marrow stroma. TGC motif is crucial for Maf binding, the TRE/CRE The transforming activity of Maf proteins is context core can be more degenerate. MAFA transactivation dependent and they can occasionally display tumor activity and stability is regulated by post-trans-lational suppressor-like activity in specific cellular settings. modifications (phosphorylation, ubiquityla-tion and Their transforming activity relies on overexpression sumoylation) mostly occuring on the transactivation and does not require an activating mutation (no domain. GSK-3 was identified as the major protein activating mutation has been identified to be associated kinase regulating MAFA activity and oncogenic with human cancers). It is regulated by post- properties. translational modifications, notably phospho-rylation. Expression Endogenous MAFA protein is detected and phos- References phorrylated in pancreatic beta cells. Benkhelifa S, Provot S, Lecoq O, Pouponnot C, Calothy G, Localisation Felder-Schmittbuhl MP. mafA, a novel member of the maf proto-oncogene family, displays developmental regulation and Nucleus. mitogenic capacity in avian neuroretina cells. Oncogene. 1998 Jul 16;17(2):247-54 Function Ogino H, Yasuda K. Induction of lens differentiation by During development, Maf proteins are involved early in activation of a bZIP , L-Maf. Science. 1998 specification and later in terminal differen-tiation. Apr 3;280(5360):115-8 MAFA is involved in the regulation of insulin gene Benkhelifa S, Provot S, Nabais E, Eychène A, Calothy G, expression in pancreatic beta cells. Accordingly, Felder-Schmittbuhl MP. Phosphorylation of MafA is essential MAFA ablation in mice leads to diabetes. for its transcriptional and biological properties. Mol Biol. Besides their roles during development, large Maf 2001 Jul;21(14):4441-52 proteins, MAFA, MAFB, and MAF/c-MAF are also Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H. involved in oncogenesis. MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem. 2002 Homology Dec 20;277(51):49903-10 MAFB and MAF/c-MAF are the closest MAFA Olbrot M, Rud J, Moss LG, Sharma A. Identification of beta- homologs. The MAFA entire protein sequence shares cell-specific insulin gene transcription factor RIPE3b1 as 52%, 48% and 40% identity with those of MAFB, mammalian MafA. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6737-42 MAF/c-MAF and NRL, respectively. MAFA DNA binding domain (EHR + b-ZIP) shares 82%, 83%, 64% Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Members of the large Maf transcription and 55-60% identity with those of MAFB, MAF/c- family regulate insulin gene transcription in islet beta cells. Mol MAF, NRL and small MAFs, respectively. MAFA and Cell Biol. 2003 Sep;23(17):6049-62 JUN share 30% sequence identity in their b-ZIP Nishizawa M, Kataoka K, Vogt PK. MafA has strong cell domain (20% identity in their entire sequence). transforming ability but is a weak transactivator. Oncogene. 2003 Sep 11;22(39):7882-90

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 236 MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A

Hanamura I, Iida S, Ueda R, Kuehl M, Cullraro C, Bergsagel L, Han SI, Aramata S, Yasuda K, Kataoka K. MafA stability in Sawyer J, Barlogie B, Shaughnessy Jr J.. Identification of three pancreatic beta cells is regulated by glucose and is dependent novel chromosomal translocation partners involving the on its constitutive phosphorylation at multiple sites by glycogen immunoglobulin loci in newly diagnosed myeloma and human synthase kinase 3. Mol Cell Biol. 2007 Oct;27(19):6593-605 myeloma cell lines. Blood (ASH Annual Meeting Abstracts) 2005; 106:1552. Rocques N, Abou Zeid N, Sii-Felice K, Lecoin L, Felder- Schmittbuhl MP, Eychène A, Pouponnot C. GSK-3-mediated Sii-Felice K, Pouponnot C, Gillet S, Lecoin L, Girault JA, phosphorylation enhances Maf-transforming activity. Mol Cell. Eychène A, Felder-Schmittbuhl MP. MafA transcription factor is 2007 Nov 30;28(4):584-97 phosphorylated by p38 MAP kinase. FEBS Lett. 2005 Jul 4;579(17):3547-54 Eychène A, Rocques N, Pouponnot C. A new MAFia in cancer. Nat Rev Cancer. 2008 Sep;8(9):683-93 Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Shao C, Cobb MH. Sumoylation regulates the transcriptional Kudo T, Engel JD, Yamamoto M, Takahashi S. MafA is a key activity of MafA in pancreatic beta cells. J Biol Chem. 2009 Jan regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 30;284(5):3117-24 2005 Jun;25(12):4969-76 This article should be referenced as such: Pouponnot C, Sii-Felice K, Hmitou I, Rocques N, Lecoin L, Druillennec S, Felder-Schmittbuhl MP, Eychène A. Cell context Pouponnot C, Eychène A. MAFA (v-maf musculoaponeurotic reveals a dual role for Maf in oncogenesis. Oncogene. 2006 fibrosarcoma oncogene homolog A (avian)). Atlas Genet Mar 2;25(9):1299-310 Cytogenet Oncol Haematol. 2010; 14(3):235-237. Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol. 2007 Dec;20(4):571-96

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Gene Section Review

MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Hui Hui Tang, Kam C Yeung Department of Cancer Biology and Biochemistry, College of Medicine, Univeristy of Toledo, Health Science Campus, 3035 Arlington Ave., Toledo, OH 43614, USA (HHT, KCY)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID454ch6q15.html DOI: 10.4267/2042/44699 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

of housekeeping genes: the absence of TATA box, the Identity presence of CpG island and SP1 binding sites. Other names: TAK1; TGF1a Transcription HGNC (Hugo): MAP3K7 Four alternatively spliced transcripts encoding 4 Location: 6q15 distinct isoforms because of the presence or absence of alternative exons 12 or/and 16 are detected. DNA/RNA Variant A: It lacks an in-frame coding segment, exon 12. Description Variant B: This variant contains both alternative exons MAP3K7/TAK1 gene spans 71 kb of DNA and 12 and 16 and encodes the longest isoform. contains 17 exons and 16 introns. Exon 1 contains the Variant C: Variant C lacks the exon 16 resulting in a 5' UTR of the mRNA and encodes 40 amino acid of N- frame shift in exon 17. The resulting isoform C has a terminal of the protein. Exons 2 to 8 encode the kinase distinct and shorter C terminus when compared with domain. Exon 17 encodes the carboxyl end of the variants A and B. TAK1 protein and contains the 3'UTR. Exon 12 and Variant D: Variant D lacks both exons 12 and 16. exon 16 are alternative exons. The regulation of the TAK1 mRNA alternative splicing The promoter is located between 799 bp and 1215 bp is tissue specific. The different variants of TAK1 may upsteam of the exon 1. The promoter has the character have specialized functions.

A: The 17 exons are shown as black vertical bars. The exon numbers are shown on top of each exon. The CpG island is shown as a white box. The positions of exons in the cDNA are 1-282, 283-393, 394-459, 460-505, 506-644, 645-768, 770-898, 899-1029, 1030-1111, 1112-1242, 1243-1372, 1373-1453, 1454-1518, 1519-1624, 1625-1686, 1687-1802, and 1803-2850. The sizes (in base pairs) of intron 1 to 16 are 14956, 3073, 6891, 1407, 3451, 2913, 1278, 1499, 2290, 659, 2625, 8150, 12553, 4358, 695, and 1765, respectively.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 238 MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC

B: MAP3K7 transcripts.

Pseudogene Independently, Sakurai et al. (1998) cloned hTAK1 as well as two alternatively spliced isoforms. Human No pseudogene of MAP3K7/TAK1 was reported in TAK1a (Variant A) has 99.3% identity to murine human. TAK1. TAK1b (Variant B) had an insertion of 27 amino acids and TAK1c had a deletion of 39 amino Protein acids in the carboxyl-terminal region. The catalytic Note domains of these three isoforms were 100% identical to MAP3K7/TAK1 isoform B contains 606 amino acids that of murine TAK1. The mRNA for TAK1a and (aa) and has a predicted molecular weight of 67 kDa, TAK1b were expressed in Hela, Jurkat and THP1 cells isoform D contains 491 aa and has a predicted and TAK1a mRNA expessed predominantly in these molecular weight of 53.7 kDa, isoform C contains 518 cell lines. TAK1c mRNA (Variant C) was expressed aa and has a predicted molecular weight of 56.7 kDa, only in Hela cells. Northern blot analysis revealed the and isoform A contains 579 aa and has a predicted expression of TAK1 mRNA in all the human tissues molecular weight of 64 kDa. examined with the size of 3.2 and 5.7 kb. Dempsey et al. (2000) identified a fourth splice variant of TAK1 Description called TAK1d (Variant D). TAK1d lacked the two MAP3K7/TAK1 was first identified by screening a alternative exons and encoded a 491 amino acid mouse cDNA library for clones that could act as protein. TAK1a and b were the most abundant forms in MAPKKKs. The mouse TAK1 cDNA encodes a 579- most tissues examined. The carboxyl-end variant amino acid protein. The mouse TAK1 protein contains TAK1 proteins were unlikely to interfere with the a 300-residue COOH-terminal domain and a putative catalytic activity of TAK1 or its interaction with TAB1 NH2-terminal protein kinase catalytic domain. since both of which involve the N terminus, but may The kinase domain has approximately 30% identity to affect its interaction with TAB2 which associates with the catalytic domains of Raf-1 and MEKK1. Kondo et the carboxyl-ends of the TAK1 proteins. al. (1998) cloned human TAK1 from lung cDNA Expression library by screening with mouse TAK1 sequence. Human TAK1 gene encodes a 579-amino-acid protein. TAK1 was ubiquitously expressed in all tissues. The hTAK1 gene has 91.8% identity with the mTAK1 TAK1a (variant A) was the most abundant form in gene at the nucleotide level and has 99.3% to that at the heart, liver, skeletal muscle, ovary, spleen and amino acid level. Human TAK1 mRNA with a size of peripheral blood mononuclear cells; TAK1b (Variant 3.0 kb was observed to express in all the tissues B) was more abundant in brain, kidney, prostate and examined by Northern blotting. Kondo et al. (1998) small intestine; TAK1c (Variant C) is ubiquitously found 2 isoforms of TAK1. Isoform 2 had an insertion expressed and predominantly in prostate; and TAK1d of 27 amino acids between amino acids 403 and 404 of (Variant D) existed in most tested tissues as a minor isoform 1 which corresponded to the mTAK1 sequence variant. previously identified by Yamaguchi et al. (1995). The Localisation two isoforms were expressed at different ratios. TAK1 is mostly localized in cytoplasm. Isoform 1 (Variant A) was predominantly expressed in brain, heart and spleen while the isoform 2 (Variant B) Function was preferentially in the kidney. TAK1 is a member of the serine/threonine protein

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 239 MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC

kinase family. It can be activated by transforming growth factor-beta (TGF-b) and TAK1 deletion mutant Implicated in missing the N-terminal 22 amino acid is constitutively Breast cancer active. In response to TGF-b, TAK1 can phosphorylate and activate MAP kinase kinases MKK3, MKK4 and Note MKK6. TAK1 can activate NF-kB in the presence of TGF-b1 signaling is involved in tumor angiogenesis TAB1. TAK1 is also involved in pro-inflammatory and metastasis by regulating matrix proteosis. MMP-9 cytokines signaling by activa-ting two kinase pathways. is an important component of these TGF-b1 responses. One is a MAPK cascade that leads to the activation of TAK1 is important for TGF-b1 regulation of MMP9 JNK and the other is IkB kinase cascade that causes the and metastatic potential of breast cancer cell line activation of NF-kB. It was shown that TRAF6 is a MDA-MB231. Suppression of TAK1 reduces the signal mediator that activates IKK and JNK in response expression of MMP9 and tumor cell invasion. TAK1 to pro-inflammatory cytokine interleukin 1. The and NFkB are required for the human MCF10A-CA1a activation of IKK by TRAF6 requires two intermediary breast cancer cells to undergo invasion in response to factors, TRAF6-regulated IKK activator 1 (TRIKA1) TGF-b. A novel TAB1:TAK1: IKKb: NFkB signaling and TRIKA2. TRIKA1 is an ubiquitin-conjugating axis forms aberrantly in breast cancer cells and enables enzyme complex consisted of Ubc13 and Uev1A. oncogenic signaling by TGF-b. TRIKA1, together with TRAF6, catalyze the formation Lung cancer of a Lys63-linked polyubi-quitin chain that mediates Note IKK activation. TRIKA2 is composed of TAK1, TAB1 Mutation analysis: Study on 39 lung cancer specimens and TAB2. The activation of TAK1 kinase complex is and 16 lung cancer cell lines indicated that hTAK1 was dependent on its polyubiquitination by the TRAF6-Ubc not a frequent target for genetic alternations in lung complex and phosphorylation of several residues within cancer. the kinase activation loop by yet-to-be identified TAK1 variant D activated by siRNAs of specific kinases. The ubiquitinated TAK1 can phosphorylate sequences leads to down stream activation of p38 IKKbeta specifically at S177 and S181. Mutation MAPK and JNK but not NFkB pathway. In human lung analysis revealed that a point mutation in the ATP- cancer cell line NCI-H460 the activation of these binding domain of TAK1 (K63W), which abolished its pathway cause cell cycle arrest and apoptosis. It kinase activity, was unable to activate IKK. TAK1 was suggests that TAK1 D may be a new and promising activated by auto-phosphorylation on Ser192 and dual therapeutic target for the treatment of non-small cell phosphorylation of Thr-178 and Thr-184 residues lung cancer. Telomeres are essential elements at the within the activation loop. Mutation of a conserved ends of that contribute to chromosomal serine residue (Ser192) in the activation loop between stability. The length of the telomere is maintained by kinase domain VII and VIII abrogated the the telomerase holoenzyme, which contains the reverse phosphorylation and activation of TAK1. TAK1 is trans-criptase hTERT as a major enzymatic subunit. linked to TRAFs by two adaptor proteins TAB2 and The activity of telomerase is absent in most normal TAB3. The interaction of TAB2/TAB3 with TAK1 is human cells because of the downregulation of the essential for the activation of signaling pathway hTERT transcript resulting in the shortening of mediated by IL-1. telomeres after each replicative cycle. However, in It was shown that protein phosphatase 2Cepsilon immortalized cells and cancer cells, the telomere (PP2Cepsilon) inhibited the IL-1 and TAK1 induced lengths are maintained through an increase in hTERT activation of MKK4-JNK or MKK3-p38 signaling expression. TAK1 can repress the transcription of pathway. PP2Cepsilon inactivated TAK1 by hTERT in A549 human lung adenocarcinoma cell line associating with and dephosphorylating TAK1. A type- and this repression is caused by recruitment of HDAC 2A phosphatase, protein phosphatase 6 (PP6), was also to the hTERT promoter. identified as a TAK1-binding protein. PP6 repressed TAK1 activity by dephos-phorylating Thr187. Cervical carcinoma Homology Note Tumor necrosis factor (TNF)-related apoptosis- Human TAK1-like (TAKL) gene encoded a 242 amino inducing ligand (TRAIL), a member of TNFa ligand acid protein which shared a homology with human TAK1. The amino acid sequences of TAK1 were family, induces apoptosis in a variety of tumor cells. highly conserved between human and mouse. TRAIL induced the delayed phospho-rylation of TAK1 in human cervical carcinoma HeLa cells. TRAIL Mutations induced apoptosis was enhanced by downregulation of TAK1. Note No mutation of human MAP3K7 was reported.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 240 MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC

Head and neck squamous cell Sakurai H, Shigemori N, Hasegawa K, Sugita T. TGF-beta- activated kinase 1 stimulates NF-kappa B activation by an NF- carcinoma kappa B-inducing kinase-independent mechanism. Biochem Note Biophys Res Commun. 1998 Feb 13;243(2):545-9 NFkB was constitutively activated in head and neck Dempsey CE, Sakurai H, Sugita T, Guesdon F. Alternative squamous cell carcinoma (HNSCC). Constitutive splicing and gene structure of the transforming growth factor beta-activated kinase 1. Biochim Biophys Acta. 2000 Dec activation of NFkB in HNSCC was caused by 15;1517(1):46-52 constitutive activation of IKK. Constitutive activa-tion Kishimoto K, Matsumoto K, Ninomiya-Tsuji J. TAK1 mitogen- of NFkB is mediated through the TRADD-TRAF2- activated protein kinase kinase kinase is activated by RIP-TAK1-IKK pathway. autophosphorylation within its activation loop. J Biol Chem. Arthritis 2000 Mar 10;275(10):7359-64 Lee J, Mira-Arbibe L, Ulevitch RJ. TAK1 regulates multiple Note protein kinase cascades activated by bacterial Exercise/joint mobility has therapeutic potency for lipopolysaccharide. J Leukoc Biol. 2000 Dec;68(6):909-15 inflammatory joint diseases such as rheumatoid and Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. osteoarthritis. The biomechanical signals at TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. physiological magnitudes are potent inhibitors of 2001 Jul 19;412(6844):346-51 inflammation induced by NFkB activation in Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, fibrochondrocytes. The biomechanical signals exert Matsumoto K, Kobayashi T, Tamura S. Regulation of the anti-inflammatory effects by inhibiting phosphory- interleukin-1-induced signaling pathways by a novel member of lation of TAK1. the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003 Apr 4;278(14):12013-21 JNK is essential for metalloproteinase (MMP) and joint destruction in inflammatory Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, arthritis. TAK1 is an upstream kinase of JNK. TAK1 Matsumoto K, Gaynor RB. TAK1 is critical for IkappaB kinase- mediated activation of the NF-kappaB pathway. J Mol Biol. play an important role for the IL1b induced JNK 2003 Feb 7;326(1):105-15 activation and the JNK induced gene expression in Li J, Ji C, Yang Q, Chen J, Gu S, Ying K, Xie Y, Mao Y. fibroblast-like synoviocytes (FLSs). It suggests that Cloning and characterization of a novel human TGF-beta TAK1 is a potential therapeutic target to modulate activated kinase-like gene. Biochem Genet. 2004 Apr;42(3- synoviocyte activation in rheumatoid arthritis (RA). 4):129-37 Inflammation Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya-Tsuji J. TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and Note assembly of TRAF6 with IKK in the IL-1 signaling pathway. Pro-inflammatory molecules lipopolysaccharide and Genes Cells. 2005 May;10(5):447-54 Interleukin 1 trigger the activation of TAK1, which in Choo MK, Kawasaki N, Singhirunnusorn P, Koizumi K, Sato S, turn activates multiple kinase JNK, p38, IKK and Akira S, Saiki I, Sakurai H. Blockade of transforming growth PKB/Akt which are important components of kinase factor-beta-activated kinase 1 activity enhances TRAIL- induced apoptosis through activation of a caspase cascade. cascades involved in inflammation. Thus TAK1 plays Mol Cancer Ther. 2006 Dec;5(12):2970-6 an important role in inflammation. Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Human airway epithelial cells Brautigan DL, Matsumoto K, Ninomiya-Tsuji J. Protein phosphatase 6 down-regulates TAK1 kinase activation in the Note IL-1 signaling pathway. J Biol Chem. 2006 Dec Act1/TRAF6/TAK1-mediated NF-kB activation 29;281(52):39891-6 stimulated by IL-17A regulates gene induction in Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, human airway epithelial cells. Dominant negative Lin SC, Wu H, Darnay BG. TAK1-dependent signaling requires TAK1 reduces IL-17A induced gene expression. functional interaction with TAB2/TAB3. J Biol Chem. 2007 Feb 9;282(6):3918-28 References Hammaker DR, Boyle DL, Inoue T, Firestein GS. Regulation of the JNK pathway by TGF-beta activated kinase 1 in Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten rheumatoid arthritis synoviocytes. Arthritis Res Ther. AM. TAK1: molecular cloning and characterization of a new 2007;9(3):R57 member of the superfamily. Mol Endocrinol. 1994 Dec;8(12):1667-80 Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB. Evidence that Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, et al. TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates Identification of a member of the MAPKKK family as a potential constitutive NF-kappaB activation and proliferation in human mediator of TGF-beta signal transduction. Science. 1995 Dec head and neck squamous cell carcinoma. Oncogene. 2007 22;270(5244):2008-11 Mar 1;26(10):1385-97 Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A, Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Takagi K, Takahashi T, Takahashi T. Molecular cloning of Guttridge DC, Agarwal S. Biomechanical signals suppress human TAK1 and its mutational analysis in human lung cancer. TAK1 activation to inhibit NF-kappaB transcriptional activation Int J Cancer. 1998 Feb 9;75(4):559-63 in fibrochondrocytes. J Immunol. 2007 Nov 1;179(9):6246-54

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 241 MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC

Maura M, Katakura Y, Miura T, Fujiki T, Shiraishi H, Shirahata Safina A, Ren MQ, Vandette E, Bakin AV. TAK1 is required for S.. Molecular Mechanism of TAK1-Induced Repression of TGF-beta 1-mediated regulation of matrix metalloproteinase-9 hTERT Transcription. Cell Technology for Cell Products, R. and metastasis. Oncogene. 2008 Feb 21;27(9):1198-207 Smith (ed.), 91-93. 2007 Springer. Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, et al. Honorato B, Alcalde J, Martinez-Monge R, Zabalegui N, Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is Garcia-Foncillas J. TAK1 mRNA expression in the tumor tissue required for interleukin (IL)-1-mediated optimal NFkappaB and of locally advanced head and neck Cancer Patients. Gene AP-1 activation as well as IL-6 gene expression. J Biol Chem. Regulation and Systems Biology. 2008;2: 63-70. 2008 Sep 5;283(36):24497-505

Kodym R, Kodym E, Story MD. Sequence-specific activation of This article should be referenced as such: TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells. RNA. 2008 Mar;14(3):535-42 Tang HH, Yeung KC. MAP3K7 (mitogen-activated protein kinase kinase kinase 7). Atlas Genet Cytogenet Oncol Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase Haematol. 2010; 14(3):238-242. interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res. 2008 Mar 1;68(5):1462-70

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 242 Atlas of Genetics and Cytogenetics

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Gene Section Mini Review

MCPH1 (microcephalin 1) Yulong Liang, Shiaw-Yih Lin, Kaiyi Li Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA (SYL)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/MCPH1ID44370ch8p23.html DOI: 10.4267/2042/44700 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

and/or tumour development. In addition, indivi-duals Identity who harbor a germline mutation of MCPH1 gene may Other names: BRIT1; MCT be highly susceptible to an autosomal recessive HGNC (Hugo): MCPH1 neurological disorder, called primary microcephaly. Location: 8p23.1 DNA/RNA Local order: According to NCBI Map Viewer, genes flanking MCPH1 in telomere to centromere direction Description on 8p23.1 are: ANGPT2 (angiopoietin 2); MCPH1 According to -Gene, MCPH1 gene maps to (also BRIT1); AGPAT5 (1-acylglycerol-3-phosphate NC_000008.9 in the region between 6251529 and O-acyltransferase 5 (lysophosphatidic acid 6493434 on the plus strand and spans across 241.9 kilo acyltransferase, epsilon)); XKR5 (XK, Kell blood bases. According to GenBank, MCPH1 has 14 exons, group complex subunit-related family, member 5); the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110, DEFB1 (defensin, beta 1); DEFA6 (defensin, alpha 6, 38, 163, 78, 238, and 5512 bp. Paneth cell-specific). Transcription Note MCPH1 is one of DNA damage response proteins that 8032 bp mRNA (NM_024596.2), 2508 bp open reading interact with other DNA damage and repair proteins frame. and signal transducers, form a DNA damage response protein complex which can be seen through Protein immunofluorescent microscopy, and participate into Note DNA repair, cell cycle checkpoint control, and MCPH1 has three BRCA1 carboxyl-terminal (BRCT) eventually maintain genomic integrity. The aberrant domains, so it is regarded as a protein family member expression of MCPH1 is observed in ovarian cancer involved in DNA damage repair and checkpoint and breast cancer tissues and cell lines. Thus, control. functional impairment of MCPH1 may significantly contribute to tumour susceptibility

The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA, amino acids).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 243 MCPH1 (microcephalin 1) Liang Y, et al.

Description duplex and facilitating the homology search during the establishment of joint molecules. Lack of MCPH1 can MCPH1 protein contains 835 amino acids with about alleviate localization of RAD51 onto the DNA break 110 kDa of the molecular weight. According to sites. So MCPH1 is strongly implicated in HR. MotifScan prediction, MCPH1 has three BRCT Role of BRIT1 in cell cycle control: MCPH1 has been domains, one nuclear localization signal motif and the demonstrated to regulate the expression of BRCA1 and large central IMPDH domain as depicted in the Chk1 and required for activation of intra-S and G2/M diagram above. The BRCT domains of MCPH1, one in cell cycle checkpoint after cellular exposure to ionizing N-terminus (N-BRCT), the other two tandemly radiation. In the absence of MCPH1, BRCA1 and arranged in C-terminus (C-BRCTs), specifically bind to ChK1 expression is significantly reduced and NBS1 the phosphorylated proteins commonly involved in fails to be phosphorylated, leading to loss of intra-S and DNA damage response pathways. The N-BRCT is G2/M checkpoint control. Cells derived from a micro- required for centrosomal localization in irradiated cells, cephaly patient (MCPH1 defective) maintain a and also essential to rescue the premature persistent level of CDC25A and reduced level of Cdk1- condensation in MCPH1-deficient cells. C-BRCTs cyclin B complex, both of which attributes to entry of direct self-oligo-merization of MCPH1, and are mitosis. So besides expression control of ChK1 and necessary for ionizing radiation-induced foci formation. BRCA1, MCPH1 prevents premature entry into mitosis The function of IMPDH domain predicted by in an ATR-dependent and ATR-independent manner. MotifScan is not clear yet. However, the region (residues 376-485) in the central IMPDH domain (or Homology middle domain), binding with Condension II, According to NCBI-HomoloGene: participates in homologous recombination. Chimpanzee (Pan troglodytes): MCPH1 Expression (NP_001009010.1, 835 aa) Dog (Canis familiaris): MCPH1 (NP_001003366.1, MCPH1 is ubiquitously expressed in human with the 850 aa) higher levels observed in the brain, testes, pancreas and Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986 liver. It is a putative tumor suppressor and the aberrant aa) expression of MCPH1 is correlated with ovarian and Mouse (Mus musculus): MCPH1 (NP_775281.2, 822 breast cancer. This reduced expression of MCPH1 may aa) have been caused by gene deletion detected by high- Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1, density array comparative genomic hybridization 422 aa) (CGH). Drosophila (Drosophila melanogaster): CG30038 Localisation (NP_725086.2, 219 aa) Mainly localized in nucleus. Mutations Function MCPH1 function in DNA damage response: MCPH1 Note can modulate activities of two distinct DNA damage Three point mutations in the autosomal recessive repair networks, the ATM (ataxia telangiectaisia mental retardation patients have been described for mutated) pathway and the ATR (ATM and Rad3- MCPH1 so far. Two mutations (S25X and 427insA) related) pathway. Upon exposure to DNA damaging lead to premature stop condon, and one (T27R) leads to reagents, MCPH1 co-localizes with numerous proteins missense mutation in the N-terminal BRCT domain. A associated with these two signaling pathways including non-synonymous SNP (V761A in BRCA1 C-terminus gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR, (BRCT) domain) of MCPH1 is significantly associated p-RAD17 and p-RPA34. In the absence of MCPH1, all with cranial volume in Chinese males. In addition, a of these proteins with the exception of gamma-H2AX, deletion of approximately 150-200 kb, encompassing fail to localize to sites of DNA damage. The depletion the promoter and the first six exons of the MCPH1 of MCPH1 inhibits the recruitment of phosphorylated gene, was revealed by Array-based homozygosity ATM to double-stranded DNA break ends, and mapping and high-resolution microarray-based subsequently impair t phosphory-lation of multiple comparative genomic hybridization (array CGH). down-stream members of the ATM pathway. MCPH1 However, the patients with this deletion just showed deficiency also abolishes the UV-induced borderline of mild microcephaly. phosphorylation of RPA34 and reduces the levels of phosphorylated RAD17, suggesting the roles of Implicated in MCPH1 in the ATR path-way. Rad51, a homolog of the bacterial RecA, is a central executioner in Ovarian cancers homologous recombination (HR), catalyzing the Note invasion of the single stranded DNA in a homologous Aberrations of MCPH1 have been identified in various human cancers.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 244 MCPH1 (microcephalin 1) Liang Y, et al.

Disease Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson MCPH1 DNA copy number was substatially decreased AP. Mutations in microcephalin cause aberrant regulation of in 40% of advanced epithelial ovarian cancer, and its chromosome condensation. Am J Hum Genet. 2004 mRNA levels were also dramatically decreased in 63% Aug;75(2):261-6 of ovarian cancer. Xu X, Lee J, Stern DF. Microcephalin is a DNA damage Breast cancers response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004 Aug 13;279(33):34091-4 Disease Lin SY, Rai R, Li K, Xu ZX, Elledge SJ. BRIT1/MCPH1 is a MCPH1 mRNA and protein levels was aberrantly DNA damage responsive protein that regulates the Brca1- reduced in several breast cancer cell lines. Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proc Natl Acad Sci U S A. 2005 Oct Prognosis 18;102(42):15105-9 Additionally, reduced MCPH1 expression correla-ted Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, with the duration of the relapse-free intervals and with Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, the occurrence of metastasis in breast cancers. BRIT1 Neitzel H. The first missense alteration in the MCPH1 gene deficiency may contribute to development and causes autosomal recessive microcephaly with an extremely aggressive nature of breast tumors. mild cellular and clinical phenotype. Hum Mutat. 2005 Nov;26(5):496 Primary microcephaly Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Disease Jackson AP, Jeggo PA, O'Driscoll M. Regulation of mitotic Primary microcephaly is an autosomal recessive entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol. 2006 Jul;8(7):725-33 disorder, in which there is a marked reduction in brain size. One form of primary microcephaly, MCPH, is Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY. caused by mutation in the gene encoding microcephalin BRIT1/MCPH1: a guardian of genome and an enemy of tumors. Cell Cycle. 2006 Nov;5(22):2579-83 1 (that is, MCPH1). In these patients, the MCPH1- deficient cells show cellular phenotype of premature Garshasbi M, Motazacker MM, Kahrizi K, Behjati F, Abedini SS, Nieh SE, Firouzabadi SG, Becker C, Rüschendorf F, chromosome condensation in the early G2 phase of the Nürnberg P, Tzschach A, Vazifehmand R, Erdogan F, Ullmann cell cycle, which, therefore, appears to be a useful R, Lenzner S, Kuss AW, Ropers HH, Najmabadi H. SNP array- diagnostic marker for these individuals. As mentioned based homozygosity mapping reveals MCPH1 deletion in above, several mutations of MCPH1 have been family with autosomal recessive mental retardation and mild observed in these patients, including S25X, 427insA, microcephaly. Hum Genet. 2006 Feb;118(6):708-15 T27R, V761A and 5'-deletion of a large portion Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP, encompassing the promoter region and first six exons, Liang J, Mills GB, Meric-Bernstam F, Lin SY. BRIT1 regulates early DNA damage response, chromosomal integrity, and especially the later two showing strong correlation with cancer. Cancer Cell. 2006 Aug;10(2):145-57 micro-cephaly. Wood JL, Singh N, Mer G, Chen J. MCPH1 functions in an PCC syndrome H2AX-dependent but MDC1-independent pathway in response to DNA damage. J Biol Chem. 2007 Nov 30;282(48):35416-23 Disease Premature chromosome condensation (PCC) syndrome Jeffers LJ, Coull BJ, Stack SJ, Morrison CG. Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced is characterized by premature chromosome focus formation and centrosomal localization. Oncogene. 2008 condensation in the early G2 phase. This disorder is Jan 3;27(1):139-44 similar to microcephalin 1, and can also be caused by Wang JK, Li Y, Su B. A common SNP of MCPH1 is associated MCPH1 mutations. with cranial volume variation in Chinese population. Hum Mol Genet. 2008 May 1;17(9):1329-35 References Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1 associates with the Condensin II complex to function in Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, homologous recombination repair. J Biol Chem. 2008 Oct Mannan J, Karbani G, Corry P, Levene MI, Mueller RF, 24;283(43):29586-92 Markham AF, Lench NJ, Woods CG. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22- Yang SZ, Lin FT, Lin WC. MCPH1/BRIT1 cooperates with pter. Am J Hum Genet. 1998 Aug;63(2):541-6 in the activation of checkpoint, DNA repair and apoptosis. EMBO Rep. 2008 Sep;9(9):907-15 Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. This article should be referenced as such: Identification of microcephalin, a protein implicated in Liang Y, Lin SY, Li K. MCPH1 (microcephalin 1). Atlas Genet determining the size of the human brain. Am J Hum Genet. Cytogenet Oncol Haematol. 2010; 14(3):243-245. 2002 Jul;71(1):136-42

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Atlas of Genetics and Cytogenetics

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Gene Section Mini Review

NKX3-1 (NK3 homeobox 1) Liang-Nian Song, Edward P Gelmann Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA (LNS, EPG)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html DOI: 10.4267/2042/44701 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

terminal domain (residues 1-123), one homeo-domain Identity (residues 124-183), and one C-terminal domain Other names: NKX3 BAPX2; NKX3A; NKX3.1 (residues 184-234). HGNC (Hugo): NKX3-1 Expression Location: 8p21.2 Expression is restricted to the adult murine prostate and Local order: Gene orientation: telomere-3' NKX3.1 5'- bulbourethral gland. During early murine centromere. embryogenesis NKX3-1 expression has also been detected in developing somites and testes. In the adult DNA/RNA human expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands. Description Localisation The gene has two exons and one intron. Nuclear. Transcription Function Transcription takes place in a centromere --> telomere Binds to DNA to suppress transcription. Interacts with orientation. The length of the processed mRNA is transcription factors, e.g. , to about 3200 bp. enhance transcriptional activation. Binds to and Pseudogene potentiates topoisomerase I DNA resolving activity. Not known. Acts as prostate tumor suppressor. Homology Protein Homeodomain protein with membership of the NKX Description family. 234 amino acids; 35-38 kDa, contains one N-

The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and stop codons are indicated.

NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 246 NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP

Pten+/- background. Further-rmore, by a variety of Mutations mechanisms NKX3.1 expression is reduced in Germinal noninvasive and early stage human prostate cancer, suggesting that its decreased expression is one of the Twenty-one germ-line variants have been identified in earliest steps in the majority of human prostate cancers. 159 probands of hereditary prostate cancer families. These variants were linked to prostate cancer risk in References hereditary prostate cancer families. For example, the C154T (11% of the population) polymorphism He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, mutation is associated with prostatic enlargement and Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ, Gelmann EP, Abate-Shen C, Carter KC. A novel human prostate cancer risk. A T164A mutations in one family prostate-specific, androgen-regulated homeobox gene cosegregates with prostate cancer in three affected (NKX3.1) that maps to 8p21, a region frequently deleted in brothers. For a more complete list of identified prostate cancer. Genomics. 1997 Jul 1;43(1):69-77 mutations, please visit Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen MM, http://cancerres.aacrjournals.org/cgi/content/full/66/1/6 Abate-Shen C. Tissue-specific expression of murine Nkx3.1 in 9. the male urogenital system. Dev Dyn. 1997 May;209(1):127-38 Somatic Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC, Gelmann EP. Coding region of NKX3.1, a prostate-specific None. homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Res. 1997 Oct 15;57(20):4455-9 Implicated in Prescott JL, Blok L, Tindall DJ. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate. Prostate Cancer 1998 Apr 1;35(1):71-80 Disease Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Prostate cancer is the most commonly diagnosed cancer Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate- Shen C, Shen MM. Roles for Nkx3.1 in prostate development in American men and the second leading cause of and cancer. Genes Dev. 1999 Apr 15;13(8):966-77 cancer-related deaths. Prostate cancer predominantly occurs in the peripheral zone of the human prostate, Tanaka M, Lyons GE, Izumo S. Expression of the Nkx3.1 homobox gene during pre and postnatal development. Mech with roughly 5 to 10% of cases found in the central Dev. 1999 Jul;85(1-2):179-82 zone. Disease development involves the temporal and Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, spatial loss of the basal epithelial compartment Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, accompanied by increased proliferation and Gelmann EP. Loss of NKX3.1 expression in human prostate dedifferentiation of the luminal (secretory) epithelial cancers correlates with tumor progression. Cancer Res. 2000 cells. Prostate cancer is a slow developing disease that Nov 1;60(21):6111-5 is typically found in men greater than 60 years of age Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S, and incidence increases with increasing age. Pretlow TG, Saatcioglu F. Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and Prognosis regulation by both androgens and estrogens. Gene. 2000 Dec PSA test combined with digital-rectal exams are used 30;260(1-2):25-36 to screen for the presence of disease. If the digital- Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted rectal exams are positive, additional tests including disruption of the Nkx3.1 gene in mice results in morphogenetic needle core biopsies are taken to assess disease stage defects of minor salivary glands: parallels to glandular duct and grade. Patients with localized, prostate-restricted morphogenesis in prostate. Mech Dev. 2000 Jul;95(1-2):163- 74 disease are theoretically curable with complete removal of the prostate (radical prostatectomy). Patients with Steadman DJ, Giuffrida D, Gelmann EP. DNA-binding sequence of the human prostate-specific homeodomain protein extra-prostatic disease are treated with hormone NKX3.1. Nucleic Acids Res. 2000 Jun 15;28(12):2389-95 (androgen ablation) therapy, radiation, and/or antiandrogens; however, no curative treatments are Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, available for nonorgan confined metastatic disease. regulates epithelial ductal branching and proliferation of the Cytogenetics prostate and palatine glands. Dev Dyn. 2000 Oct;219(2):248- 60 Various forms of aneuploidy. Xu LL, Srikantan V, Sesterhenn IA, Augustus M, Dean R, Moul Oncogenesis JW, Carter KC, Srivastava S. Expression profile of an Nkx3.1 plays an essential role in normal murine androgen regulated prostate specific homeobox gene NKX3.1 prostate development. Loss of function of Nkx3.1 leads in primary prostate cancer. J Urol. 2000 Mar;163(3):972-9 to defects in prostatic protein secretions and in ductal Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck morphogenesis. Loss-of-function of Nkx3.1 also MR, Vocke CD, Linehan WM, Ferretti JA. Expression studies contributes to prostate carcinogenesis. For example, and mutational analysis of the androgen regulated homeobox Nkx3.1 mutant mice develop prostatic dysplasia. gene NKX3.1 in benign and malignant prostate epithelium. J Urol. 2001 Apr;165(4):1329-34 Nkx3.1 loss potentiates prostate carcinogenesis in a

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 247 NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP

Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, homeoprotein NKX3.1 and serum response factor. J Mol Biol. Humphrey PA, Milbrandt J. Conditional loss of Nkx3.1 in adult 2006 Jul 28;360(5):989-99 mice induces prostatic intraepithelial neoplasia. Mol Cell Biol. 2002 Mar;22(5):1495-503 Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol. Gelmann EP, Steadman DJ, Ma J, Ahronovitz N, Voeller HJ, 2006 Apr;26(8):3008-17 Swope S, Abbaszadegan M, Brown KM, Strand K, Hayes RB, Stampfer MJ. Occurrence of NKX3.1 C154T polymorphism in Rodriguez Ortner E, Hayes RB, Weissfeld J, Gelmann EP. men with and without prostate cancer and studies of its effect Effect of homeodomain protein NKX3.1 R52C polymorphism on protein function. Cancer Res. 2002 May 1;62(9):2654-9 on prostate gland size. Urology. 2006 Feb;67(2):311-5 Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons Simmons SO, Horowitz JM. Nkx3.1 binds and negatively R, Shen MM, Abate-Shen C. Cooperativity of Nkx3.1 and Pten regulates the transcriptional activity of Sp-family members in loss of function in a mouse model of prostate carcinogenesis. prostate-derived cells. Biochem J. 2006 Jan 1;393(Pt 1):397- Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2884-9 409 Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM. J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J, Nkx3.1; Pten mutant mice develop invasive prostate Gruschus J, Isaacs WB, Gelmann EP, Xu J. Germ-line adenocarcinoma and lymph node metastases. Cancer Res. mutation of NKX3.1 cosegregates with hereditary prostate 2003 Jul 15;63(14):3886-90 cancer and alters the homeodomain structure and function. Cancer Res. 2006 Jan 1;66(1):69-77 Gelmann EP, Bowen C, Bubendorf L. Expression of NKX3.1 in normal and malignant tissues. Prostate. 2003 May 1;55(2):111- Bowen C, Stuart A, Ju JH, Tuan J, Blonder J, Conrads TP, 7 Veenstra TD, Gelmann EP. NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity. Cancer Magee JA, Abdulkadir SA, Milbrandt J. Haploinsufficiency at Res. 2007 Jan 15;67(2):455-64 the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell. 2003 Mogal AP, van der Meer R, Crooke PS, Abdulkadir SA. Mar;3(3):273-83 Haploinsufficient prostate tumor suppression by Nkx3.1: a role for accessibility in dosage-sensitive gene regulation. Shen MM, Abate-Shen C. Roles of the Nkx3.1 homeobox gene J Biol Chem. 2007 Aug 31;282(35):25790-800 in prostate organogenesis and carcinogenesis. Dev Dyn. 2003 Dec;228(4):767-78 Abate-Shen C, Shen MM, Gelmann E. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in Korkmaz CG, Korkmaz KS, Manola J, Xi Z, Risberg B, prostate organogenesis and carcinogenesis. Differentiation. Danielsen H, Kung J, Sellers WR, Loda M, Saatcioglu F. 2008 Jul;76(6):717-27 Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis. J Urol. 2004 Sep;172(3):1134- Holmes KA, Song JS, Liu XS, Brown M, Carroll JS. Nkx3-1 and 9 LEF-1 function as transcriptional inhibitors of activity. Cancer Res. 2008 Sep 15;68(18):7380-5 Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, Gelmann EP. Deletion, methylation, and Markowski MC, Bowen C, Gelmann EP. Inflammatory expression of the NKX3.1 suppressor gene in primary human cytokines induce phosphorylation and ubiquitination of prostate prostate cancer. Cancer Res. 2005 Feb 15;65(4):1164-73 suppressor protein NKX3.1. Cancer Res. 2008 Sep 1;68(17):6896-901 Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, Jenkins RB, Bieberich CJ, De Marzo AM. Decreased NKX3.1 protein Zhang Y, Fillmore RA, Zimmer WE. Structural and functional expression in focal prostatic atrophy, prostatic intraepithelial analysis of domains mediating interaction between the bagpipe neoplasia, and adenocarcinoma: association with gleason homologue, Nkx3.1 and serum response factor. Exp Biol Med score and chromosome 8p deletion. Cancer Res. 2006 Nov (Maywood). 2008 Mar;233(3):297-309 15;66(22):10683-90 This article should be referenced as such: Ju JH, Maeng JS, Zemedkun M, Ahronovitz N, Mack JW, Ferretti JA, Gelmann EP, Gruschus JM. Physical and Song LN, Gelmann EP. NKX3-1 (NK3 homeobox 1). Atlas functional interactions between the prostate suppressor Genet Cytogenet Oncol Haematol. 2010; 14(3):246-248.

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Gene Section Mini Review

PLXNB1 (plexin B1) José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José Fernando Val-Bernal Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain (JJGR, MN, SL, JFVB)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/PLXNB1ID43413ch3p21.html DOI: 10.4267/2042/44702 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Pseudogene No. Other names: KIAA0407; MGC149167; OTTHUMP00000164806; PLEXIN-B1; PLXN5; SEP Protein HGNC (Hugo): PLXNB1 Location: 3p21.31 Description Local order: The Plexin B1 gene is located between 2135 Amino acids (AA). Plexins are receptors for axon FBXW12 and CCDC51 genes. molecular guidance molecules semaphorins. Plexin signalling is important in pathfinding and patterning of both neurons and developing blood vessels. Plexin-B1 is a surface cell receptor. When it binds to its ligand SEMA4D it activates several pathways by binding of cytoplasmic ligands, like RHOA activation and subsequent changes of the actin cytoskeleton, axon guidance, invasive growth and cell migration. It monomers and heterodimers with PLXNB2 after proteolytic processing. Binds RAC1 that has been activated by GTP binding. It binds PLXNA1 and by similarity ARHGEF11, Note ARHGEF12, ERBB2, MET, MST1R, RND1, NRP1 Size: 26,200 bases. and NRP2. Orientation: minus strand. This family features the C-terminal regions of various plexins. The cytoplasmic region, which has been called DNA/RNA a SEX domain in some members of this family is involved in downstream signalling pathways, by Description interaction with proteins such as Rac1, RhoD, Rnd1 and other plexins. Functioning gene. 21.00 kb; 37 Exons. Three copies of a cysteine rich repeat are found in Transcription Plexin. The function of the repeat is unknown. 7097.00 bp; Number of transcripts: 1; Type: Expression Messenger. It is highly expressed in fetal kidney, digestive system Two alternatively truncated spliced variant, coding (from esophagus to colon), thyroid, prostate and secreted proteins (lacking the part of the extracellular trachea and at slightly lower levels in fetal brain, lung, domains).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 249 PLXNB1 (plexin B1) Gómez-Román JJ, et al.

female reproductive system (breast, uterus and ovary) and liver.

Plexin B1 policlonal antibody in foetal human central nervous system. Positive staining in developing neurons.

Localisation mutations in the cytoplasmic domain of the PLXNB1 Three isoforms have been identified: The isoform 1 is gene in prostate cancer tissue. Mutations were found in located in cell membrane and the isoforms 2 and 3 are 8 (89%) of 9 prostate cancer bone metastases, in 7 secreted proteins. (41%) of 17 lymph node meta-stases, and in 41 (46%) Function of 89 primary cancers. Forty percent of prostate cancers Plexin B1 has several molecular functions, like a contained the same mutation, and the majority of the receptor activity, transmembrane receptor activity, primary tumors showed overexpression of the plexin- protein binding, semaphorin receptor and semaphorin B1 protein. In vitro functional expression studies of the receptor binding. It is implicated in the next biological 3 most common mutations showed that the mutant processes: Signal transduction, intracellular signalling proteins resulted in increased cell motility, inva-sion, cascade, multicellular organismal development, cell adhesion, and lamellipodia extension compared to migration and posi-tive regulation of axonogenesis. wildtype. The mutations acted by hindering RAC1 and RRAS binding and GTP activity. Homology It belongs to the plexin family and it contains 3 Implicated in IPT/TIG domains and one Sema domain. Breast cancer Mutations Prognosis Loss of protein Plexin B1 expression is associated with Somatic poor outcome in breast cancer ER (estrogen positive) Wong et al. (2007) identified 13 different somatic patients.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 250 PLXNB1 (plexin B1) Gómez-Román JJ, et al.

ACHN, a marked reduction in proliferation rate is Renal cell carcinoma found. Note Prostate carcinoma By reverse transcription-polymerase chain reaction Note 13 somatic missense mutations in the cytoplasmic plexin B1 is expressed in nonneoplastic renal tissue, domain of the Plexin-B1 gene have been reported. and it is severely downregulated in clear cell renal Mutations were found in cancer bone metastases, carcinomas. By immunohistochemistry on tissue lymph node metastases, and in primary cancers. microarrays it was shown that plexin B1 protein is Forty percent of prostate cancers contained the same absent in more than 80% of renal cell carcinomas. mutation. Overexpression of the Plexin-B1 protein was Otherwise, all kinds of renal tubules showed strong found in the majority of primary tumors. The mutations membrane reactivity. hinder Rac and R-Ras binding and R-RasGAP activity, When plexin B1 expression is induced with an resulting in an increase in cell motility, invasion, expression vector in the renal adenocarcinoma cell line adhesion, and lamellipodia.

Plexin B1 in normal kidney tissue. Tubular cortical and medular cells reactive The same immunostaining after blocking peptide incubation.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 251 PLXNB1 (plexin B1) Gómez-Román JJ, et al.

Plexin B1 loss of expression in three cases of renal cell carcinoma (clear cell upper right and left), and papillary (bottom right). One case of renal clear cell carcinoma with PlexinB1 expression (bottom left).

activation by Plexin-B1 and induces cell contraction in COS-7 Osteoarthritis cells. J Biol Chem. 2003 Jul 11;278(28):25671-7 Note Usui H, Taniguchi M, Yokomizo T, Shimizu T. Plexin-A1 and Using semi-quantitative reverse transcription plexin-B1 specifically interact at their cytoplasmic domains. polymerase chain reaction (RT-PCR) analysis, plexin Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31 B1 (PLXNB1) was confirmed to be consis-tently Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. expressed at lower levels in osteoarthritis. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004 Jul 1;23(30):5131-7 Disease Degenerative bone disease. Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R- References Ras. Science. 2004 Aug 6;305(5685):862-5 Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF- Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano mediated RhoA activation involves the receptor tyrosine kinase M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80 family of transmembrane proteins with homology to the MET- Torres-Vázquez J, Gitler AD, Fraser SD, Berk JD, Van N hepatocyte growth factor receptor. Proc Natl Acad Sci U S A. Pham, Fishman MC, Childs S, Epstein JA, Weinstein BM. 1996 Jan 23;93(2):674-8 Semaphorin-plexin signaling guides patterning of the Fujii T, Nakao F, Shibata Y, Shioi G, Kodama E, Fujisawa H, developing vasculature. Dev Cell. 2004 Jul;7(1):117-23 Takagi S. Caenorhabditis elegans PlexinA, PLX-1, interacts Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 with transmembrane semaphorins and regulates epidermal induces endothelial cell migration through the activation of morphogenesis. Development. 2002 May;129(9):2053-63 PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Mol Cell Biol. 2005 Aug;25(16):6889-98 Comoglio PM, Di Renzo MF. Novel somatic mutations of the Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, MET oncogene in human carcinoma metastases activating cell Comoglio PM, Bussolino F, Giordano S. Sema4D induces motility and invasion. Cancer Res. 2002 Dec 1;62(23):7025-30 angiogenesis through Met recruitment by Plexin B1. Blood. Oinuma I, Katoh H, Harada A, Negishi M. Direct interaction of 2005 Jun 1;105(11):4321-9 Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 252 PLXNB1 (plexin B1) Gómez-Román JJ, et al.

Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and B1 and the small GTPase Rac1. J Mol Biol. 2008 Apr Rho kinase to promote the integrin-dependent activation of Akt 11;377(5):1474-87 and ERK and endothelial cell motility. J Biol Chem. 2007 Nov 30;282(48):34888-95 Gómez Román JJ, Garay GO, Saenz P, Escuredo K, Sanz Ibayondo C, Gutkind S, Junquera C, Simón L, Martínez A, Harduf H, Goldman S, Shalev E. Human uterine epithelial Fernández Luna JL, Val-Bernal JF. Plexin B1 is downregulated RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin in renal cell carcinomas and modulates cell growth. Transl B1. Fertil Steril. 2007 Jun;87(6):1419-27 Res. 2008 Mar;151(3):134-40 Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Swiercz JM, Worzfeld T, Offermanns S. ErbB-2 and met Shen L, Park HW, Buck M. Binding of Rac1, Rnd1, and RhoD reciprocally regulate cellular signaling via plexin-B1. J Biol to a novel Rho GTPase interaction motif destabilizes Chem. 2008 Jan 25;283(4):1893-901 dimerization of the plexin-B1 effector domain. J Biol Chem. 2007 Dec 21;282(51):37215-24 Tong Y, Hota PK, Hamaneh MB, Buck M. Insights into oncogenic mutations of plexin-B1 based on the solution Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, structure of the Rho GTPase binding domain. Structure. 2008 Bott SR, Nariculam J, Box G, Munson P, Constantinou J, Feb;16(2):246-58 Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A, Masters JR, Williamson M. Plexin-B1 mutations in prostate This article should be referenced as such: cancer. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19040-5 Gómez-Román JJ, Nicolas Martínez M, Lazuén Fernández S, Val-Bernal JF. PLXNB1 (plexin B1). Atlas Genet Cytogenet Bouguet-Bonnet S, Buck M. Compensatory and long-range Oncol Haematol. 2010; 14(3):249-253. changes in picosecond-nanosecond main-chain dynamics upon complex formation: 15N relaxation analysis of the free and bound states of the ubiquitin-like domain of human plexin-

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Gene Section Mini Review

RUVBL1 (RuvB-like 1 (E. coli)) Valérie Haurie, Aude Grigoletto, Jean Rosenbaum INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (VH, AG, JR)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL1ID44415ch3q21.html DOI: 10.4267/2042/44703 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

The monomers contain three domains, of which the Identity first and the third are involved in ATP binding and Other names: ECP54; INO80H; NMP238; PONTIN; hydrolysis. The second domain is a DNA/RNA-binding Pontin52; RVB1; TAP54-alpha; TIH1; TIP49; TIP49A domain as demonstrated by structural homology and HGNC (Hugo): RUVBL1 nucleic acid binding assays. RUVBL1 assembles into an hexameric structure with a central channel. Pure Location: 3q21.3 RUVBL1 displays a marginal ATPase activity in vitro and no detectable helicase activity (Matias et al., 2006). DNA/RNA RUVBL1 interacts with RUVBL2 to form a dodecamer Description (Puri et al., 2007). This RUVBL1/ RUVBL2 complex displays a significant ATPase activity and is likely one 11 exons spamming 42840bp, 1371bp open reading of the functional forms of the proteins. frame. Sumoylation of RUVBL1 was reported in metastatic Transcription prostate cancer cells (Kim et al., 2007). 1785bp mRNA. Expression Expression is ubiquitous but especially abundant in Protein heart, skeletal muscle and testis (Salzer et al., 1999). RUVBL1 is overexpressed in several tumors : liver (Li Description et al., 2005), colon (Carlson et al., 2003; Lauscher et 456 amino acids, 50.2 kDa. RUVBL1 belongs to the al., 2007), lymphoma (Nishiu et al., 2002), non-small AAA+ ATPase superfamily (ATPases associa-ted with cell lung (Dehan et al., 2007). Overexpressions of diverse cellular activities) sharing conserved Walker A RUVBL1 in a large number of cancers and its possible and B motifs, arginine fingers, and sensor domains. role in human cancers have been reported (reviewed in The structure of RuvBL1 has been determined by X-ray Huber et al., 2008). crystallography and published in 2006 (Matias et al., 2006). Localisation Cytoplasm and nucleus.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 254 RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.

Function References RUVBL1 plays roles in essential signaling path-ways Makino Y, Mimori T, Koike C, Kanemaki M, Kurokawa Y, Inoue such as the c- and beta-catenin pathways. S, Kishimoto T, Tamura T. TIP49, homologous to the bacterial RUVBL1 appears notably required for the trans- DNA helicase RuvB, acts as an autoantigen in human. forming activity of c-myc (Wood et al., 2000), beta- Biochem Biophys Res Commun. 1998 Apr 28;245(3):819-23 catenin (Feng et al., 2003) and of the viral oncoprotein Salzer U, Kubicek M, Prohaska R. Isolation, molecular E1A (Dugan et al., 2002). characterization, and tissue-specific expression of ECP-51 and RUVBL1 participates in the remodelling of chromatin ECP-54 (TIP49), two homologous, interacting erythroid as a member of several complexes such as TRRAP, cytosolic proteins. Biochim Biophys Acta. 1999 Sep 3;1446(3):365-70 several distinct HAT complexes and BAF53 (Wood et al., 2000; Park et al., 2002; Feng et al., 2003). Wood MA, McMahon SB, Cole MD. An ATPase/helicase complex is an essential cofactor for oncogenic transformation It is also involved in transcriptional regulation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30 (reviewed in Gallant, 2007), DNA repair (Gospodinov et al., 2008), snoRNP biogenesis (Watkins et al., 2002), Hawley SB, Tamura T, Miles LA. Purification, cloning, and characterization of a profibrinolytic plasminogen-binding and telomerase activity (Venteicher et al., 2008). protein, TIP49a. J Biol Chem. 2001 Jan 5;276(1):179-86 RUVBL1 has a mitosis-specific function in regulating microtubule assembly (Ducat et al., 2008). Dugan KA, Wood MA, Cole MD. TIP49, but not TRRAP, modulates c-Myc and E2F1 dependent apoptosis. Oncogene. RUVBL1 has been found expressed on the cell surface 2002 Aug 29;21(38):5835-43 where it participates in the activation of plasminogen Nishiu M, Yanagawa R, Nakatsuka S, Yao M, Tsunoda T, (Hawley et al., 2001). Nakamura Y, Aozasa K. Microarray analysis of gene- expression profiles in diffuse large B-cell lymphoma: Implicated in identification of genes related to disease progression. Jpn J Cancer Res. 2002 Aug;93(8):894-901 Colon cancer Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear Disease complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002 By immunohistochemistry, RUVBL1 expression was Mar;22(5):1307-16 found higher in 22 out of 26 cases where information Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of was available (Lauscher et al., 2007). The staining was the box C/D motif is essential for nucleolar localization and is increased at the invasive margin of the tumors. required, along with the 15.5K protein, for the hierarchical Increased RUVBL1 transcripts levels were also assembly of the box C/D snoRNP. Mol Cell Biol. 2002 reported in a smaller series (Carlson et al., 2003). Dec;22(23):8342-52 Large B cell lymphoma Carlson ML, Wilson ET, Prescott SM. Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a. Disease Mol Cancer. 2003 Dec 15;2:42 Microarray analysis has identified an over-expression Feng Y, Lee N, Fearon ER. TIP49 regulates beta-catenin- of RUVBL1 in Advanced lymphomas as compared mediated neoplastic transformation and T-cell factor target with localized lymphomas (Nishiu et al., 2002). gene induction via effects on chromatin remodeling. Cancer Res. 2003 Dec 15;63(24):8726-34 Non Small cell lung cancer Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, Man XB, Hong Disease Y, Zhang L, Li L, Xia QC, Wu JR, Wang HY, Zeng R. Microarray analysis and subsequent RT-PCR have Proteomic analysis of hepatitis B virus-associated hepatocellular carcinoma: Identification of potential tumor shown an overexpression of RUVBL1 in NSCLC markers. Proteomics. 2005 Mar;5(4):1125-39 (Dehan et al., 2007). Matias PM, Gorynia S, Donner P, Carrondo MA. Crystal Cytogenetics structure of the human AAA+ protein RuvBL1. J Biol Chem. There is a frequent amplification of 3q21 in the same 2006 Dec 15;281(50):38918-29 samples (Dehan et al., 2007). Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S, Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G, Hepatocellular carcinoma Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z, Disease Kaminski N. Chromosomal aberrations and gene expression Proteomic analysis found an overexpression of profiles in non-small cell lung cancer. Lung Cancer. 2007 May;56(2):175-84 RUVBL1 in 4 out of 10 cases (Li et al., 2005). Gallant P. Control of transcription by Pontin and Reptin. Trends Autoimmune diseases Cell Biol. 2007 Apr;17(4):187-92 Disease Kim JH, Lee JM, Nam HJ, Choi HJ, Yang JW, Lee JS, Kim Auto-antibodies to RUVBL1 were found in the serum MH, Kim SI, Chung CH, Kim KI, Baek SH. SUMOylation of of patients with polymyositis/dermato-myositis and pontin chromatin-remodeling complex reveals a signal integration code in prostate cancer cells. Proc Natl Acad Sci U autoimmune hepatitis (Makino et al., 1998). S A. 2007 Dec 26;104(52):20793-8

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 255 RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.

Lauscher JC, Loddenkemper C, Kosel L, Gröne J, Buhr HJ, Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Huber O. Increased pontin expression in human colorectal Identification of ATPases pontin and reptin as telomerase cancer tissue. Hum Pathol. 2007 Jul;38(7):978-85 components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57 Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92 in response to DNA damage is modulated by TIP49. Int J Biochem Cell Biol. 2009 Apr;41(4):925-33 Ducat D, Kawaguchi S, Liu H, Yates JR 3rd, Zheng Y. Regulation of microtubule assembly and organization in mitosis This article should be referenced as such: by the AAA+ ATPase Pontin. Mol Biol Cell. 2008 Jul;19(7):3097-110 Haurie V, Grigoletto A, Rosenbaum J. RUVBL1 (RuvB-like 1 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum 14(3):254-256. J. Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res. 2008 Sep 1;68(17):6873-6

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RUVBL2 (RuvB-like 2 (E. coli)) Aude Grigoletto, Valérie Haurie, Jean Rosenbaum INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (AG, VH, JR)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL2ID42185ch19q13.html DOI: 10.4267/2042/44704 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RUVBL2 is phosphorylated on an ATM/ATR Identity consensus site following DNA damage (Matsuoka et Other names: CGI-46; ECP51; INO80J; REPTIN; al., 2007). RVB2; Reptin52; Rvb2; TAP54-beta; TIH2; TIP48; Expression TIP49B Expression of RUVBL2 is ubiquitous but especially HGNC (Hugo): RUVBL2 abundant in thymus and testis (Salzer et al., 1999; Location: 19q13.33 Parfait et al., 2000). RUVBL2 is overexpressed in hepatocellular carci- DNA/RNA noma (Rousseau et al., 2007). Overexpression of RUVBL2 in several cancers and its possible role in Description human cancers has been reported (reviewed in Huber et 15 exons, 14 introns (Parfait et al., 2000). al., 2008). Transcription Localisation 1518bp mRNA with 463aa open reading frame. Cytoplasm and nucleus. Function Protein RUVBL2 interacts with c-myc (Wood et al., 2000) and Description also modulates transcriptional regulation by the beta- catenin/TCF-LEF complex (Bauer et al., 2000) and 463 amino acids, 52 kDa. ATF2 (Cho et al., 2001). RUVBL2 participates in the RUVBL2 belongs to the AAA+ ATPase super-family remodelling of chromatin as a member of several (ATPases associated with diverse cellular activities) complexes such as TIP60 (Ikura et al., 2000), INO80 sharing conserved Walker A and B motifs, arginine (Jin et al., 2005), SRCAP (Cai et al., 2005). fingers, and sensor domains. The monomers contain It is also involved in transcriptional regulation two domains, which are involved in ATP binding and (reviewed in Gallant, 2007), DNA repair (Gospodinov hydrolysis respectively. RUVBL2 assembles into an et al., 2008), snoRNP biogenesis (Watkins et al., 2002), hexameric structure with a central channel. and telomerase activity (Venteicher et al., 2008). RUVBL2 interacts with RUVBL1 to form a dodecamer RUVBL2 silencing in fibroblasts induces a senescent (Puri et al., 2007). This RUVBL1/ RUVBL2 complex phenotype (Chan et al., 2005). displays a significant ATPase activity and is likely one of the functional forms of the proteins. Sumoylation of Implicated in RUVBL2 has been reported on Lys456 in invasive prostate cancer cells (Kim et al., Hepatocellular carcinoma (HCC) 2006). Disease

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 257 RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.

RUVBL2 was found to be overexpressed in 75% of Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai cases in a series of 96 human HCC studied with real- Z. TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Mol Cell Biol. 2001 time RT-PCR (Rousseau et al., 2007). It was also Dec;21(24):8398-413 increased in a smaller 15 cases series (Iizuka et al., Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of 2006). No mutations in the coding sequence were the box C/D motif is essential for nucleolar localization and is identified (Rousseau et al., 2007). required, along with the 15.5K protein, for the hierarchical Prognosis assembly of the box C/D snoRNP. Mol Cell Biol. 2002 Dec;22(23):8342-52 Overexpression of RUVBL2 was an independent factor of poor prognosis (Rousseau et al., 2007). Cai Y, Jin J, Florens L, Swanson SK, Kusch T, Li B, Workman JL, Washburn MP, Conaway RC, Conaway JW. The Oncogenesis mammalian YL1 protein is a shared subunit of the RUVBL2 depletion with siRNAs led to HCC cell TRRAP/TIP60 histone acetyltransferase and SRCAP growth arrest and apoptosis, whereas over-expression complexes. J Biol Chem. 2005 Apr 8;280(14):13665-70 in HCC cells allowed these cells to give rise to more Chan HM, Narita M, Lowe SW, Livingston DM. The p400 E1A- progressive tumors in xenografts than control cells associated protein is a novel component of the p53 --> p21 (Rousseau et al., 2007). senescence pathway. Genes Dev. 2005 Jan 15;19(2):196-201 Jin J, Cai Y, Yao T, Gottschalk AJ, Florens L, Swanson SK, Colon cancer Gutiérrez JL, Coleman MK, Workman JL, Mushegian A, Disease Washburn MP, Conaway RC, Conaway JW. A mammalian chromatin remodeling complex with similarities to the yeast RUVBL2 was overexpressed in a series of 18 colon INO80 complex. J Biol Chem. 2005 Dec 16;280(50):41207-12 cancers (Graudens et al., 2006). Kim JH, Kim B, Cai L, Choi HJ, Ohgi KA, Tran C, Chen C, Melanoma Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG, Baek SH. Transcriptional regulation of a metastasis suppressor Disease gene by Tip60 and beta-catenin complexes. Nature. 2005 Apr RUVBL2 was overexpressed in a series of 45 14;434(7035):921-6 melanomas (Talantov et al., 2005). Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, Bladder carcinoma Atkins D, Wang Y. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Disease Res. 2005 Oct 15;11(20):7234-42 RUVBL2 was overexpressed in a series of 108 bladder Weiske J, Huber O. The histidine triad protein Hint1 interacts carcinomas (Sanchez-Carbayo et al., 2006). with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. J Cell Sci. 2005 Jul 15;118(Pt 14):3117-29 Prostate cancer Graudens E, Boulanger V, Mollard C, Mariage-Samson R, Oncogenesis Barlet X, Grémy G, Couillault C, Lajémi M, Piatier-Tonneau D, In conjunction with beta-catenin, RUVBL2 represses Zaborski P, Eveno E, Auffray C, Imbeaud S. Deciphering the expression of the anti-metastasis gene KAI-1 (Kim cellular states of innate tumor drug responses. Genome Biol. 2006;7(3):R19 et al., 2005) and is involved in the invasive phenotype of cultured prostate cancer cells (Kim et al., 2006). Iizuka N, Tsunedomi R, Tamesa T, Okada T, Sakamoto K, Hamaguchi T, Yamada-Okabe H, Miyamoto T, Uchimura S, Hamamoto Y, Oka M. Involvement of c-myc-regulated genes in References hepatocellular carcinoma related to genotype-C hepatitis B virus. J Cancer Res Clin Oncol. 2006 Jul;132(7):473-81 Salzer U, Kubicek M, Prohaska R. Isolation, molecular characterization, and tissue-specific expression of ECP-51 and Kim JH, Choi HJ, Kim B, Kim MH, Lee JM, Kim IS, Lee MH, ECP-54 (TIP49), two homologous, interacting erythroid Choi SJ, Kim KI, Kim SI, Chung CH, Baek SH. Roles of cytosolic proteins. Biochim Biophys Acta. 1999 Sep sumoylation of a reptin chromatin-remodelling complex in 3;1446(3):365-70 cancer metastasis. Nat Cell Biol. 2006 Jun;8(6):631-9 Bauer A, Chauvet S, Huber O, Usseglio F, Rothbächer U, Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon- Aragnol D, Kemler R, Pradel J. Pontin52 and reptin52 function Cardo C. Defining molecular profiles of poor outcome in as antagonistic regulators of beta-catenin signalling activity. patients with invasive bladder cancer using oligonucleotide EMBO J. 2000 Nov 15;19(22):6121-30 microarrays. J Clin Oncol. 2006 Feb 10;24(5):778-89 Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Gallant P. Control of transcription by Pontin and Reptin. Trends Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the Cell Biol. 2007 Apr;17(4):187-92 TIP60 histone acetylase complex in DNA repair and apoptosis. Cell. 2000 Aug 18;102(4):463-73 Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Parfait B, Giovangrandi Y, Asheuer M, Laurendeau I, Olivi M, Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate Vodovar N, Vidaud D, Vidaud M, Bièche I. Human analysis reveals extensive protein networks responsive to DNA TIP49b/RUVBL2 gene: genomic structure, expression pattern, damage. Science. 2007 May 25;316(5828):1160-6 physical link to the human CGB/LHB gene cluster on chromosome 19q13.3. Ann Genet. 2000 Apr-Jun;43(2):69-74 Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human Wood MA, McMahon SB, Cole MD. An ATPase/helicase TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92 complex is an essential cofactor for oncogenic transformation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30 Rousseau B, Ménard L, Haurie V, Taras D, Blanc JF, Moreau- Gaudry F, Metzler P, Hugues M, Boyault S, Lemière S, Canron

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 258 RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.

X, Costet P, Cole M, Balabaud C, Bioulac-Sage P, Zucman- Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation Rossi J, Rosenbaum J. Overexpression and role of the in response to DNA damage is modulated by TIP49. Int J ATPase and putative DNA helicase RuvB-like 2 in human Biochem Cell Biol. 2009 Apr;41(4):925-33 hepatocellular carcinoma. Hepatology. 2007 Oct;46(4):1108-18 This article should be referenced as such: Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum J. Pontin and reptin, two related ATPases with multiple roles in Grigoletto A, Haurie V, Rosenbaum J. RUVBL2 (RuvB-like 2 cancer. Cancer Res. 2008 Sep 1;68(17):6873-6 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):257-259. Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57

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Gene Section Mini Review

SH3GL2 (SH3-domain GRB2-like 2) Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata 700026, India (CKP, AG, GPM)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/SH3GL2ID44345ch9p22.html DOI: 10.4267/2042/44705 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

recycling of synaptic vesicles. SH3GL2 by its LPAAT Identity activity may induce negative membrane curvature by Other names: CNSA2; EEN-B1; Endophilin-1; converting an inverted cone shaped lipid to a cone FLJ20276; FLJ25015; OTTHUMP00000021084; shaped lipid in the cytoplasmic leaflet of the bilayer. SH3D2A; SH3P4 Through this action, SH3GL2 works with dynamin to HGNC (Hugo): SH3GL2 mediate synaptic vesicle invagination from the plasma membrane and fission. SH3GL2 in complex with CBL Location: 9p22.2 and CIN85 participates in activated EGF receptor Local order: Next to ADAMTSL1 and FAN154A. (Stimulated by EGF) endocytosis from the membrane surface and its subsequent lysosomal degradation. DNA/RNA The SH3 domain of SH3GL2 binds to a 24 amino acid proline rich domain (PRD) in the third intracellular Description loop of the G-protein coupled-1-adrenergic receptor. 10 exons; spans 217.93kb. SH3GL2 overexpression increased isoproterenol- Transcription induced receptor inter-nalization by 25% and decreased coupling of receptor to the G-protein. mRNA of 2483 and 2417bp (there are two transcripts). The SH3 domain of SH3GL2 also binds to a proline rich domain within the cytoplasmic tail of metallo- Protein protease disintegrins, transmembrane glycoproteins acting in cell adhesion and growth factor signaling. Description SH3GL2 binds preferentially to the pro-form found in 352 amino acids; 39.96kDa and 330 amino acids; the trans-Golgi network. Therefore SH3GL2 binding 37.51kDa. may regulate intracellular transit and maturation of Expression metalloprotease disintegrin. Rat germinal centre kinse-like kinase (rGLK), a Highest expression found in brain followed by pituitary serine/threonine cytosolic kinase, interacted with gland and kidney. Expression has also been reported in SH3GL2. rGLK modulated c-Jun N-terminal kinase bladder, eye, heart, cervix, breast, head and neck (JNK) activity by phosphorylation and binds to the tissues etc. SH3 domain of SH3GL2 through a C-terminal proline Localisation rich domain. Coexpression of rGLK and full length Cytoplasmic (diffuse cytoplasmic distribution in resting SH3GL2 increased JNK activity two fold, whereas cells and a colocalization with EGF receptor in coexpression with the SH3 domain of SH3GL2 endocytic vesicles after EGF stimulation). abrogated rGLK-induced JNK activation. SH3GL2, therefore, modulated the mitogen-activated protein Function kinase pathway through physical association with SH3GL2 is a presynaptic protein that binds to dynamin, rGLK. a GTPase that is implicated in endo-cytosis and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 260 SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.

Homology Howard L, Nelson KK, Maciewicz RA, Blobel CP. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3GL2 contains a C-terminal SH3 domain, which SH3 domain-containing proteins, endophilin I and SH3PX1. J shares 92% and 84% amino acid Biol Chem. 1999 Oct 29;274(44):31693-9 with the SH3 domain of SH3GL3 and SH3GL1, Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, respectively. The SH3 domain of SH3GL2 also shows Podtelejnikov AV, Witke W, Huttner WB, Söling HD. Endophilin high homology to the C-terminal SH3 domain of I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature. 1999 Sep GRB2. 9;401(6749):133-41 Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, Mutations DeCamilli P, Lefkowitz RJ. Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1- Somatic adrenergic receptor. Proc Natl Acad Sci U S A. 1999 Oct In SH3GL2, mutation in SH3 domain has only been 26;96(22):12559-64 reported. Huttner WB, Schmidt A. Lipids, lipid modification and lipid- protein interaction in membrane budding and fission--insights from the roles of endophilin A1 and synaptophysin in synaptic Implicated in vesicle endocytosis. Curr Opin Neurobiol. 2000 Oct;10(5):543- Sporadic cancer 51 Ramjaun AR, Angers A, Legendre-Guillemin V, Tong XK, Disease McPherson PS. Endophilin regulates JNK activation through its Reduced expressions of SH3GL2 due to different types interaction with the germinal center kinase-like kinase. J Biol of molecular alterations are involved in tumor Chem. 2001 Aug 3;276(31):28913-9 formation in head and neck, breast and gastric tissues. Reutens AT, Begley CG. Endophilin-1: a multifunctional Prognosis protein. Int J Biochem Cell Biol. 2002 Oct;34(10):1173-7 The prognostic significance of down regulation of Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic SH3GL2 in sporadic tumors is not understood clearly. I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002 Mar Cytogenetics 14;416(6877):183-7 Chromosomal deletions, chromosomal gain or Verstreken P, Kjaerulff O, Lloyd TE, Atkinson R, Zhou Y, amplification and chromosomal breakpoints are Meinertzhagen IA, Bellen HJ. Endophilin mutations block frequent. clathrin-mediated endocytosis but not neurotransmitter release. Cell. 2002 Apr 5;109(1):101-12 Oncogenesis LOH on 9p22 is one of the most frequent events Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G, Zhang JF. Formation of an endophilin-Ca2+ channel complex identified in head and neck tumor, breast carcinoma, is critical for clathrin-mediated synaptic vesicle endocytosis. pituitary adenoma, neuroblastoma etc. However, Cell. 2003 Oct 3;115(1):37-48 promoter methylation appears to be another common Hirayama S, Bajari TM, Nimpf J, Schneider WJ. Receptor- mechanism of SH3GL2 inactivation. mediated chicken oocyte growth: differential expression of endophilin isoforms in developing follicles. Biol Reprod. 2003 Alzheimer disease May;68(5):1850-60 Disease Otsuki M, Itoh T, Takenawa T. Neural Wiskott-Aldrich The increased expression level of SH3GL2 in neuron is syndrome protein is recruited to rafts and associates with linked to an increase in the activation of the stress endophilin A in response to epidermal growth factor. J Biol kinase c-Jun N-terminal kinase with the subsequent Chem. 2003 Feb 21;278(8):6461-9 death of the neuron. Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y, Mochizuki N. Endophilin BAR domain drives membrane Prognosis curvature by two newly identified structure-based mechanisms. SH3GL2 overexpression is now considered as a new EMBO J. 2006 Jun 21;25(12):2889-97 indicator of the progression of Alzhemier disease. Shang C, Fu WN, Guo Y, Huang DF, Sun KL. Study of the SH3-domain GRB2-like 2 gene expression in laryngeal carcinoma. Chin Med J (Engl). 2007 Mar 5;120(5):385-8 Cytogenetics Potter N, Karakoula A, Phipps KP, Harkness W, Hayward R, Increase in aneuploidy or aberration, but chromosomal Thompson DN, Jacques TS, Harding B, Thomas DG, Palmer RW, Rees J, Darling J, Warr TJ. Genomic deletions correlate loss or gain in aneuploid cell was not specific. In some with underexpression of novel candidate genes at six loci in forms of Alzheimer disease, a specific type of pediatric pilocytic astrocytoma. Neoplasia. 2008 aneuploidy-trisomy 21 mosaicism has been reported. Aug;10(8):757-72 Ren Y, Xu HW, Davey F, Taylor M, Aiton J, Coote P, Fang F, References Yao J, Chen D, Chen JX, Yan SD, Gunn-Moore FJ. Endophilin I expression is increased in the brains of Alzheimer disease Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella Valle G, patients. J Biol Chem. 2008 Feb 29;283(9):5685-91 Migone N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Sinha S, Chunder N, Mukherjee N, Alam N, Roy A, Genomics. 1997 May 1;41(3):427-34 Roychoudhury S, Kumar Panda C. Frequent deletion and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 261 SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.

methylation in SH3GL2 and CDKN2A loci are associated with This article should be referenced as such: early- and late-onset breast carcinoma. Ann Surg Oncol. 2008 Apr;15(4):1070-80 Panda CK, Ghosh A, Maiti GP. SH3GL2 (SH3-domain GRB2- like 2). Atlas Genet Cytogenet Oncol Haematol. 2010; Ghosh A, Ghosh S, Maiti GP, Sabbir MG, Alam N, Sikdar N, 14(3):260-262. Roy B, Roychoudhury S, Panda CK. SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit. J Pathol. 2009 Feb;217(3):408-19

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Gene Section Review

TOPORS (topoisomerase I binding, arginine/serine-rich) Jafar Sharif, Asami Tsuboi, Haruhiko Koseki Developmental Genetics Group, RIKEN Center for Allergy and Immunology (RCAI), Suehirocho 1-7-22, Tsurumi-ku, Yokohama-shi, Kanagawa-ken, Japan 230-0045 (JS, AT, HK)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/TOPORSID42663ch9p21.html DOI: 10.4267/2042/44706 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Pseudogene None reported. Other names: EC 6.3.2.-; LUN; OTTHUMP00000021182; OTTHUMP00000021184; Protein OTTHUMP00000045227; P53BP3; RP31; TP53BPL; p53BP3 Description HGNC (Hugo): TOPORS TOPORS transcript 1 encodes a protein containing Location: 9p21.1 1,045 amino acids (ENSP00000353735). TOPORS transcript 2 encodes a protein containing 980 DNA/RNA amino acids (ENSP00000369187). The 1045aa human TOPORS contains a RING family Description zinc-finger domain and a (LZ) domain in Spans approximately 8kbs of DNA in the reverse strand the N-terminal. It also possesses a C-terminal bipartite of . nuclear localization signal (NLS), five sequences rich in proline, glutamine, serine and threonine (PEST Transcription sequences) and an arginine rich domain. Two splicing variants. Transcript 1 (ENST00000360538): Transcript length Expression 4145 bps, three exons, first one non-coding. Widely expressed. Transcript 2 (ENST00000379858): Transcript length Localisation 3,621 bps, two exons, first one non-coding. Nucleus.

The two splicing variants of TOPORS are shown. Transcript 1 (ENST00000360538) has three exons, the first one non-coding. Transcript 2 (ENST00000379858) has two exons, the first one non-coding. The coding regions are shown in yellow boxes and the non-coding regions (untranslated regions, UTRs) are shown in open boxes.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 263 TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.

dominant retinitis pigmentosa (Bowne et al., 2008). Another study reported that mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy (Chakarova et al., 2007). Valuable information on the cellular roles for TOPORS came through several biochemical studies. It was shown that in the nucleus TOPORS undergoes SUMO- 1 modifications (Weger et al., 2003). Interestingly, Homology between murine Topors and human TOPORS is TOPORS itself has the ability to sumoylate other shown. The N-terminal Ring-finger (RF, red) and leucine zipper proteins by functioning as a SUMO-1 E3 ligase. For (LZ, green) domains show 93% homology and the C-terminal example, TOPORS can sumoylate p53 and the nuclear localization signal (NLS, blue) domain shows 90% homology between mouse and human. The P53 binding chromatin modifying protein Sin3A (Shinbo et al., regions of TOPORS, located inside the NLS domain, are 2005; Weger et al., 2005; Pungaliya et al., 2007). highlighted with red lines. Furthermore, TOPORS induce the accumulation of Function polysumoylated forms of DNA topoisomerase I in vitro and in vivo (Hammer et al., 2007). Intriguingly, apart The RING finger protein TOPORS contains a RING from its role as a SUMO-1 E3 ligase, TOPORS can family zinc-finger domain, a putative leucine zipper also function as an E3 ubiquitin ligase. In fact, (LZ) domain, five sequences rich in proline, glutamine, TOPORS was the first example of a protein that serine and threonine (PEST sequences), an possesses dual-roles as an E3 ligase for sumoylation arginine/serine (RS) domain and a bipartite nuclear and ubiquitination of other proteins. It was reported localization signal (NLS). TOPORS was first identified that Topors works as an E3 ubiquitin ligase with as a human topoisomerase I-interacting protein by yeast specific E2 enzymes to ubiquitinate the p53 protein and two-hybrid screening (Haluska et al., 1999). TOPORS the prostrate tumor suppressor protein NKX3.1 is localized in the nucleus and has been reported to be (Rajendra et al., 2004; Guan et al., 2008). Intense closely associated with the PML bodies (Weger et al., investigations have been undertaken in recent years to 2003; Rasheed et al., 2002). An important role of elucidate the mechanisms of molecules that have dual TOPORS is its ability to interact with the tumor E3 ligase activities for sumoylation and ubiquitination suppressor protein P53 (Zhou et al., 1999). Forced such as TOPORS. These studies have discovered a new expression of murine Topors during DNA damage family of proteins, designated as the small ubiquitin- stabilizes p53, enhances the p53-dependent related modifier (SUMO)-targeted ubiquitin ligases transcriptional activities of waf1, MDM2 and Bax (STUbLs), which directly links sumoylation and waf1 promoters and elevates the level of endogenous p21 ubiquitination (Perry et al., 2008). It has been mRNA (Lin et al., 2005). These findings suggest an suggested that similar to STUbLs, TOPORS may be anti-oncogenic role for TOPORS. Indeed, it was shown recruited to its targets through SUMO-associated that TOPORS expression is decreased or undetectable interactions and stimulate their ubiquitination in a in colon adenocarcinomas relative to normal colon RING finger-dependent manner (Perry et al., 2008). tissue, and the protein level of TOPORS is undetected Furthermore, TOPORS has been connected with in several colon cancer cell lines (Saleem et al., 2004). transcriptional regulation because of its role as an E3 Repression of TOPORS expression was also reported ubiquitin ligase. In drosophila, the homolog of human in progression and development of non-small cell lung TOPORS (dTopors) ubiquitinates the Hairy cancer (Oyanagi et al., 2004). transcriptional repressor, suggesting that TOPORS Furthermore, loss of heterozygosity in the region 9p21, could be involved in regulating other transcription the chromosomal locus harboring TOPORS, has been factors as well (Secombe et al., 2004). Indeed, it was frequently associated with different malignancies (Puig shown that TOPORS interacts with the adeno- et al., 2005). A high-resolution genomewide mapping associated virus type 2 (AAV-2) Rep78/68 proteins and study identified deletion of the TOPORS genomic enhances the expression of a Rep78/68 dependent locus in human glial tumors, suggesting a possible role AAV-2 gene in the absence of the helper virus (Weger for TOPORS in gliomagenesis (Bredel et al., 2005). A et al., 2002). Finally, it was shown that drosophila missense mutation in the TOPORS gene was dTopors was required for the nuclear organization of a implicated in autosomal dominant pericentral retinal chromatin insulator, suggesting a role for TOPORS in dystrophy, showing that mutations in the TOPORS regulation of the chromatin (Capelson et al., 2005). gene can lead to genetic disorders (Selmer et al., 2009). Concomitant with these observations, point mutations Homology and small insertions and deletions in the TOPORS gene Widely conserved among different species. Murine was found to cause approximately 1% of autosomal Topors shows high similarity with human TOPORS.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 264 TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.

gene expression was down-regulated in smokers Mutations (Oyanagi et al., 2004). These findings show that there Germinal is a reverse correlation between NSCLC and TOPORS expression and suggest that TOPORS may act as a TOPORS has been implicated in autosomal dominant tumor sup-pressor gene for lung cancers. pericentral retinal dystrophy (adPRD), an atypical form of retinitis pigmentosa. Retinitis pigmentosa is the Glial brain tumor collective name for a group of genetically induced eye Disease disorders that are frequenctly associated with night Glial brain tumors arise from glial cells and are highly blindness and tunnel vision. The TOPORS gene was lethal. Glial brain tumors include astrocytomas, sequenced in 19 affected members of a large oligodendrogliomas and oligoastro-cytomas. Norwegian family. A novel missense mutation, Oncogenesis c.1205a>c, resulting in an amino acid substitution p.Q402P, was found in all of the cases. Furthermore, A recent study investigated copy number alterations of the mutation showed complete co-segregation with the 42,000 mapped human cDNA clones in a series of 54 disease in the family, with the LOD score of 7.3. This gliomas of varying histogenesis and tumor grade by mutation was not detected in 207 unrelated and healthy comparative genomic hybridization technology. This Norwegian subjects (Selmer et al., 2009). A separate study reported a set of genetic alterations study showed that mutations in the TOPORS gene are predominantly associated with either astrocytic or responsible for autosomal dominant retinitis oligodendrocytic tumor phenotype. Among these pigmentosa (adRP). Mutations that included an genetic alterations, a minimally deleted region insertion and a deletion were identified in two adRP- containing the TOPORS gene was identified, affected families (Chakarova et al., 2007). Finally, suggesting a role for TOPORS in gliomagenesis another recent study investigated whether mutation(s) (Bredel et al., 2005). in the TOPORS gene is associated with autosomal Colon cancer dominant retinitis pigmentosa (adRP). The frequency Disease of TOPORS mutation was analyzed in an adRP cohort Cancerous growth in colon, rectum or the appendix are of 215 families and two different mutations, namely, collectively addressed as colon cancer or colorectal p.Glu808X and p.Arg857GlyfsX9, were identified. cancer. This is the third most frequent form of cancer This study concluded that point mutations and small and a major cause of cancer-related death all over the insertions or deletions in TOPORS may cause world. approximately 1% of adRP (Bowne et al., 2008). Oncogenesis Implicated in TOPORS expression is decreased or undetected in colon adenocarcinomas compared to normal colon Non-small cell lung cancer (NSCLC) tissues. Furthermore, TOPORS protein is not detectable Disease in several colon cancer cell lines, suggesting an anti- oncogenic role for TOPORS (Saleem et al., 2004). Non-small cell lung cancer (NSCLC) is the major form of lung cancer, with a frequency of 80~90% of all lung Autosomal dominant retinitis carcinomas. NSCLCs are usually classified into three pigmentosa (adRP) groups, namely, squamous cell carcinoma, Disease adenocarcinoma and large-cell carci-noma. The Autosomal dominant retinitis pigmentosa (adRP) is a squamous cell carcinoma is linked with smoking and form of retinitis pigmentosa, a collective title for a accounts for approximately 25~30% of all lung group of genetically induced eye disorders that are cancers, which are usually found in the middle of the frequenctly associated with night blindness and tunnel lungs or near a bronchus. Adenocarci-noma is vision. frequently spotted in the outer part of the lungs and is thought to be responsible for ~40% of all lung cancers. Prognosis About 10~15% of lung cancers are large-cell Mutations and small insertions or deletions of the carcinomas, which can start in any part of the lung and TOPORS gene have been associated with adRP. has the ability to grow and spread quickly, making this TOPORS has been associated with autosomal dominant type of lung cancers difficult to treat. pericentral retinal dystrophy (adPRD), which has a Oncogenesis favorable prognosis compared to classical retinitis pigmentosa (RP). A novel mis-sense mutation, Expression of TOPORS was found to be signifi-cantly c.1205a>c, resulting in an amino acid substitution repressed in lung cancer tissues compared to normal p.Q402P, was observed in all affected members of a lung tissues. TOPORS gene expression was slightly large Norweigian family (Selmer et al., 2009). In down-regulated along with progression of primary another study, an adRP cohort of 215 families was tumors, and strongly downregulated along with nodal investigated and two different mutations, namely, metastases. Interestingly, in normal tissues TOPORS

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 265 TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.

p.Glu808X and p.Arg857GlyfsX9, were identified Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD, (Bowne at al., 2008). TOPORS has also been Sikic BI. High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res. 2005 May implicated in autosomal dominant retinitis pigmentosa 15;65(10):4088-96 with perivascular retinal pigment atrophy, a disorder Capelson M, Corces VG. The ubiquitin ligase dTopors directs that showed a distinct phenotype at the earlier stage of the nuclear organization of a chromatin insulator. Mol Cell. the disease, with an unusual perivascular cuff of retinal 2005 Oct 7;20(1):105-16 pigment epithelium atrophy, which was found Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, surrounding the superior and inferior arcades in the Zhang JH, Simonds WF, Nakagawara A, Koseki H. topors, a retina. This study reported mutations in the TOPORS p53 and topoisomerase I-binding RING finger protein, is a gene that included an insertion and a deletion was coactivator of p53 in growth suppression induced by DNA identified in two adRP-affected families (Chakarova et damage. Oncogene. 2005 May 12;24(21):3385-96 al., 2007). Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. References Int J Oncol. 2005 Mar;26(3):641-8 Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 Puig S, Ruiz A, Lázaro C, Castel T, Lynch M, Palou J, Vilalta E3 ligase for p53 in vitro and in vivo. FEBS Lett. 2005 Sep A, Weissenbach J, Mascaro JM, Estivill X. Chromosome 9p 12;579(22):5007-12 deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 Chakarova CF, Papaioannou MG, Khanna H, Lopez I, (CDKN2) gene. Am J Hum Genet. 1995 Aug;57(2):395-402 Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott de Q, Haluska P Jr, Saleem A, Rasheed Z, Ahmed F, Su EW, Liu LF, Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP, Rubin EH. Interaction between human topoisomerase I and a Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, novel RING finger/arginine-serine protein. Nucleic Acids Res. Swaroop A, Koenekoop RK, Bhattacharya SS. Mutations in 1999 Jun 15;27(12):2538-44 TOPORS cause autosomal dominant retinitis pigmentosa with Zhou R, Wen H, Ao SZ. Identification of a novel gene encoding perivascular retinal pigment epithelium atrophy. Am J Hum a p53-associated protein. Gene. 1999 Jul 22;235(1-2):93-101 Genet. 2007 Nov;81(5):1098-103 Rasheed ZA, Saleem A, Ravee Y, Pandolfi PP, Rubin EH. The Hammer E, Heilbronn R, Weger S. The E3 ligase Topors topoisomerase I-binding RING protein, topors, is associated induces the accumulation of polysumoylated forms of DNA with promyelocytic leukemia nuclear bodies. Exp Cell Res. topoisomerase I in vitro and in vivo. FEBS Lett. 2007 Nov 2002 Jul 15;277(2):152-60 27;581(28):5418-24 Weger S, Hammer E, Heilbronn R. Topors, a p53 and Pungaliya P, Kulkarni D, Park HJ, Marshall H, Zheng H, topoisomerase I binding protein, interacts with the adeno- Lackland H, Saleem A, Rubin EH. TOPORS functions as a associated virus (AAV-2) Rep78/68 proteins and enhances SUMO-1 E3 ligase for chromatin-modifying proteins. J AAV-2 gene expression. J Gen Virol. 2002 Mar;83(Pt 3):511-6 Proteome Res. 2007 Oct;6(10):3918-23 Oyanagi H, Takenaka K, Ishikawa S, Kawano Y, Adachi Y, Bowne SJ, Sullivan LS, Gire AI, Birch DG, Hughbanks- Ueda K, Wada H, Tanaka F. Expression of LUN gene that Wheaton D, Heckenlively JR, Daiger SP. Mutations in the encodes a novel RING finger protein is correlated with TOPORS gene cause 1% of autosomal dominant retinitis development and progression of non-small cell lung cancer. pigmentosa. Mol Vis. 2008 May 19;14:922-7 Lung Cancer. 2004 Oct;46(1):21-8 Guan B, Pungaliya P, Li X, Uquillas C, Mutton LN, Rubin EH, Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Bieberich CJ. Ubiquitination by TOPORS regulates the Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin prostate tumor suppressor NKX3.1. J Biol Chem. 2008 Feb EH. Topors functions as an E3 ubiquitin ligase with specific E2 22;283(8):4834-40 enzymes and ubiquitinates p53. J Biol Chem. 2004 Aug Perry JJ, Tainer JA, Boddy MN. A SIM-ultaneous role for 27;279(35):36440-4 SUMO and ubiquitin. Trends Biochem Sci. 2008 Saleem A, Dutta J, Malegaonkar D, Rasheed F, Rasheed Z, May;33(5):201-8 Rajendra R, Marshall H, Luo M, Li H, Rubin EH. The Selmer KK, Grøndahl J, Riise R, Brandal K, Braaten O, topoisomerase I- and p53-binding protein topors is differentially Bragadottir R, Undlien DE. Autosomal dominant pericentral expressed in normal and malignant human tissues and may retinal dystrophy caused by a novel missense mutation in the function as a tumor suppressor. Oncogene. 2004 Jul TOPORS gene. Acta Ophthalmol. 2010 May;88(3):323-8 8;23(31):5293-300 Secombe J, Parkhurst SM. Drosophila Topors is a RING This article should be referenced as such: finger-containing protein that functions as a ubiquitin-protein Sharif J, Tsuboi A, Koseki H. TOPORS (topoisomerase I isopeptide ligase for the hairy basic helix-loop-helix repressor binding, arginine/serine-rich). Atlas Genet Cytogenet Oncol protein. J Biol Chem. 2004 Apr 23;279(17):17126-33 Haematol. 2010; 14(3):263-266.

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in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Yoshiro Suzuki, Matthias A Hediger Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland (YS, MAH)

Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/TRPV6ID44425ch7q34.html DOI: 10.4267/2042/44707 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

The regions encoding the ankyrin repeats, 6 trans- Identity membrane domains and a pore region are indicated. Other names: CaT1; ECaC2; CATL; ABP/ZF; Several VDREs (vitamin D responsive element) have LP6728; ZFAB been identified in its promoter region. HGNC (Hugo): TRPV6 A haplotype containing 3 non-synonymous polymorphisms (C157R+M378V+M681T) repre-sent a Location: 7q34 recent positive selection in human evolution. The same Local order: Colocalized with another Ca2+-selective haplotype seems to be associated with renal calcium epithelial channel gene, TRPV5. stone formation. DNA/RNA Transcription There is an alterative splice variant which missed 25- Description 192 (a.a.). In EST database, there seems to be at least TRPV6 gene consists of 15 exons and 14 introns one more variant using different exon 1 (V2) and a including a coding, and a 5'-/3'- non-coding region. variant starting from another site (P3) just upstream of exon 2 (V3).

Schematic representation of human TRPV6 gene and neighbouring genes.

Genomic structure of human TRPV6. The coding region is shown by open bars. The non-translated regions are shown by filled bars.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 267 TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA

increase in proliferation and apoptotic resistance in cancer cells. Protein Homology 73% identity with human TRPV5. 89% identity with mouse TRPV6. Implicated in Prostate cancer Oncogenesis Expression of TRPV6 may be a predictor for prostate cancer progression since TRPV6 mRNA and protein levels are elevated in prostatic carcinoma compared to benign prostatic hyperplasia and positively correlated with Gleason grade/score in prostatic carcinoma. TRPV6 is involved in an increase in proliferation and apoptotic resistance in cancer cells, suggesting that Schematic representation of TRPV6 protein. Four subunits makes one channel pore. Several ankyrin repeats, one N- TRPV6 could be a new therapeutic target for the glycosylation site and several calmodulin binding sites (CaM) treatment for advanced prostate cancer. are indicated. Breast cancer Description Oncogenesis Glycosylated membrane protein (725 a.a., MW ~70 TRPV6 mRNA was also found to be increased in breast kDa) with 6 transmembrane regions and a pore-forming cancer tissues compared to normal breast tissues. loop. N- and C-terminal tails are in cytoplasmic side. TRPV6 could be a prognostic marker for breast cancer 2+- This protein forms a Ca selective ion channel in the and therapeutic target for breast cancer treatment. plasma membrane. TRPV6 interacts with calmodulin which contribute to the intracellular References Ca2+-dependent inactivation to avoid an increase 2+ Hediger MA, Peng JB, Brown EM Inventors.. Compositions of free Ca concentration. The ankyrin repeats Corresponding to a Calcium Transporter and Methods of may play a role in the interaction between Making and Using Same. US patent 6,534,642. subunits. TRPV6 can form a homo-tetramer as Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, well as a hetero-tetramer with TRPV5, which Brown EM, Hediger MA. Molecular cloning and characterization of a channel-like transporter mediating exhibits distinct channel properties. intestinal calcium absorption. J Biol Chem. 1999 Aug Expression 6;274(32):22739-46 Highly expressed in placenta, moderately expressed in Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium exocrine pancreas, mammary gland and salivary gland. transport protein CaT1. Biochem Biophys Res Commun. 2000 Highly induced in small intestine under low calcium Nov 19;278(2):326-32 conditions or by 1,25-dihydroxyvitamin D3 treatment. Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Highly induced in prostate, breast and other cancer Competitive regulation of CaT-like-mediated Ca2+ entry by tissues during tumor progression. protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5 Localisation Peng JB, Brown EM, Hediger MA. Structural conservation of Plasma membrane. Localized in the apical membrane the genes encoding CaT1, CaT2, and related cation channels. of the epithelial cells in the duodenum, and Genomics. 2001 Aug;76(1-3):99-109 syncytiotrophoblasts in placenta. Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown Function EM, Hediger MA, Freeman MR. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Apical Ca2+ entry pathway for total body calcium Commun. 2001 Apr 6;282(3):729-34 homeostasis in the small intestine under the control of Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans 1,25-dihydroxyvitamin D3. TRPV6 likely also be I, Van Herck E, Kato S, Bindels RJ, Collen D, Carmeliet P, involved in the placental Ca2+ transport from mother to Bouillon R, Carmeliet G. Duodenal calcium absorption in fetus to maintain fetal bone mineralization. -knockout mice: functional and molecular 2+ aspects. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13324- TRPV6 may play a role in the Ca entry pathway 9 essential for keratinocyte differentiation. Although its exact function in cancer cells and tumor progression is Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. still under investigation, TRPV6 is involved in an Expression of CaT-like, a novel calcium-selective channel,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 268 TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA

correlates with the malignancy of prostate cancer. J Biol Chem. Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos 2001 Jun 1;276(22):19461-8 CH, Zhuang L, Freeman MR, Gouveia CH, Wu J, Luo H, Mauro T, Brown EM, Hediger MA. Marked disturbance of Nilius B, Prenen J, Hoenderop JG, Vennekens R, Hoefs S, calcium homeostasis in mice with targeted disruption of the Weidema AF, Droogmans G, Bindels RJ. Fast and slow Trpv6 calcium channel gene. J Bone Miner Res. 2007 inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 Feb;22(2):274-85 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3. J Biol Chem. Lehen'kyi V, Beck B, Polakowska R, Charveron M, Bordat P, 2002 Aug 23;277(34):30852-8 Skryma R, Prevarskaya N. TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger keratinocytes. J Biol Chem. 2007 Aug 3;282(31):22582-91 MA, Freeman MR. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is Lehen'kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6 aberrantly expressed in human malignancies. Lab Invest. 2002 channel controls prostate cancer cell proliferation via Dec;82(12):1755-64 Ca(2+)/NFAT-dependent pathways. Oncogene. 2007 Nov 15;26(52):7380-5 Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H. Expression of the Ca2+-selective cation channel TRPV6 in Bolanz KA, Hediger MA, Landowski CP. The role of TRPV6 in human prostate cancer: a novel prognostic marker for tumor breast carcinogenesis. Mol Cancer Ther. 2008 Feb;7(2):271-9 progression. Oncogene. 2003 Oct 30;22(49):7858-61 Hughes DA, Tang K, Strotmann R, Schöneberg T, Prenen J, Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius Nilius B, Stoneking M. Parallel selection on TRPV6 in human B, Bindels RJ. Homo- and heterotetrameric architecture of the populations. PLoS One. 2008 Feb 27;3(2):e1686 epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003 Feb 17;22(4):776-85 Stumpf T, Zhang Q, Hirnet D, Lewandrowski U, Sickmann A, Wissenbach U, Dörr J, Lohr C, Deitmer JW, Fecher-Trost C. Moreau R, Simoneau L, Lafond J. Calcium fluxes in human The human TRPV6 channel protein is associated with trophoblast (BeWo) cells: calcium channels, calcium-ATPase, cyclophilin B in human placenta. J Biol Chem. 2008 Jun and sodium-calcium exchanger expression. Mol Reprod Dev. 27;283(26):18086-98 2003 Feb;64(2):189-98 Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. Hediger MA. Calcium channel TRPV6 is involved in murine Ca2+-selective transient receptor potential V channel maternal-fetal calcium transport. J Bone Miner Res. 2008 architecture and function require a specific ankyrin repeat. J Aug;23(8):1249-56 Biol Chem. 2004 Aug 13;279(33):34456-63 Suzuki Y, Landowski CP, Hediger MA. Mechanisms and Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption regulation of epithelial Ca2+ absorption in health and disease. across epithelia. Physiol Rev. 2005 Jan;85(1):373-422 Annu Rev Physiol. 2008;70:257-71 Akey JM, Swanson WJ, Madeoy J, Eberle M, Shriver MD. Suzuki Y, Pasch A, Bonny O, Mohaupt MG, Hediger MA, Frey TRPV6 exhibits unusual patterns of polymorphism and FJ. Gain-of-function haplotype in the epithelial calcium channel divergence in worldwide populations. Hum Mol Genet. 2006 Jul TRPV6 is a risk factor for renal calcium stone formation. Hum 1;15(13):2106-13 Mol Genet. 2008 Jun 1;17(11):1613-8

Meyer MB, Watanuki M, Kim S, Shevde NK, Pike JW. The This article should be referenced as such: human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that Suzuki Y, Hediger MA. TRPV6 (transient receptor potential mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cation channel, subfamily V, member 6). Atlas Genet cells. Mol Endocrinol. 2006 Jun;20(6):1447-61 Cytogenet Oncol Haematol. 2010; 14(3):267-269.

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Gene Section Review

ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Shian-Ying Sung Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan (SYS)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html DOI: 10.4267/2042/44708 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

mitotic arrest deficient 2beta. ADAM9 has implicated Identity mediated by stress, such as oxidation during Other names: MDC9; Meltrin-gamma; MLTNG; inflammation and cancer progression. MCMP; KIAA0021 HGNC (Hugo): ADAM9 DNA/RNA Location: 8p11.23 Note Local order: TACC1 - PLEKHA2 - HTRA4 - TM2D2 The ADAM9 gene transcript 2 isoforms of mRNA with - ADAM9 - ADAM32 - ADAM5p - ADAM3A - altered splicing results the lost of exon 18 in the second ADAM18 - ADAM2; TACC1; 8P11; Transforming, isoform of ADAM9 mRNA and early stop codon. acidic coiled-coil containing protein 1; PLEKHA2; Description 8P11.23; Pleckstrin homology domain containing, ADAM9 gene extends 108,276 base pairs with 22 family A member 2; HTRA4; 8P11.23; HtrA serine exons which gives rise to 2 different ADAM9 trans- peptidase 4; TM2D2; 8P11.23; TM2 domain containing cripts with differential splicing. The mRNA of 2; ADAM9; 8P11.23; a disintegrin and ADAM9 isoform 1 is 4111 and isoform 2 is metalloproteinase domain 9; ADAM32; 8p11.23; 4005. ADAM9 isoform 2 lacks exon 18 of iso-form 1 ADAM metalloproteinase domain 32; ADAM5P; in the coding region, which results in a frameshift and 8p11.23; ADAM metallopeptidase domain 5 an early stop codon. The isoform 2 lacks the c-terminal pseudogene; ADAM3A; 8p11.23; ADAM transmembrane and cyto-plasmic domains and is a metallopeptidase domain 3A (Cyritestin 1); ADAM18; secreted form. 8p11.22; ADAM metallopeptidase domain 18; ADAM2; 8p11.22; ADAM metallopeptidase domain 2. Transcription Note Isoform 1 mRNA of ADAM9 (NM_003816) has a size The ADAM9 gene, a member of the ADAM super- of 4111 bp, isoform 2 mRNA (NM_001005845) has a family has metalloprotease, integrin binding and cell size of 4005 bp. ADAM9 mRNA is equally expressed adhesion capacities. It shown the metallo-protease in many tissue. Among cancer progression, ADAM9 domain cleaves insulin beta-chain, TNF-alpha, gelatin, mRNA is relatively highly expressed in prostate cancer beta-casein, fibronectin, as well as shedding of EGF, and breast cancer. However, little is known of HB-EGF and FGFR2IIIB. The integrin domain differential expression between different isoform of mediates cellular adhesion through alpha6beta1 and ADAM9. alphavbeta5 integrins. The cytoplasmic tail of ADAM9 Pseudogene has been reported to interact with endophilin 1 (SH3GL2), SH3PX1 and No pseudogene has reported for ADAM9.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 270 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY

ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19.

alteration and lost of exon 18 of ADAM9 causes lost of Protein transmembrane domain and early stop in soluble form Note of ADAM9. Two different isoform of ADAM9 was reported, the Localisation full length and soluble form of ADAM9. Recent report Full length has N-terminal signal peptide and a single suggests promoter polymorphisms regulated ADAM9 hydrophobic region predicted to be transmembrane transcription that plays a protective role against domain. Hence, the full length of ADAM9 is localized Alzheimer's disease. to the plasma membrane. Soluble ADAM9 lack the Description transmembrane domain and cytoplasmic domain and to The predicted molecular mass of ADAM9 is about 84 be released out of cell. KDa. ADAM9 contained coding sequence of 2460 Function nucleotides which encoding amino acid of 819 1. Ectodomain shedding: Metalloproteinase domain of residues. The full length of active ADAM9 contained ADAM9 is zinc dependent. Metallo-proteinase has several functional regions including metalloproteinase, been showed to involve ectodomain shedding (see table disintegrin, cystein rich, EGF-like, transmembrane and below). One such protein is the heparin-binding EGF- cytoplasmic domains. The pro-domain of ADAM9 was like growth factor (HB-EGF) and amyloid precursor removed by furin-type convertase during ADAM9 protein (APP). translocated onto membrane and become active form. 2. Matrix Degradation: purified metalloproteinase Recent reports indicated soluble form of ADAM9 domain of ADAM9 showed the ability to digest cloned from human cDNA library that showed fibronectin, gelatin and beta-casein. Secreted form of increased of cancer invasion in malignant progression. ADAM9 showed the ability to digest laminin and Expression promote cancer invasion. ADAM9 is ubiquitously expressed. SAGE analyses of 3. Cell contact: ADAM9 specifically bind to integrin ADAM9 expression demonstrated that ADAM9 is alpha6beta1, a laminin receptor, via disintegrin region of expressed in the bone marrow, lymph node, brain, ADAM9 through non-RGD mechanism. ADAM9 also retina, heart, skin, muscle, lung, prostate, breast and have been implicated in binding of avbeta5 in divalent placenta. Increased expression of ADAM9 was cation dependent condition, suggests ADAM9 can reported in several cancers, including gastric, breast, function as adhesion molecule for cell-cell and cell- prostate, colon, and pancreatic cancers. Splicing martrix interaction. Secreted form of ADAM9 binds directly to alpha6beta4 and alpha2beta1 integrin and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 271 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY

Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell. ability to cleave laminin and promote cancer Homology progression. The table below gives homology between the human 4. Cysteine-Rich domain: The ADAM Cysteine-rich ADAM9 and others organisms. domain is not found in other organisms, such as virus, archaeal, bacterial or plant. The function of cysteine- rich domain might involved in complement the binding Mutations ability of disintegrin-mediated interactions. Note Single nucleotide polymorphosim analyses of TABLE: Substrate and Peptide Sequence Cleaved. demonstrated about 356 SNP in the Peptide sequence cleaved chromosome 8p11.23. Most of them are located in Substrate (*: cleave site) intron of ADAM9. No mutation was reported in ADAM9 coding sequence. Recent evidence sug-gests Amyloid promoter polymorphisms that may upregulate ADAM9 precursor EVHH*QKLVFFAE transcription, such as -1314C has higher of protein transcription activities. TNF-a SPLA*QAVRS*SSR P75 TNF SMAPGAVH*LPQP receptor c-kit ligand LPPVA*A*S*SLRND Insulin B LVEALY*LVCGERGFFY*TPKA Chain

HB-EGF GLSLPVE*NRLYTYD

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 272 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY

ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T.

demonstrated copy number abnormalities occurred in Implicated in ADAM9 gene. Prostate cancer Lung cancer Note Note ADAM9 has been implicated in prostate cancer The increased of ADAM9 expression in lung cancer progression and the production of reactive oxygen enhanced cell adhesion and invasion of non-small cell species. Large cohort of clinic evaluation demonst- lung cancer through change adhesion properties and rated ADAM9 is upregulated in prostate cancer in both sensitivity to growth factors, and increase its capacity mRNA and protein level. ADAM9 protein expression of brain metastasis. can be upregulated by androgen in AR-positive but not in AR-negative prostate cancer cells that is through Renal cell carcinoma downstream ROS as mediator to induce ADAM9 Note expression. ADAM9 protein expression is associated ADAM9 was implicated increased expression in renal with shortened PSA-relapse-free survival in clinic cell carcinoma and associated with tumor progression. evaluation. It also showed higher of ADAM9 expression is Pancreatic cancer associated with shorten patient survival rate. Note Alzheimer's disease Pancreatic ductal adenocarcinomas showing increased Note of ADAM9 expression in microarray analyses and The amyloid precursor protein (APP) of Alzheimer's clinic evaluation that correlated with poor tumor disease is a transmembrane protein processed via either differentiation and shorter overall survival rate. the non-amyloidogenic or amyloidogenic pathways. In Breast cancer the non-amyloidogenic pathway, alpha-secretase cleaves APP within the Abeta peptide region releasing Note a large soluble fragment sAPPalpha that has ADAM9 expression is 24% positive in normal breast neuroprotective properties. In the amyloidogenic tissue and 66% positive in breast carcinomas. Western pathway, beta-secretase and gamma-secretase blot studies demonstrated multiform of ADAM9 were sequentially cleave APP to generate the intact Abeta expressed in breast carcinoma. In addition, recent study peptide, which is neurotoxic.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 273 ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY

In ADAM9 expression analyses showed increase in Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical production of sAPPalpha upon phorbol ester treatment function for ADAM9 in mouse prostate cancer. Cancer Res. 2005 Oct 15;65(20):9312-9 of cell that co-express of ADAM9 and APP. ADAM9 did not cleave at the Lys16-Leu17 bone but at the Chin K, DeVries S, Fridlyand J, Spellman PT, et al. Genomic and transcriptional aberrations linked to breast cancer His14-Gln15 bone in the Abeta domain of APP cleave pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41 site. Hence, ADAM9 might play role in protective against sporadic Alzheimer's disease. Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y, Yano M, Matsuura N, Monden M, Higashiyama S. Overexpression of ADAM9 enhances growth factor-mediated References recycling of E-cadherin in human colon cancer cell line HT29 cells. Exp Cell Res. 2006 Feb 1;312(3):331-9 Shuttleworth A. Violence to healthcare staff must be tackled nationally. Prof Nurse. 1992 Jun;7(9):560 Sung SY, Kubo H, Shigemura K, Arnold RS, Logani S, et al. Oxidative stress induces ADAM9 protein expression in human Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, et al. A prostate cancer cells. Cancer Res. 2006 Oct 1;66(19):9519-26 metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and shedding of membrane-anchored heparin-binding EGF-like progression. Cancer Sci. 2007 May;98(5):621-8 growth factor. EMBO J. 1998 Dec 15;17(24):7260-72 Shigemura K, Sung SY, Kubo H, Arnold RS, Fujisawa M, Nelson KK, Schlöndorff J, Blobel CP. Evidence for an Gotoh A, Zhau HE, Chung LW. Reactive oxygen species interaction of the metalloprotease-disintegrin tumour necrosis mediate - and serum starvation-elicited factor alpha convertase (TACE) with mitotic arrest deficient 2 downstream signaling of ADAM9 expression in human prostate (MAD2), and of the metalloprotease-disintegrin MDC9 with a cancer cells. Prostate. 2007 May 15;67(7):722-31 novel MAD2-related protein, MAD2beta. Biochem J. 1999 Nov Fritzsche FR, Jung M, Tölle A, Wild P, Hartmann A, et al. 1;343 Pt 3:673-80 ADAM9 expression is a significant and independent prognostic Cao Y, Kang Q, Zhao Z, Zolkiewska A. Intracellular processing marker of PSA relapse in prostate cancer. Eur Urol. 2008 of metalloprotease disintegrin ADAM12. J Biol Chem. 2002 Jul Nov;54(5):1097-106 19;277(29):26403-11 Fritzsche FR, Wassermann K, Jung M, Tölle A, Kristiansen I, Hotoda N, Koike H, Sasagawa N, Ishiura S. A secreted form of Lein M, Johannsen M, Dietel M, Jung K, Kristiansen G. human ADAM9 has an alpha-secretase activity for APP. ADAM9 is highly expressed in renal cell cancer and is Biochem Biophys Res Commun. 2002 May 3;293(2):800-5 associated with tumour progression. BMC Cancer. 2008 Jun 26;8:179 Grützmann R, Foerder M, Alldinger I, Staub E, Brümmendorf T, Röpcke S, Li X, Kristiansen G, Jesnowski R, Sipos B, Löhr Boelens MC, Kok K, van der Vlies P, van der Vries G, Sietsma M, Lüttges J, Ockert D, Klöppel G, Saeger HD, Pilarsky C. H, Timens W, Postma DS, Groen HJ, van den Berg A. Gene expression profiles of microdissected pancreatic ductal Genomic aberrations in squamous cell lung carcinoma related adenocarcinoma. Virchows Arch. 2003 Oct;443(4):508-17 to lymph node or distant metastasis. Lung Cancer. 2009 Dec;66(3):372-8 Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. Oxidative and osmotic stress signaling in tumor cells is Dijkstra A, Postma DS, Noordhoek JA, Lodewijk ME, Kauffman mediated by ADAM proteases and heparin-binding epidermal HF, ten Hacken NH, Timens W. Expression of ADAMs ("a growth factor. Mol Cell Biol. 2004 Jun;24(12):5172-83 disintegrin and metalloprotease") in the human lung. Virchows Arch. 2009 Apr;454(4):441-9 Grützmann R, Lüttges J, Sipos B, Ammerpohl O, Dobrowolski F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H, Guaiquil V, Swendeman S, Yoshida T, Chavala S, Schackert HK, Saeger HD, Klöppel G, Pilarsky C. ADAM9 Campochiaro PA, Blobel CP. ADAM9 is involved in expression in pancreatic cancer is associated with tumour type pathological retinal neovascularization. Mol Cell Biol. 2009 and is a prognostic factor in ductal adenocarcinoma. Br J May;29(10):2694-703 Cancer. 2004 Mar 8;90(5):1053-8 Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. Shintani Y, Higashiyama S, Ohta M, Hirabayashi H, Yamamoto EGFR and ADAMs cooperate to regulate shedding and S, Yoshimasu T, Matsuda H, Matsuura N. Overexpression of endocytic trafficking of the desmosomal cadherin desmoglein ADAM9 in non-small cell lung cancer correlates with brain 2. Mol Biol Cell. 2009 Jan;20(1):328-37 metastasis. Cancer Res. 2004 Jun 15;64(12):4190-6 Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Asayesh A, Alanentalo T, Khoo NK, Ahlgren U. Developmental Tani H, Yamashita Y, Iwasaki H. Up-regulated expression of expression of metalloproteases ADAM 9, 10, and 17 becomes ADAM17 in gastrointestinal stromal tumors: coexpression with restricted to divergent pancreatic compartments. Dev Dyn. EGFR and EGFR ligands. Cancer Sci. 2009 Apr;100(4):654-62 2005 Apr;232(4):1105-14 Singh B, Schneider M, Knyazev P, Ullrich A. UV-induced Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Röcken EGFR signal transactivation is dependent on proligand C. The disintegrin-metalloproteinases ADAM9, ADAM12, and shedding by activated metalloproteases in skin cancer cell ADAM15 are upregulated in gastric cancer. Int J Oncol. 2005 lines. Int J Cancer. 2009 Feb 1;124(3):531-9 Jan;26(1):17-24 This article should be referenced as such: Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. A secreted form of ADAM9 promotes Sung SY. ADAM9 (ADAM metallopeptidase domain 9 (meltrin carcinoma invasion through tumor-stromal interactions. Cancer gamma)). Atlas Genet Cytogenet Oncol Haematol. 2010; Res. 2005 Jun 1;65(11):4728-38 14(3):270-274.

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CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Maria Norlin Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Sweden (MN)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/CYP7B1ID40255ch8q21.html DOI: 10.4267/2042/44709 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Pseudogene No pseudogenes reported. Other names: CBAS3; CP7B; SPG5A; CYP7B HGNC (Hugo): CYP7B1 Protein Location: 8q21.3 Description Note CYP7B1 is a steroid hydroxylase involved in meta- The human CYP7B1 protein consists of 506 amino bolism of sex hormones, oxysterols (a type of acids and has a molecular weight of 58,256. The N- cholesterol derivatives) and neurosteroids. terminal membrane-binding domain (residues 1 to 38) is highly hydrophobic. The ATG start codon is located DNA/RNA 204 nucleotides downstream of the trans-cription start site (Wu et al., 1999). Similarly as other members of Description the cytochrome P450 (CYP) enzyme superfamily, CYP7B1 contains heme iron as a cofactor. Human The human CYP7B1 DNA maps to NM_004820 CYP7B1 shares 40% seq-uence identity with human (Entrez-Gene) and spans a region of 202.66 kB. CYP7A1, the other member of the CYP7 family. CYP7B1 is located on chromosome 8 and consists of six exons. Expression Transcription Expression of CYP7B1 is reported in many human tissues including brain, kidney, liver, lung, heart, The full length CYP7B1 mRNA is 2,395 bp with an prostate, testis, ovary, placenta, pancreas, intestine, open reading rame of 1,521 bp. colon and thymus (Wu et al., 1999).

Human CYP7B1 gene structure. Exons are represented by red bars with exon numbers at the bottom.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 275 CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M

Localisation study comparing allele frequency in an Oriental (Korean) population and a Caucasian (Swedish) Most reports indicated localization to the membrane of population, the frequency of the uncommon G-allele the endoplasmic reticulum. There are some data was found to be much lower in the Oriental population indicating possible CYP7B1-related activity also in (Jakobsson et al., 2004). mitochondria but it is unclear whether this activity represents CYP7B1 or another enzyme species (Axelson et al., 1992; Pandak et al., 2002). Implicated in Function Prostate cancer CYP7B1 converts a number of steroids into their Note 7alpha-hydroxyderivatives (Toll et al., 1994; Rose et High expression of CYP7B1 protein is found in high- al., 1997; Yau et al., 2006; Norlin and Wikvall, 2007). grade prostatic intraepithelial neoplasia (PIN) and In addition to 7alpha-hydroxylation, forma-tion of adenocarcinomas (Olsson et al., 2007). Local 6alpha, 6beta-, and 7beta-hydroxyderiva-tives also has methylation of the CYP7B1 promoter is suggested to been reported for this enzyme. Some well-known be important for regulation of CYP7B1 in human substrates for CYP7B1 are: 27-hydro-xycholesterol and prostate tissue. In addition, a functional C-G 25-hydroxycholesterol (choles-terol derivatives); polymorphism in the CYP7B1 promoter has been dehydroepiandrosterone (DHEA) and pregnenolone associated with a different allele frequency in two (sex hormone precursors and neurosteroids); 5alpha- ethnic populations with great differences in the androstane-3beta,17beta-diol and 5-androstene- incidence of prostate cancer (Swedes and Koreans) 3beta,17beta-diol (estrogen recap-tor ligands). The (Jakobsson et al., 2004). A connection between catalytic reactions performed by CYP7B1 may lead to CYP7B1 and prostate cancer may be related to the elimination of the steroids from the cell and thereby action of (ERbeta), since reduce the cellular levels of the substrates for this metabolism by CYP7B1 is reported to affect the levels enzyme. Also, several of the products formed by of ligands for ERbeta, which is believed to have anti- CYP7B1 are reported to have physiological effects. proliferative effects (Weihua et al., 2002; Martin et al., Thus, CYP7B1 may in some cases be part of 2004). Sex hormones are important for growth of biosynthetic pathways to form active compounds. prostate and other tissues, both during normal and Homology malignant conditions. A potential role for CYP7B1 in tissue growth is supported by data indicating that the The CYP7B1 gene is conserved in chimpanzee, dog, Akt/PI3K (phosphoinositide 3-kinase) cascade, a cow, mouse, rat, chicken, and zebrafish. signalling pathway important for cellular growth, affects the CYP7B1 gene (Tang et al., 2008). In human Mutations prostate cancer LNCaP cells, CYP7B1 promoter activity is affected by both androgens and estrogens, Germinal suggesting important functions in hormonal signalling A homozygous mutation in the CYP7B1 gene (R388X) (Tang and Norlin, 2006). was identified in an infant boy with defective bile acid synthesis and severe cholestasis (Setchell et al., 1998). Spastic Paraplegia Type 5A The patient was the offspring of first cousins. Note Mutations in the CYP7B1 gene (S363F, G57R, R417H, Mutations in the coding region of the CYP7B1 gene F216S, R388X) have been associated with a form of has been found in patients with spastic paraplegia type hereditary spastic paraplegia (HSP type 5) 5, an upper-motor-neuron degenerative disease which characterized by motor neuron degeneration in affected affects lower limb movement and results in extremity individuals of several families (Tsaousidou et al., weakness and spasticity, sometimes accompanied by 2008). S363F and F216S was predicted to affect additional symptoms. Hereditary spastic paraplegia phosphorylation of the mature protein. In addition, (HSP) is characterized by axonal degeneration of studies on non-consanguineous cases of hereditary neurons in the corticospinal tracts and dorsal columns. spastic para-plegia indicate that a coding CYP7B1 Sequence alterations in CYP7B1, believed to affect the polymor-phism (c.971G>A) is associated with a functionality of the enzyme, have been associated with phenotype of cerebellar signs believed to complicate a a pure form of autosomal-recessive HSP in several primary HSP phenotype (Schule et al., 2009). families (Tsaousidou et al., 2008). The association of A functional polymorphism was reported in the human an abnormal CYP7B1 gene with this neurodegene- CYP7B1 promoter consisting of a C-G change located - rative condition suggest that the pathogenic basis for 104 nucleotides from the trans-cription start site this disease is related either to effects on cholesterol (Jakobsson et al., 2004). The C-G alteration at -104 homeostasis in the brain (i e on CYP7B1-mediated creates a putative C/EBPbeta binding site and was control of the levels of 27-hydroxycholesterol) or to shown to result in higher transcriptional activity. In a effects on the metabolism of dehydroepiandrosterone and other neurosteroids.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 276 CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M

Congenital Bile Acid Defect Type 3 inflammation and progressive destruction of the joints. (CBAS3) Other tissues also may be affected. Studies in a mouse model for collagen-induced arthritis indicate Note correlation of increased CYP7B1 activity with disease A mutation in the CYP7B1 gene was linked to progression (Dulos et al., 2004). In humans, CYP7B1 is defective bile acid production, cholestasis and liver found in synovial tissues (connective tissues cirrhosis in an infant boy who died at the age of < 1 surrounding the joints) from patients with rheumatoid year due to complications following liver trans- arthritis and CYP7B1 levels are up-regulated by plantation (Setchell et al., 1998). Other symptoms proinflammatory cytokines in human synoviocytes included hepatosplenomegaly, jaundice and increased (Dulos et al., 2005). Chronic inflam-matory diseases bleeding. The pathological findings were consistent including rheumatoid arthritis are known to be with accumulation of hepatotoxic unsaturated associated with changes in levels of several steroids. It monohydroxy bile acids. The patient had 4,500 times has been proposed that the CYP7B1-formed 7alpha- higher levels of 27-hydroxycholes-terol than normal hydroxy-DHEA might counteract the and liver samples showed no 27-hydroxycholesterol immunosuppressive effects of gluco-corticoids, which 7alpha-hydroxylase activity. Failure to detect CYP7A1- are used in treatment of rheuma-toid arthritis. mediated 7alpha-hydroxylase activity in this patient as well as in other infants of the same age led the authors References to suggest that CYP7B1 may be more important for bile acid synthesis in early life than in adulthood Axelson M, Shoda J, Sjövall J, Toll A, Wikvall K. Cholesterol is converted to 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in liver (Setchell et al., 1998). mitochondria. Evidence for a mitochondrial sterol 7 alpha- Alzheimer's Disease hydroxylase. J Biol Chem. 1992 Jan 25;267(3):1701-4 Note Toll A, Wikvall K, Sudjana-Sugiaman E, Kondo KH, Björkhem I. 7 alpha hydroxylation of 25-hydroxycholesterol in liver Some patients with Alzheimer's disease, a progress-sive microsomes. Evidence that the enzyme involved is different neurodegenerative disease that strongly impairs from cholesterol 7 alpha-hydroxylase. Eur J Biochem. 1994 cognition and memory, are reported to have altered Sep 1;224(2):309-16 levels of CYP7B1 expression and/or CYP7B1-formed Rose KA, Stapleton G, Dott K, Kieny MP, Best R, Schwarz M, metabolites. Some studies indi-cate reduced brain Russell DW, Björkhem I, Seckl J, Lathe R. Cyp7b, a novel expression of CYP7B1 in Alzheimer's disease (Yau et brain cytochrome P450, catalyzes the synthesis of neurosteroids 7alpha-hydroxy dehydroepiandrosterone and al., 2003) whereas others report increased CYP7B1- 7alpha-hydroxy pregnenolone. Proc Natl Acad Sci U S A. 1997 formed metabo-lites in serum from patients with this May 13;94(10):4925-30 disease (Attal-Khemis et al., 1998). The potential Attal-Khémis S, Dalmeyda V, Michot JL, Roudier M, Morfin R. role(s) of CYP7B1 in connection with Alzheimer's Increased total 7 alpha-hydroxy-dehydroepiandrosterone in disease remains unclear. Alzheimer's disease is serum of patients with Alzheimer's disease. J Gerontol A Biol associated with build-up of neuritic plaques and Sci Med Sci. 1998 Mar;53(2):B125-32 neurofibrillary tangles and progressive loss of neurons Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL, and synapses in several parts of the brain. The etiology Lathe R, Thompson HR, Weslie Tyson R, Sokol RJ, Russell of Alzheimer's disease is not well understood and the DW. Identification of a new inborn error in bile acid synthesis: underlying mechanisms are most likely complex. It has mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998 Nov been suggested that disturbed metabolism of 1;102(9):1690-703 neurosteroids and/or other brain lipids may be one of Wu Z, Martin KO, Javitt NB, Chiang JY. Structure and the contributing factors (Yau et al., 2003; Bjorkhem et functions of human oxysterol 7alpha-hydroxylase cDNAs and al., 2006). In some types of brain cells, CYP7B1- gene CYP7B1. J Lipid Res. 1999 Dec;40(12):2195-203 dependent hydroxylation is the main metabolic fate for Pandak WM, Hylemon PB, Ren S, Marques D, Gil G, Redford neurosteroids dehydro-epiandrosterone and K, Mallonee D, Vlahcevic ZR. Regulation of oxysterol 7alpha- pregnenolone. Also, the levels of CYP7B1 are higher in hydroxylase (CYP7B1) in primary cultures of rat hepatocytes. the hippocampus than in other parts of the brain, Hepatology. 2002 Jun;35(6):1400-8 supporting a potential role for this enzyme related to Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine memory and cognition (Yau et al., 2003). pathway in the prostate, ERbeta, AR, 5alpha-androstane- 3beta,17beta-diol, and CYP7B1, regulates prostate growth. Rheumatoid Arthritis and Inflammation Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94 Note Yau JL, Rasmuson S, Andrew R, Graham M, Noble J, Olsson Increased production of the CYP7B1-formed T, Fuchs E, Lathe R, Seckl JR. Dehydroepiandrosterone 7- metabolite 7alpha-hydroxy-DHEA has been suggested hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease. to contribute to the chronic inflammation observed in Neuroscience. 2003;121(2):307-14 patients with rheumatoid arthritis (Dulos et al., 2005). Rheumatoid arthritis is a chronic inflammatory disorder Dulos J, Verbraak E, Bagchus WM, Boots AM, Kaptein A. Severity of murine collagen-induced arthritis correlates with with unclear etiology characterized by joint increased CYP7B activity: enhancement of

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 277 CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M

dehydroepiandrosterone metabolism by interleukin-1beta. Norlin M, Wikvall K. Enzymes in the conversion of cholesterol Arthritis Rheum. 2004 Oct;50(10):3346-53 into bile acids. Curr Mol Med. 2007 Mar;7(2):199-218 Jakobsson J, Karypidis H, Johansson JE, Roh HK, Rane A, Olsson M, Gustafsson O, Skogastierna C, Tolf A, Rietz BD, Ekström L. A functional C-G polymorphism in the CYP7B1 Morfin R, Rane A, Ekström L. Regulation and expression of promoter region and its different distribution in Orientals and human CYP7B1 in prostate: overexpression of CYP7B1 during Caucasians. Pharmacogenomics J. 2004;4(4):245-50 progression of prostatic adenocarcinoma. Prostate. 2007 Sep 15;67(13):1439-46 Martin C, Ross M, Chapman KE, Andrew R, Bollina P, Seckl JR, Habib FK. CYP7B generates a selective estrogen receptor Tang W, Pettersson H, Norlin M. Involvement of the PI3K/Akt beta agonist in human prostate. J Clin Endocrinol Metab. 2004 pathway in estrogen-mediated regulation of human CYP7B1: Jun;89(6):2928-35 identification of CYP7B1 as a novel target for PI3K/Akt and MAPK signalling. J Steroid Biochem Mol Biol. 2008 Nov;112(1- Dulos J, van der Vleuten MA, Kavelaars A, Heijnen CJ, Boots 3):63-73 AM. CYP7B expression and activity in fibroblast-like synoviocytes from patients with rheumatoid arthritis: regulation Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, by proinflammatory cytokines. Arthritis Rheum. 2005 Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton Mar;52(3):770-8 MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol Björkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U. homeostasis in motor-neuron degeneration. Am J Hum Genet. Oxysterols and Alzheimer's disease. Acta Neurol Scand Suppl. 2008 Feb;82(2):510-5 2006;185:43-9 Schüle R, Brandt E, Karle KN, Tsaousidou M, Klebe S, Klimpe Tang W, Norlin M. Regulation of steroid hydroxylase CYP7B1 S, Auer-Grumbach M, Crosby AH, Hübner CA, Schöls L, by androgens and estrogens in prostate cancer LNCaP cells. Deufel T, Beetz C. Analysis of CYP7B1 in non- Biochem Biophys Res Commun. 2006 Jun 2;344(2):540-6 consanguineous cases of hereditary spastic paraplegia. Yau JL, Noble J, Graham M, Seckl JR. Central administration Neurogenetics. 2009 Apr;10(2):97-104 of a cytochrome P450-7B product 7 alpha- hydroxypregnenolone improves spatial memory retention in This article should be referenced as such: cognitively impaired aged rats. J Neurosci. 2006 Oct Norlin M. CYP7B1 (cytochrome P450, family 7, subfamily B, 25;26(43):11034-40 polypeptide 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):275-278.

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EPHA3 (EPH receptor A3) Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd Leukaemia Foundation Research Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Brisbane Queensland 4006, Australia (BS, BD, JM, AB); Department of Biochemistry and Molecular Biology, PO Box 13D, Monash University, Clayton Victoria 3800, Australia (ML); Department of Medicine, University of Queensland, St Lucia Queensland 4067, Australia (AB)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/EPHA3ID40463ch3p11.html DOI: 10.4267/2042/44710 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: EC 2.7.10.1; ETK; ETK1; EphA3; Note HEK; HEK4; TYRO4 EPHA3 spans the human tile path clones CTD- HGNC (Hugo): EPHA3 2532M17, RP11-784B9 and RP11-547K2. Location: 3p11.2 Description Local order: (tel) C3orf38 (ENSG00000179021) ->, EPHA3 consists of 17 exons and 16 introns and spans 949,562bp, EPHA3 (374,609bp) ->, 720,071bp, <- 375kb of genomic DNA. It is the second largest of the AC139337.5 (ENSG00000189002) (cen) EPH genes after EPHA6. Note EPHA3 is flanked by two gene deserts.

Figure 1: Chromosomal location of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)). Figure 2: Genomic neighbourhood of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 279 EPHA3 (EPH receptor A3) Stringer B, et al.

Figure 3: Genomic organisation of EPHA3. Transcription present in sponges, worms and fruit flies. The expansion in the number of Eph receptor-encoding Two alternatively spliced transcript variants have been genes along with genes encoding their ligands, the described (NM_005233.5, a 5,807 nucleotide mRNA ephrins (Eph receptor interacting proteins), is proposed and NM_182644.2, a 2,684 nucleotide mRNA). The to have contributed to the increase in complexity of the shorter transcript results in truncation within the bilaterian body plan. Genes encoding EphA3 are found extracellular domain of EphA3 and is predicted to in the genomes of representative members of at least produce a soluble protein. The 5' end of EPHA3 is five of the seven classes of vertebrates including bony associated with a CpG island, a feature common to all fish (zebrafish, pufferfish, medaka), amphibians EPH genes. The EPHA3 promoter also lacks a TATA (African clawed frog), reptiles (green anole lizard), box and transcription initiates from multiple start sites. birds (chicken) and mammals (platypus, possum, Pseudogene human). None identified. Fourteen Eph receptors have been identified in vertebrates. These are subdivided into either EphA Protein (EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphA10) or EphB (EphB1, EphB2, Note EphB3, EphB4, EphB6) subclasses which differ The Eph receptors constitute the largest of the 20 primarily in the structure of their ligand binding subfamilies of human receptor tyrosine kinases. The domains. EphA receptors also exhibit greater affinity founding member of this group was isolated originally for binding GPI-linked ephrin-A ligands while EphB from an erythropoietin producing hepato-ma cell line. receptors bind transmembrane ephrin-B ligands. While interactions are somewhat promis-cuous, and some cross-class binding occurs, each Eph receptor displays distinct affinity for the different ephrin ligands. The high affinity ligands for EphA3 are ephrin-A2 and ephrin-A5. EphA3 also binds ephrin-A3 and ephrin-A4 with lower affinity. Eph-ephrin binding involves contact between cells. Upon binding, receptor-ligand dimers form heterotetramers, which further assemble into higher order signalling clusters. Several moieties in the EphA3 receptor extracellular region mediate ephrin binding. A Figure 4: Domain organisation of EphA3. high-affinity binding site in the N-terminal ephrin Description binding domain mediates inter-cellular Eph-ephrin The EPHA3 gene encodes a 983 amino acid protein interaction. Two additional lower-affinity ephrin- with a calculated molecular weight of 110.1kDa and an binding sites, one in the ephrin-binding domain and the isoelectric point of 6.7302. Amino acids 1-20 constitute other in the cysteine-rich region, are involved in a signal peptide. The predicted mole-cular mass of the clustering of Eph-ephrin complexes. translated protein minus the signal peptide is 92.8kDa. Following ephrin-A5-mediated EphA3 receptor The 521 amino acid extra-cellular domain contains five clustering, intracellular signalling by EphA3 receptors potential sites for N-glycosylation such that EphA3 is is initiated by autophosphorylation of three defined typically detected as a 135kDa glycoprotein. This tyrosine residues, two in the highly conserved mature isoform of EphA3 is a single-pass juxtamembrane region and the third in the activation transmembrane receptor tyrosine kinase. At its N- loop of the kinase domain (Y779). Rapid reorganisation terminus is a 174 amino acid ligand binding domain, a of the actin and myosin cytoskeleton follows, leading 14 amino acid EGF-like domain and two membrane to retraction of cellular protrusions, membrane proximal fibro-nectin type III repeats. Amino acids 21- blebbing and cell detachment, following association of 376 of the extracellular domain also are rich in cysteine the adaptor protein CrkII with tyrosine phosphorylated residues. The intracellular domain contains the tyrosine EphA3 and activation of RhoA signalling. kinase domain and a sterile alpha motif. EphA3 lacks a Such Eph-ephrin interaction triggers bidirectional PDZ domain interacting motif present in EphA7, signalling, that is signalling events within both Eph- EphB2, EphB3, EphB5 and EphB6. Activation of the and ephrin-bearing cells, an unusual phenomenon for EphA3 receptor tyrosine kinase domain is associated receptor tyrosine kinases, most of which interact with with two tyrosine residues in the juxtamembrane region soluble ligands. Subsequently, depending on the (Y596, Y602) that are sites of autophosphorylation and cellular context (including the identity of the interact with the kinase domain to modulate its activity. interacting Eph-ephrin receptor-ligand pairs, their EphA3 belongs to an evolutionarily ancient subfamily relative levels on interacting cells, the presence of of receptor tyrosine kinases with mem-bers being additional Ephs and ephrins and their alternative

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 280 EPHA3 (EPH receptor A3) Stringer B, et al.

isoforms, and the net effect of interaction with apparently unique to individual Ephs) additional additional signalling pathways) this either results in effectors of EphA3 signalling output are likely. repulsion or promotes adhesion of the interacting cells. Expression Cellular repulsion and the termination of Eph-ephrin signalling require disruption of the receptor-ligand EphA3 was first identified as an antigen expressed at complex. This is brought about either by enzymatic high levels (10,000-20,000 copies per cell) on the cleavage of the tethered ephrin ligand in cis or in trans surface of the LK63 pre-B cell acute lymphoblastic or by endocytosis of Eph-ephrin complexes. EphA3- leukaemia cell line. It also was found to be expressed ephrin-A2 receptor-ligand complexes are shed from by JM, HSB-2 and MOLT-4 T-cell leukaemic cell ephrin-A2 bearing cells following receptor-ligand lines, in CD28-stimulated Jurkat cells, and in 16 of 42 binding when ADAM10 (a disintegrin and cases of primary T-cell lymphoma (but not normal metalloprotease 10), associated with ephrin-A2, cleaves peripheral T lymphocytes nor in any subset of thymus- ephrin-A2. Conversely, intercellular EphA3-ephrin-A5 derived developing T cells), as well as at low frequency receptor-ligand complexes are broken when EphA3- in acute myeloid leukaemia and chronic lymphocytic associated ADAM10 cleaves ephrin-A5 on opposing leukaemia EphA3 is not expressed by many other cells, following binding to EphA3. The post-cleavage haematopoietic cell lines. ephrin-A5-EphA3 complex is then endocytosed by the Subsequently, EphA3 expression has been shown to be EphA3-expressing cell. most abundant, and also highly regulated both While cellular repulsion is often the outcome of Eph- temporally and spatially, during vertebrate ephrin interaction, in some circumstances adhesion development. Prominent EphA3 expression occurs in may persist. For example, ADAM10 has been observed the neural system, including the retinal ganglion cells not to cleave ephrin-A5 following EphA3-ephrin-A5 of the embryonic retina in a graded distribution from interaction involving LK63 cells in which high anterior/nasal (lowest) to posterior /temporal (highest); intracellular protein tyrosine phosphatase activity also the cerebrum, thalamus, striatum, olfactory bulb, appears to counter ephrin-A5 stimulated anterior commissure, and corpus callosum of the phosphorylation of EphA3, holding the receptor in an forebrain; and the medial motor column ventral motor inactive, unphosphorylated state. Also cis interaction neurons of the spinal cord; and extraneurally by between EphA3 and ephrin-A2 expressed on the same mesodermally-derived tissues including the paraxial cell surface has been reported to block EphA3 musculature, tongue musculature, submucosa of the activation by ephrins acting in trans, the cis interaction soft palate, capsule of the submandibular gland, cortical site being independent of the ligand binding domain. rim of bone, thymic septae, media of the pharynx, Another mechanism that may favour stable cell-cell trachea, great vessels, small intestine and portal vein, adhesion involves truncated Eph receptor isoforms cardiac valves, and the renal medulla. In adult tissues acting in a dominant negative manner. While activation EphA3 expression is more restricted and detected at of full length EphA7 by ephrin-A5 results in cellular significantly lower levels than during early repulsion, ephrin-A5-induced phosphorylation of development. EphA7 is inhibited by two EphA7 splice variants with Localisation truncated kinase domains and adhesion results. A splice Isoform 1: Cell membrane; single-pass type I variant of EPHA3 also has been reported and is membrane protein. predicted to give rise to a soluble isoform of EphA3. Isoform 2: Secreted. Whether this soluble variant of EphA3, which is truncated before the transmembrane domain, functions Function in a similar manner to the shorter EphA7 isoforms has Eph receptors modulate cell shape and movement not been established. through reorganisation of the cytoskeleton and changes While important details of EphA3 signalling have been in cell-cell and cell-substrate adhesion, and are determined, more complete understanding of EphA3 involved in many cellular migration, sorting (tissue activity will require knowledge of the full complement patterning) and guidance events, most often during of EphA3 interacting proteins. Substrates that are development, and in particular involving the nervous targets for the tyrosine kinase activity of EphA3 have system. There is evidence too that Eph receptor yet to be defined and potential mediators or modulators signalling influences cell proliferation and cell-fate of EphA3 signalling output such as Src family kinases, determination and growing recognition that Eph additional phosphotyrosine binding adaptors, SAM receptors function in adult tissue homeostasis. domain interacting factors, interaction with other EphA3 is thought to play a role in retinotectal mapping, receptor kinases and crosstalk with other signalling the tightly patterned projection of retinal ganglion cell pathways, and the regulatory role of phosphatases all axons from the retina to the optic tectum (or superior remain to be explored. Based on the range of colliculus in mammals). In chicks, posterior retinal interacting proteins identified for other Eph receptors ganglion axons expressing highest levels of EphA3 (some common to more than one Eph, others project to the anterior tectum where the graded

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expression of ephrin-A2 and ephrin-A5 is lowest and (NP_005224), EphA4 (NP_004429), EphA5 are excluded from projecting more posteriorly where (NM_004439), EphA6 (ENSP00000374323), EphA7 ephrin-A2/A5 expression is highest. More direct (NP_004431), EphA8 (NP_065387), EphA10 evidence of non-redundant function for EphA3 has (NP_001092909), EphB1 (NP_004432), EphB2 come from phenotypic analysis of EphA3 knockout (NP_004433), EphB3 (NP_004434), EphB4 mice. Approximately 70-75% of EphA3 null mice die (NP_004435) and EphB6 (NP_004436). within 48 hours of birth with post-mortem evidence of pulmonary oedema secondary to cardiac failure. These mice exhibit hypoplastic atrioventricular endocardial cushions and subsequent atri-oventricular valve and atrial membranous septal defects, with endocardial cushion explants from these mice giving rise to fewer migrating cells arising from epithelial to mesenchymal trans-formation. Expression of EphA3 in the spinal cord appears to be redundant as axial muscle targeting by medial motor column motor axons and the organisation of the motor neuron columns is not altered. EphA4 is the only other EphA receptor also expressed by developing spinal cord motor neurons and in mice lacking EphA3 and EphA4 these receptors together repel axial motor axons from neighbouring ephrin-A-expressing sensory axons, inhibiting Mutations intermingling of motor and sensory axons and preventing mis-projection of motor axons into the Note dorsal root ganglia. In contrast to the chick, EphA3 is Seven nonsynonymous single nucleotide polymer- not expressed by mouse retinal ganglion cells. Instead phisms (all missense) are recorded in the dbSNP the closely related receptors EphA5 and EphA6 (see database for EPHA3. Recognised allelic variation homology below) are expressed in a low nasal to high occurs for the following EphA3 amino acids: I564V temporal gradient. However, if EphA3 is ectopically (rs56081642), C568S (rs56077781), L590P expressed in retinal ganglion cells in mice these axons (rs56081642), T608A (rs17855794), G777A project to more rostral positions in the superior (rs34437982), W924R (rs35124509) and H914R colliculus. (rs17801309). A function for soluble EphA3 has not been reported although potentially this isoform might play a role in Germinal promoting cell adhesion (see above) or act as a tumour To date no germinal mutations in EPHA3 have been suppressor protein (see below). associated with disease. Homology Somatic Phylogenetic tree for the Eph receptors. Amino acid Somatic mutations in EPHA3 have been detected in sequences used for this compilation were EphA1 lung adenocarcinoma (T166N, G187R, S229Y, (NP_005223), EphA2 (NM_004431), EphA3 W250R, M269I, N379K, T393K, A435S, D446Y,

Figure 6: Sites of somatic mutations in EphA3 identified in lung adenocarcinoma colorectal carcinoma, glioblastoma multiforme and metastatic melanoma.

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S449F, G518L, T660K, D678E, R728L, K761N, G766E, T933M), colorectal carcinoma (T37K, N85S, References I621L, S792P, D806N), glioblastoma multi-forme Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F. A novel (K500N, A971P) and metastatic melanoma (G228R). putative tyrosine kinase receptor encoded by the eph gene. Science. 1987 Dec 18;238(4834):1717-20 Implicated in Boyd AW, Ward LD, Wicks IP, Simpson RJ, Salvaris E, Wilks A, Welch K, Loudovaris M, Rockman S, Busmanis I. Isolation Prostate cancer and characterization of a novel receptor-type protein tyrosine kinase (hek) from a human pre-B cell line. J Biol Chem. 1992 Note Feb 15;267(5):3262-7 EPHA3 was among the genes whose expression was Wicks IP, Wilkinson D, Salvaris E, Boyd AW. Molecular cloning upregulated during androgen-independent progresssion of HEK, the gene encoding a receptor tyrosine kinase in an LNCaP in vitro cell model of prostate cancer. expressed by human lymphoid tumor cell lines. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1611-5 Melanoma Kilpatrick TJ, Brown A, Lai C, Gassmann M, Goulding M, Note Lemke G. Expression of the Tyro4/Mek4/Cek4 gene A melanoma patient with an especially favourable specifically marks a subset of embryonic motor neurons and evolution of disease, associated with a very strong and their muscle targets. Mol Cell Neurosci. 1996 Jan;7(1):62-74 sustained anti-tumour cytotoxic T lymphocyte Lackmann M, Mann RJ, Kravets L, Smith FM, Bucci TA, response, was found to have a lytic CD4 clone that Maxwell KF, Howlett GJ, Olsson JE, Vanden Bos T, Cerretti DP, Boyd AW. Ligand for EPH-related kinase (LERK) 7 is the recognised an EphA3 antigen presented by the HLA preferred high affinity ligand for the HEK receptor. J Biol Chem. class II molecule HLA- DRB1*1101. 94% (75 of 80) of 1997 Jun 27;272(26):16521-30 melanomas examined expressed EphA3 in contrast to Hock B, Böhme B, Karn T, Yamamoto T, Kaibuchi K, Holtrich normal melanocytes which do not express detectable U, Holland S, Pawson T, Rübsamen-Waigmann H, Strebhardt EphA3. K. PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein Lung cancer, Sarcoma, and Renal cell AF6 depends on the kinase activity of the receptor. Proc Natl carcinoma Acad Sci U S A. 1998 Aug 18;95(17):9779-84 Note Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M, Kravets L, Boyd AW. Distinct subdomains of the EphA3 44% (11 of 25) of small cell lung cancer, 24% (10 of receptor mediate ligand binding and receptor dimerization. J 41) of non-small cell lung cancer, 58% (17 of 29) of Biol Chem. 1998 Aug 7;273(32):20228-37 sarcomas, and 31% (12 of 38) of renal cell carcinomas Dottori M, Down M, Hüttmann A, Fitzpatrick DR, Boyd AW. expressed EphA3 at levels significantly higher than the Cloning and characterization of EphA3 (Hek) gene promoter: corresponding normal tissues. DNA methylation regulates expression in hematopoietic tumor cells. Blood. 1999 Oct 1;94(7):2477-86 Breakpoints Brown A, Yates PA, Burrola P, Ortuño D, Vaidya A, Jessell TM, Pfaff SL, O'Leary DD, Lemke G. Topographic mapping Note from the retina to the midbrain is controlled by relative but not No reported breakpoints identified to date nor absolute levels of EphA receptor signaling. Cell. 2000 Jul recognised fusion proteins involving EphA3. 7;102(1):77-88 Castresana J. Selection of conserved blocks from multiple To be noted alignments for their use in phylogenetic analysis. Mol Biol Evol. 2000 Apr;17(4):540-52 Note Chiari R, Hames G, Stroobant V, Texier C, Maillère B, Boon T, Soluble forms of EphA3 appear to inhibit tumour Coulie PG. Identification of a tumor-specific shared antigen angiogenesis and tumour progression suggesting that derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res. 2000 Sep 1;60(17):4855- specific inhibition by soluble EphA3 may be 63 therapeutically useful. The IIIA4 monoclonal antibody originally raised Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science. 2000 Aug against LK63 human acute pre-B leukemia cells and 25;289(5483):1360-5 used to affinity isolate EphA3 binds the native EphA3 globular ephrin-binding domain with sub-nanomolar Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase -10 family of the . Oncogene. 2000 Nov affinity (KD ~5x10 mol/L). Like ephrin-A5, pre- 20;19(49):5548-57 clustered IIIA4 effectively triggers EphA3 activation, Boyd AW, Lackmann M. Signals from Eph and ephrin proteins: contraction of the cytoskeleton, and cell rounding. a developmental tool kit. Sci STKE. 2001 Dec Moreover, radio-metal conju-gates of ephrin-A5 and 11;2001(112):re20 IIIA4 retain their EphA3-binding affinity, and in mouse Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, xenografts localise to, and are internalised rapidly into Henkemeyer M, Nikolov DB. Crystal structure of an Eph EphA3-positive, human tumours. receptor-ephrin complex. Nature. 2001 Dec 20- 27;414(6866):933-8

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 283 EPHA3 (EPH receptor A3) Stringer B, et al.

Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, AG, Wooster R, Stratton MR, Futreal PA. Somatic mutations of Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, Lin the protein kinase gene family in human lung cancer. Cancer C, Chen J. Soluble Eph A receptors inhibit tumor angiogenesis Res. 2005 Sep 1;65(17):7591-5 and progression in vivo. Oncogene. 2002 Oct 10;21(46):7011- 26 Day B, To C, Himanen JP, Smith FM, Nikolov DB, Boyd AW, Lackmann M. Three distinct molecular surfaces in ephrin-A5 Drescher U. Eph family functions from an evolutionary are essential for a functional interaction with EphA3. J Biol perspective. Curr Opin Genet Dev. 2002 Aug;12(4):397-402 Chem. 2005 Jul 15;280(28):26526-32 Lawrenson ID, Wimmer-Kleikamp SH, Lock P, Schoenwaelder Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SM, Down M, Boyd AW, Alewood PF, Lackmann M. Ephrin-A5 SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, induces rounding, blebbing and de-adhesion of EphA3- Nikolov DB. Adam meets Eph: an ADAM substrate recognition expressing 293T and melanoma cells by CrkII and Rho- module acts as a molecular switch for ephrin cleavage in trans. mediated signalling. J Cell Sci. 2002 Mar 1;115(Pt 5):1059-72 Cell. 2005 Oct 21;123(2):291-304 Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Kudo C, Ajioka I, Hirata Y, Nakajima K. Expression profiles of Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein EphA3 at both the RNA and protein level in the developing B, Velculescu VE. Mutational analysis of the tyrosine kinome in mammalian forebrain. J Comp Neurol. 2005 Jul 4;487(3):255- colorectal cancers. Science. 2003 May 9;300(5621):949 69 Cheng N, Brantley D, Fang WB, Liu H, Fanslow W, Cerretti Vearing C, Lee FT, Wimmer-Kleikamp S, Spirkoska V, To C, DP, Bussell KN, Reith A, Jackson D, Chen J. Inhibition of Stylianou C, Spanevello M, Brechbiel M, Boyd AW, Scott AM, VEGF-dependent multistage carcinogenesis by soluble EphA Lackmann M. Concurrent binding of anti-EphA3 antibody and receptors. Neoplasia. 2003 Sep-Oct;5(5):445-56 ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting Guindon S, Gascuel O. A simple, fast, and accurate algorithm reagents. Cancer Res. 2005 Aug 1;65(15):6745-54 to estimate large phylogenies by maximum likelihood. Syst Biol. 2003 Oct;52(5):696-704 Wimmer-Kleikamp SH, Lackmann M. Eph-modulated cell morphology, adhesion and motility in carcinogenesis. IUBMB Vaidya A, Pniak A, Lemke G, Brown A. EphA3 null mutants do Life. 2005 Jun;57(6):421-31 not demonstrate motor axon guidance defects. Mol Cell Biol. 2003 Nov;23(22):8092-8 Anisimova M, Gascuel O. Approximate likelihood-ratio test for branches: A fast, accurate, and powerful alternative. Syst Biol. Edgar RC. MUSCLE: multiple sequence alignment with high 2006 Aug;55(4):539-52 accuracy and high throughput. Nucleic Acids Res. 2004;32(5):1792-7 Carvalho RF, Beutler M, Marler KJ, Knöll B, Becker-Barroso E, Heintzmann R, Ng T, Drescher U. Silencing of EphA3 through Feldheim DA, Nakamoto M, Osterfield M, Gale NW, DeChiara a cis interaction with ephrinA5. Nat Neurosci. 2006 TM, Rohatgi R, Yancopoulos GD, Flanagan JG. Loss-of- Mar;9(3):322-30 function analysis of EphA receptors in retinotectal mapping. J Neurosci. 2004 Mar 10;24(10):2542-50 Chevenet F, Brun C, Bañuls AL, Jacq B, Christen R. TreeDyn: towards dynamic graphics and annotations for analyses of Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, trees. BMC Bioinformatics. 2006 Oct 10;7:439 Dietmaier W, Landthaler M, Vogt T. Differential gene expression of Eph receptors and ephrins in benign human Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, tissues and cancers. Clin Chem. 2004 Mar;50(3):490-9 Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Poliakov A, Cotrina M, Wilkinson DG. Diverse roles of eph Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, receptors and ephrins in the regulation of cell migration and Parmigiani G, Park BH, Bachman KE, Papadopoulos N, tissue assembly. Dev Cell. 2004 Oct;7(4):465-80 Vogelstein B, Kinzler KW, Velculescu VE. The consensus Smith FM, Vearing C, Lackmann M, Treutlein H, Himanen J, coding sequences of human breast and colorectal cancers. Chen K, Saul A, Nikolov D, Boyd AW. Dissecting the Science. 2006 Oct 13;314(5797):268-74 EphA3/Ephrin-A5 interactions using a novel functional Wood LD, Calhoun ES, Silliman N, Ptak J, Szabo S, Powell mutagenesis screen. J Biol Chem. 2004 Mar 5;279(10):9522- SM, Riggins GJ, Wang TL, Yan H, Gazdar A, Kern SE, 31 Pennacchio L, Kinzler KW, Vogelstein B, Velculescu VE. Smith LM, Walsh PT, Rüdiger T, Cotter TG, Mc Carthy TV, Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human Marx A, O'Connor R. EphA3 is induced by CD28 and IGF-1 cancers. Hum Mutat. 2006 Oct;27(10):1060-1 and regulates cell adhesion. Exp Cell Res. 2004 Jan Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, 15;292(2):295-303 Scarpa A, van Tilborg AA, Leenstra S, Zanon C, Bardelli A. Wimmer-Kleikamp SH, Janes PW, Squire A, Bastiaens PI, Novel somatic and germline mutations in cancer candidate Lackmann M. Recruitment of Eph receptors into signaling genes in glioblastoma, melanoma, and pancreatic carcinoma. clusters does not require ephrin contact. J Cell Biol. 2004 Mar Cancer Res. 2007 Apr 15;67(8):3545-50 1;164(5):661-6 Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 284 EPHA3 (EPH receptor A3) Stringer B, et al.

Patterns of somatic mutation in human cancer genomes. Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz Nature. 2007 Mar 8;446(7132):153-8 MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Himanen JP, Saha N, Nikolov DB. Cell-cell signaling via Eph Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, receptors and ephrins. Curr Opin Cell Biol. 2007 Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic Oct;19(5):534-42 mutations affect key pathways in lung adenocarcinoma. Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A. A Nature. 2008 Oct 23;455(7216):1069-75 critical role for the EphA3 receptor tyrosine kinase in heart Gallarda BW, Bonanomi D, Müller D, Brown A, Alaynick WA, development. Dev Biol. 2007 Feb 1;302(1):66-79 Andrews SE, Lemke G, Pfaff SL, Marquardt T. Segregation of Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani axial motor and sensory pathways via heterotypic trans-axonal A, Dhe-Paganon S. Autoregulation by the juxtamembrane signaling. Science. 2008 Apr 11;320(5873):233-6 region of the human ephrin receptor tyrosine kinase A3 Pasquale EB. Eph-ephrin bidirectional signaling in physiology (EphA3). Structure. 2008 Jun;16(6):873-84 and disease. Cell. 2008 Apr 4;133(1):38-52 Dereeper A, Guignon V, Blanc G, Audic S, Buffet S, Chevenet Singh AP, Bafna S, Chaudhary K, Venkatraman G, Smith L, F, Dufayard JF, Guindon S, Lefort V, Lescot M, Claverie JM, Eudy JD, Johansson SL, Lin MF, Batra SK. Genome-wide Gascuel O. Phylogeny.fr: robust phylogenetic analysis for the expression profiling reveals transcriptomic variation and non-specialist. Nucleic Acids Res. 2008 Jul 1;36(Web Server perturbed gene networks in androgen-dependent and issue):W465-9 androgen-independent prostate cancer cells. Cancer Lett. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, 2008 Jan 18;259(1):28-38 Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Wimmer-Kleikamp SH, Nievergall E, Gegenbauer K, Adikari S, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Mansour M, Yeadon T, Boyd AW, Patani NR, Lackmann M. Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Elevated protein tyrosine phosphatase activity provokes Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao Eph/ephrin-facilitated adhesion of pre-B leukemia cells. Blood. J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, 2008 Aug 1;112(3):721-32 Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, This article should be referenced as such: Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Stringer B, Day B, McCarron J, Lackmann M, Boyd A. EPHA3 Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson (EPH receptor A3). Atlas Genet Cytogenet Oncol Haematol. BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, 2010; 14(3):279-285.

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Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

JAZF1 (JAZF zinc finger 1) Hui Li, Jeffrey Sklar University of Virginia Medical School, Charlottesville, VA 22908, USA (HL), Department of Pathology, Yale University, New haven, CT, USA (HL, JS)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/JAZF1ID41036ch7p15.html DOI: 10.4267/2042/44711 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Expression Expressed in all the tissues tested with variable level. Other names: TIP27; ZNF802; DKFZp761K2222 The tissues or organs that express JAZF1 include HGNC (Hugo): JAZF1 cerebellum, lung, thymus, liver, kidney, Location: 7p15.2 stomach/esophagus, skeleton muscle, skin and eye. Localisation Mostly nucleus. Function JAZF1 has three C2H2-type zinc fingers. It is mostly detected within the nucleus, with lesser amounts found in the cytoplasm. JAZF1 copurifies with chromatin, and presumably has DNA-binding properties. It has been reported to interact with TAK1 and function as a transcriptional repressor of the TAK1 gene. SNPs in intron 1 of JAZF1 has been reported to be associated with type 2 diabetes and body height. SNPs in intron 2 of JAZF1 have been reported to be associated with reduced prevalence of prostate cancer. Chimeric JAZF1-JJAZ1 protein (amino acid sequence Metaphase FISH using as probe YAC908B12, which of the first three exons of JAZF1 joined to sequence of encompasses the entire JAZF1 at 7p15.2. the last 15 exons of JJAZ1) resulting from trans- splicing of precursor mRNAs and identical to a product DNA/RNA generated from the JAZF1-JJAZ1 gene fusion in endometrial tumors has been found in normal Description endometrium. 5 exons; spans 350kb. Homology Transcription Unkown. Major transcript: 2,980bp; coding sequence: 52-783. Mutations Protein Somatic Description JAZF1 has been identified at the breakpoints of a 243 amino acids. recurrent chromosomal translocation, the

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 286 JAZF1 (JAZF zinc finger 1) Li H, Sklar J

t(7;17)(p15;q21), in endometrial stromal tumors (benign nodules and sarcomas). The translocation leads Breakpoints to a JAZF1-JJAZ1 fusion gene. This gene fusion is detected in about 50% of endometrial stromal sarcomas and most endometrial stromal nodules. Another common chromosomal translocation in endometrial stroma sarcomas, the t(6;7)(p21;p15), results in a JAZF1-PHF1 fusion. About 25-30% of endometrial stromal sarcomas are reported to contain this fusion. The sites of fusion within JAZF1 RNA to JJAZ1 and PHF1 RNA sequence are the same. Both JJAZ1(also called SUZ12) and PHF1 belong to the Polycomb group (PcG) gene family. Implicated in t(7;17)(p15;q21) / endometrial stromal nodule and endometrial sarcoma Disease Endometrial stroma nodule and sarcoma. Cytogenetics References t(7;17)(p15;q21) Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Hybrid/Mutated gene Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of JAZF1-JJAZ1 the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53 Abnormal protein JAZF1-JJAZ1 Micci F, Panagopoulos I, Bjerkehagen B, Heim S. Consistent rearrangement of chromosomal band 6p21 with generation of Oncogenesis fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial The fusion protein protects cells from hypoxia-induced stromal sarcoma. Cancer Res. 2006 Jan 1;66(1):107-12 apoptosis, and also promotes proliferation when the Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. Effects of wild-type allele of JJAZ1 is silenced (as it is in rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell endometrial stromal sarcomas carrying the proliferation and survival. Proc Natl Acad Sci U S A. 2007 Dec t(7;17)(p15;q21)). 11;104(50):20001-6 Nucci MR, Harburger D, Koontz J, Dal Cin P, Sklar J. t(6;7)(p21;p15)/ endometrial stroma Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT- sarcoma PCR and fluorescence in situ hybridization in endometrial stromal neoplasms. Am J Surg Pathol. 2007 Jan;31(1):65-70 Disease Frayling TM, Colhoun H, Florez JC. A genetic link between Endometrial stroma sarcoma. type 2 diabetes and prostate cancer. Diabetologia. 2008 Cytogenetics Oct;51(10):1757-60 t(6;7)(p21;p15) Frayling TM, Colhoun H, Florez JC. A genetic link between Hybrid/Mutated gene type 2 diabetes and prostate cancer. Diabetologia. 2008 Oct;51(10):1757-60 JAZF1-PHF1 Li H, Wang J, Mor G, Sklar J. A neoplastic gene fusion mimics Abnormal protein trans-splicing of RNAs in normal human cells. Science. 2008 JAZF1-PHF1 Sep 5;321(5894):1357-61 Oncogenesis Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr The function of the JAZF1-PHF1 fusion is not N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, currently known. Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Prostate carcinoma Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole Oncogenesis GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, A SNIP in intron 2 of JAZF1 is associated with a Hoover R, Hayes RB, Hunter DJ, Chanock SJ. Multiple loci identified in a genome-wide association study of prostate somewhat decreased risk of prostate cancer, especially cancer. Nat Genet. 2008 Mar;40(3):310-5 cancers that have been classified as being less aggressive. The mechanism by which polymer-phisms Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, alter the susceptibility toward prostate cancer is not Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, currently known. Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 287 JAZF1 (JAZF zinc finger 1) Li H, Sklar J

Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Johansson A, Marroni F, Hayward C, Franklin CS, Kirichenko Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, AV, Jonasson I, Hicks AA, Vitart V, Isaacs A, Axenovich T, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Campbell S, Dunlop MG, Floyd J, Hastie N, Hofman A, Knott Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, S, Kolcic I, Pichler I, Polasek O, Rivadeneira F, Tenesa A, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Uitterlinden AG, Wild SH, Zorkoltseva IV, Meitinger T, Wilson Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, JF, Rudan I, Campbell H, Pattaro C, Pramstaller P, Oostra BA, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Wright AF, van Duijn CM, Aulchenko YS, Gyllensten U. Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Common variants in the JAZF1 gene associated with height Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M, identified by linkage and genome-wide association analysis. Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Hum Mol Genet. 2009 Jan 15;18(2):373-80 Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, DO, Henderson BE, Haiman CA. Generalizability of Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, associations from prostate cancer genome-wide association Boehnke M, Altshuler D. Meta-analysis of genome-wide studies in multiple populations. Cancer Epidemiol Biomarkers association data and large-scale replication identifies additional Prev. 2009 Apr;18(4):1285-9 susceptibility loci for type 2 diabetes. Nat Genet. 2008 May;40(5):638-45 This article should be referenced as such: Li H, Sklar J. JAZF1 (JAZF zinc finger 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):286-288.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 288

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Gene Section Review

LPAR1 (lysophosphatidic acid receptor 1) Mandi M Murph, Harish Radhakrishna University of Georgia College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, 250 W Green Street, Rm 376 Athens, Georgia 30602 USA (MMM); Global Research & Technology, The Coca- Cola Company, 1 Coca-Cola Plaza Atlanta, GA 30313 USA (HR)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/LPAR1ID40405ch9q31.html DOI: 10.4267/2042/44712 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: EDG2; GPR26; LPA-1; LPA1; Description Mrec1.3; VZG1; edg-2; rec.1.3; vzg-1 LPAR1 is an abbreviation for the LPA1 receptor, the HGNC (Hugo): LPAR1 first receptor cloned and identified from a growing Location: 9q31.3 number of LPA receptors that includes the Edg-family and the purinergic receptors. DNA/RNA Expression Note LPAR1 is ubiquitously expressed throughout cells and mRNA length 3104 or 3182 bp, depending on tissues in the body. alternative splicing. High level of expression is found in amygdale,

Figure of the LPAR1, a G protein-coupled receptor, spanning the plasma membrane seven times. The receptor has three numbered extracellular and intracellular loops that are involved in signal transduction. Also shown are the amino terminus and carboxyl terminal tail. Three regions of the carboxyl terminal tail have been shown to be important for the LPAR1 signaling and receptor regulation. LPAR1 contains a canonical Type 1 PDZ binding domain (a.a. 362-364) at the extreme C-terminus. This domain has been shown to be required for LPA-induced cell proliferation and activation of Rho family GTPases via PDZ-Rho guanine nucleotide exchange factors. Further upstream in the carboxyl terminal tail, LPAR1 contains a di-leucine sequence (a.a. 351 and 352), which is required for phorbol ester-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 289 LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H

induced internalization. Still further upstream lies a serine-rich cluster (a.a. 341-347) that is required for beta-arrestin association, which is critical for signal attenuation and receptor endocytosis. prefrontal cortex, caudate nucleus, hypothalamus, mice have deficiencies in olfactory development that medulla oblongata, olfactory bulb, parietal lobe, spinal impairs their ability to locate maternal nipples and cord and thalamus. initiate suckling required for survival. The lack of Moderately high level of expression is found in olfactant detection leads to 50% lethality among pups. adipocytes, cingulated cortex, occipital lobe, pons, Other LPAR1-null mice demonstrate alterations in whole brain, globus pallidus, subthalamic nucleus, neurotransmitters that mimic models of schizophrenia. temporal lobe, appendix, monocytes and smooth LPAR1-null mice are 10-15% shorter than wild-type muscle. mice and have gross anatomical defects due to bone Slightly above median level of expression is found in development, including incisor overgrowth that affects bronchial epithelial cells, cerebellum peduncies, dorsal ability to feed. The LPAR1 functions in normal cortical root ganglia, ciliary ganglion, uterus, uterus corpus, development and commits cortical neuroblasts to atrioventricular node, fetal lung, fetal thyroid, skeletal differentiate through the neural lineage. It may also muscle, cardiac myocytes, salivary gland, tongue and play a role in the formation of dendritic spine synapses. lymph node. It is also expressed in tissues during Through autotoxin-generated LPA, LPAR1 mediates neuronal development. The expression of LPAR1 is neuropathic pain induced by nerve injury. Activation of increased in blister skin compared to normal skin. The the LPAR1 functions in the inflammatory response; mRNA of LPAR1 is significantly increased 8 days after receptor activation stimulates the recruitment of unilateral uretheral obstruction in mice kidneys where macrophages. expression is higher in the medulla than the cortex. The The LPAR1 positively regulates motility in a variety of expression of LPAR1 is variable in cancer. cell types, exerting a dominant signal in the absence of Localisation LPAR4. It is a requirement of G protein-coupled receptor Homology functioning that receptors are embedded into The LPAR1 has significant homology with LPAR2 membranes for proper structure. The LPAR1 spans the (57%) and LPAR3 (51%), members of the original or plasma membrane seven times in a barrel conformation classical endothelial differentiation gene (Edg) family. with three extracellular and three intracellular loops. At It has approximately 33-38% homology with individual steady state, LPAR1 is located on the plasma sphingosine 1-phosphate receptors and no significant membrane at the cell surface until it binds LPA, which homology with the purinergic family of receptors that triggers dynamin2-dependent, clathrin-mediated also bind LPA. endocytosis into the cell. LPAR1 requires membrane cholesterol for association with beta-arrestin, which Mutations targets the receptor to clathrin-coated pits for internalization. In addition to LPA, phorbol ester Note stimulation of protein kinase C also induces There are several single nucleotide polymorphisms internalization of LPAR1, but this does not require (SNPs) reported within the LPAR1 gene and several of beta-arrestin. Rather, phorbol ester-dependent these are associated with altered phenotype and disease internalization of LPAR1 requires AP-2 clathrin states. adaptors. The LPAR1 is subsequently sorted through A functional SNP located in the promoter region of the Rab-5 dependent early and recycling endosomes before gene (-2,820G/A; rs10980705) is associated with it is recycled back to the cell surface or degraded in increased susceptibility to knee osteoarthritis in lysosomes. Japanese by showing an increase in binding and The receptor may also be localized to the nuclear activity. membrane in the cell. Some evidence indicates that a A change in amino acid sequence at position 125 from portion of the total cellular LPAR1 localizes to the glutamine to glutamate in the LPAR1 will result in the nuclear membrane in PC12 cells, micro-vascular ability of the receptor to recognize both S1P and LPA. endothelial cells, and human bronchial epithelial cells. A change in amino acid sequence at position 236 from The exact function of this nuclear LPAR1 pool is not threonine to lysine in the LPAR1 will result in the known. enhanced activation of serum response factor. Mutations in the LPAR1 were detected in a small Function percentage of adenomas and adenocarcinomas of rats The LPAR1 binds LPA and initiates G protein- given BHP in their drinking water. Missense mutations dependent signal transduction cascades throughout the in the LPAR1 were detected in rat hepatocellular cell that result in a number of functional outcomes, carcinomas induced by N-nitroso-diethylamine and depending on the specific cell or tissue type. The G choline-deficient l-amino acid-defined diets. alpha proteins involved are Gi, Gq and G 12/13. The Deletion of the PDZ domain of the receptor prevents receptor has critical functions that have been elucidated signal attenuation that controls LPA-mediated receptor through gene knock-out studies in mice. LPAR1-null activation and cell proliferation.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 290 LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H

LPAR1 links lung injury with pulmonary fibrosis Implicated in development. References Various cancers Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J. Note Requirement for the lpA1 lysophosphatidic acid receptor gene Overexpression of the LPAR1 in mice contributes to in normal suckling behavior. Proc Natl Acad Sci U S A. 2000 the tumorigenicity and aggressiveness of ovarian Nov 21;97(24):13384-9 cancer. Wang DA, Lorincz Z, Bautista DL, Liliom K, Tigyi G, Parrill AL. A single amino acid determines lysophospholipid specificity of Prognosis the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth Upregulation of the LPAR1 appears to enhance tumor factor receptors. J Biol Chem. 2001 Dec 28;276(52):49213-20 progression in the previous examples. Gobeil F Jr, Bernier SG, Vazquez-Tello A, Brault S, Oncogenesis Beauchamp MH, Quiniou C, Marrache AM, Checchin D, The LPAR1 is a proto-oncogene contributing to the Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A, Goetzl EJ, Chemtob S. Modulation of pro-inflammatory gene metastatic potential of breast cancers and may require expression by nuclear lysophosphatidic acid receptor type-1. J signals from ErbB2/HER2 dimerization. In a study Biol Chem. 2003 Oct 3;278(40):38875-83 designed to assess the functional conseq-uences of Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, overexpression as it relates to breast carcinogenesis, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, 1000 selected/suspected cDNAs were inserted into Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ, immortalized MCF-10A cells and a derivative cell line, Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS, Maycox PR. LPA1 receptor-deficient mice have phenotypic MCF-10A.B2 expressing an inducibly active variant of changes observed in psychiatric disease. Mol Cell Neurosci. ErbB2. The study examined three assays (cell 2003 Dec;24(4):1170-9 proliferation, migration and 3-D matrigel acinar Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H. morphogenesis) and the LPAR1 scored positive in all Agonist-induced endocytosis of lysophosphatidic acid-coupled three; thus, it was determined to be a proto-oncogene in LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent this disease. Several observations are of interest: first, pathway. J Cell Sci. 2003 May 15;116(Pt 10):1969-80 the LPAR1 induced migration in the absence of ErbB2 Avendaño-Vázquez SE, García-Caballero A, García-Sáinz JA. activation but not in the absence of dimerization which Phosphorylation and desensitization of the lysophosphatidic suggests that the LPAR1 may require weak signals acid receptor LPA1. Biochem J. 2005 Feb 1;385(Pt 3):677-84 from ligand-independent dimerization of ErbB2 to Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, induce migration; second, in the acinar morphogenesis Maycox PR, Dawson LA. Neurochemical changes in LPA1 assay, phenotypical changes of cells with the LPAR1 receptor deficient mice--a putative model of schizophrenia. included the formation of features of invasive tumor Neurochem Res. 2005 Mar;30(3):371-7 cells, such as disorganized acinar structure, large Yamada T, Ohoka Y, Kogo M, Inagaki S. Physical and structures and protrusive behavior; third, the LPAR1 functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange was capable of establishing abnormal 3-D factors (RhoGEFs). J Biol Chem. 2005 May 13;280(19):19358- morphogenesis in the absence of conditions to dimerize 63 ErbB2. Pilpel Y, Segal M. The role of LPA1 in formation of synapses Lung injury among cultured hippocampal neurons. J Neurochem. 2006 Jun;97(5):1379-92 Note Waters CM, Saatian B, Moughal NA, Zhao Y, Tigyi G, The LPAR1 mediates fibroblast migration and Natarajan V, Pyne S, Pyne NJ. Integrin signalling regulates the recruitment in the injured lung. The chemotactic nuclear localization and function of the lysophosphatidic acid activity of fibroblasts is dependent on LPAR1 receptor-1 (LPA1) in mammalian cells. Biochem J. 2006 Aug expression. 15;398(1):55-62 Disease Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron Pulmonary fibrosis B, Isakoff SJ, Brugge JS, LaBaer J. Functional proteomics The concentration of LPA is elevated in broncho- approach to investigate the biological activities of cDNAs alveolar lavage samples from patients with idio-pathic implicated in breast cancer. J Proteome Res. 2006 pulmonary fibrosis. The fibroblasts of these patients Mar;5(3):599-610 require expression of LPAR1 for the chemotactic Fukushima N, Shano S, Moriyama R, Chun J. activity present in this pathology. Data suggests that Lysophosphatidic acid stimulates neuronal differentiation of LPAR1-null mice are substantially protected from cortical neuroblasts through the LPA1-G(i/o) pathway. Neurochem Int. 2007 Jan;50(2):302-7 fibroblast accumulation. This corresponds to lung injury where aberrant wound-healing responses Murph MM, Hurst-Kennedy J, Newton V, Brindley DN, Radhakrishna H. Lysophosphatidic acid decreases the nuclear exacerbate pulmonary fibrosis pathogenesis. localization and cellular abundance of the p53 tumor Prognosis suppressor in A549 lung carcinoma cells. Mol Cancer Res. 2007 Nov;5(11):1201-11

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Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, Pradère JP, Gonzalez J, Klein J, Valet P, Grès S, Salant D, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra Bascands JL, Saulnier-Blache JS, Schanstra JP. JP. LPA1 receptor activation promotes renal interstitial fibrosis. Lysophosphatidic acid and renal fibrosis. Biochim Biophys J Am Soc Nephrol. 2007 Dec;18(12):3110-8 Acta. 2008 Sep;1781(9):582-7 Estivill-Torrús G, Llebrez-Zayas P, Matas-Rico E, Santín L, Urs NM, Kowalczyk AP, Radhakrishna H. Different Pedraza C, De Diego I, Del Arco I, Fernández-Llebrez P, Chun mechanisms regulate lysophosphatidic acid (LPA)-dependent J, De Fonseca FR. Absence of LPA1 signaling results in versus phorbol ester-dependent internalization of the LPA1 defective cortical development. Cereb Cortex. 2008 receptor. J Biol Chem. 2008 Feb 29;283(9):5249-57 Apr;18(4):938-50 Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, Stephens C, Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Fang X, Mills GB. Lysophosphatidic acid receptors determine Windle JJ, Chen CK, Fang X. Role of LPA4/p2y9/GPR23 in tumorigenicity and aggressiveness of ovarian cancer cells. J negative regulation of cell motility. Mol Biol Cell. 2008 Natl Cancer Inst. 2008 Nov 19;100(22):1630-42 Dec;19(12):5435-45 Obo Y, Yamada T, Furukawa M, Hotta M, Honoki K, Mototani H, Iida A, Nakajima M, Furuichi T, Miyamoto Y, Fukushima N, Tsujiuchi T. Frequent mutations of Tsunoda T, Sudo A, Kotani A, Uchida A, Ozaki K, Tanaka Y, lysophosphatidic acid receptor-1 gene in rat liver tumors. Mutat Nakamura Y, Tanaka T, Notoya K, Ikegawa S. A functional Res. 2009 Jan 15;660(1-2):47-50 SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese. Hum Mol Genet. 2008 Jun 15;17(12):1790-7 Yamada T, Obo Y, Furukawa M, Hotta M, Yamasaki A, Honoki K, Fukushima N, Tsujiuchi T. Mutations of lysophosphatidic Murakami M, Shiraishi A, Tabata K, Fujita N. Identification of acid receptor-1 gene during progression of lung tumors in rats. the orphan GPCR, P2Y(10) receptor as the sphingosine-1- Biochem Biophys Res Commun. 2009 Jan 16;378(3):424-7 phosphate and lysophosphatidic acid receptor. Biochem Biophys Res Commun. 2008 Jul 11;371(4):707-12 This article should be referenced as such: Murph MM, Nguyen GH, Radhakrishna H, Mills GB. Murph MM, Radhakrishna H. LPAR1 (lysophosphatidic acid Sharpening the edges of understanding the structure/function receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2010; of the LPA1 receptor: expression in cancer and mechanisms of 14(3):289-292. regulation. Biochim Biophys Acta. 2008 Sep;1781(9):547-57

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PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Montserrat Sanchez-Cespedes Programa d'Epigenetica i Biologia del Cancer-PEBC, Institut d'Investigacions Biomediques Bellvitge (IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de l'Hospitalet, 199-203 08907-L'Hospitalet de Llobregat-Barcelona, Spain (MSC)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/PIK3CAID415ch3q26.html DOI: 10.4267/2042/44713 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

(gi 5931525), the later one in the Cat Eye Syndrome Identity region. These regions are highly homolog to the Other names: EC 2.7.1.153; MGC142161; sequences of exons 9 and 11-13 of the PIK3CA gene. MGC14216 Transcription PI3K; p110-alpha The human PIK3CA transcript has an open reading HGNC (Hugo): PIK3CA frame of 3,207-bp, predicting a protein of 1,068 amino Location: 3q26.32 acid residues. Local order: centromere-KCNMB2-ZMAT3- BC032034-PIK3CA-KCNMB3-ZNF639-MFN1- Protein GNB4- telomere Description DNA/RNA The PIK3CA gene encodes the p110alpha protein which is a catalytic subunit of the class I PI 3-kinases (PI3K). Class I PI3K are heterodimeric molecules composed of a catalytic subunit, a p110, and a Relative size of the 21 exons of PIK3CA. The entire exon 1 is regulatory subunit. There are three possible calatytic UTR (untranslated region). Exon numeration corresponds to the subunits p110alpha, beta or delta. prevalent transcript (NM-006218). Description Expression The PIK3CA gene spans a total genomic size of 86,190 Widely expressed. bases and is composed of 21 exons, 20 of them coding Localisation exons of varying lengths. Putative pseudogenes of The p110alpha localizes in the cytoplasm. PIK3CA have been described on chromosomes 16 (gi 28913054) and 22q11.2

p110alpha conserved domains. Through its adaptor binding domain p110alpha interacts with the regulatory subunit. C2 domain, protein- kinase-C-homology-2 domain.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 293 PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M

Function tion has also been proposed as a mechanism for oncogene activation in some tumors (Angulo et al., Class I PI 3-kinases (PI3K) are linked to many cellular 2008). Because PIK3CA is now considered an functions, including cell growth, prolifera-tion, important oncogene implicated in the development of a differentiation, motility, survival and intra-cellular wide variety of human cancers, efforts are now being trafficking. PI3K convert PI(4,5)P2 to PI(3,4,5)P3 on directed towards the development of mole-cules that the inner leaflet of the plasma membrane. The inhibit the activity of PI3K (Garcia-Echeverria et al., PI(3,4,)P3 provokes the recruitment to cellular 2008). These could be efficient in the treatment of membranes of a variety of signalling proteins, those tumors carrying constitutive activation of PI3K containing PX domain, pleckstrin homo-logy domains pathway. PTEN is a well known tumor suppressor that (PH domains), FYVE domains and other counteracts the action of PI3K by dephosphorylating phosphoinositide-binding domains. One of these is the the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus, protein kinase B (PKB/AKT) a very well known the treatment with drugs that inhibit p110alpha activity protein that is activated as a result of its translocation to would be also potentially efficient in patients whose the cell membrane where it is then phosphorylated and tumors carry genetic alterations at PTEN. activated by another kinase, called phosphoinositide It has recently been reported that activation of the PI3K dependent kinase 1 (PDK1). The phosphorylation of pathway in breast tumors with concomitant ERBB2 AKT leads to the activation of the TSC/mTOR gene amplification, either through PIK3CA mutations pathway. PTEN, a tumor suppressor inactivated in or PTEN inactivation, underlies trastuzumab resistance. many cancers counteracts the action of PI3K by These findings may provide a biomarker to identify dephosphoryla-ting the phosphoinositide-3,4,5- patients unlikely to respond to trastuzumab-based trisphosphate (PIP3) (Lee et al., 2007).The PI3K are therapy (Berns et al., 2007). inhibited by the drugs wortmannin and LY294002 although to various degree of sensitivity among the different classes. To be noted Note Mutations Recent evidence has shown that the PIK3CA gene is mutated and amplified in a range of human cancers. Somatic Due to that p110alpha is believed to be a promising Somatic mutations at the PIK3CA gene have been drug target. A number of pharmaceutical companies are found in tumors and thus, it can be considered a bona currently designing and charactering potential fide oncogene (Samuels et al., 2004). Most of the p110alpha isoform specific inhibitors. mutations cluster in hotspots within the helical or the catalytic domains. References Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Implicated in Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High A wide variety of human cancers frequency of mutations of the PIK3CA gene in human cancers. Note Science. 2004 Apr 23;304(5670):554 (For example, colon, breast, endometrial, ovarian, Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K brain, lung, thyroid, head and neck and stomach). deregulates transcription and translation. Nat Rev Cancer. PIK3CA mutations lead to constitutive activation of 2005 Dec;5(12):921-9 p110alpha enzymatic activity, stimulate AKT Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase signaling, and allow growth factor-independent growth mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7 (Bader et al., 2005). In addition, when expressed in normal cells, these mutations allow anchorage- Qiu W, Schönleben F, Li X, Ho DJ, Close LG, Manolidis S, independent growth, further attesting to their important Bennett BP, Su GH. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2006 Mar role in cancer development (Kang et al., 2005). 1;12(5):1441-6 PIK3CA somatic mutations are frequent in a variety of Schönleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, human primary tumors and cancer cell lines such as, Remotti HE, Su GH. PIK3CA mutations in intraductal papillary among others, those of the colon, breast, and stomach mucinous neoplasm/carcinoma of the pancreas. Clin Cancer (Samuels et al., 2004). However, in other tumors, i.e. Res. 2006 Jun 15;12(12):3851-5 those of the lung, head and neck, brain, endometrium, Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans ovary, prostate, osteosarcoma and pancreas, EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, hematopoietic malignancies, PIK3CA mutations are not Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, as common (Angulo et al., 2008; Qiu et al., 2006; Bernards R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in Muller et al., 2007; Samuels et al., 2004; Schonleben et breast cancer. Cancer Cell. 2007 Oct;12(4):395-402 al., 2006). PIK3CA gene amplifica-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 294 PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M

Lee JY, Engelman JA, Cantley LC. Biochemistry. PI3K charges PIK3CA overexpression by gene amplification. J Pathol. 2008 ahead. Science. 2007 Jul 13;317(5835):206-7 Feb;214(3):347-56 Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Garcia-Echeverria C, Sellers WR. Drug discovery approaches Kawamata N, Luong QT, Koeffler HP. Rare mutations of the targeting the PI3K/Akt pathway in cancer. Oncogene. 2008 PIK3CA gene in malignancies of the hematopoietic system as Sep 18;27(41):5511-26 well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res. 2007 This article should be referenced as such: Jan;31(1):27-32 Sanchez-Cespedes M. PIK3CA (phosphoinositide-3-kinase, Angulo B, Suarez-Gauthier A, Lopez-Rios F, Medina PP, catalytic, alpha polypeptide). Atlas Genet Cytogenet Oncol Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC, Haematol. 2010; 14(3):293-295. Sanchez-Cespedes M. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective

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Gene Section Review

SFRP4 (Secreted Frizzled-Related Protein 4) Kendra S Carmon, David S Loose University of Texas Health Science Center Houston, Houston, TX 77030, USA (KSC, DSL)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/SFRP4ID42277ch7p14.html DOI: 10.4267/2042/44714 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Transcription The SFRP4 mRNA transcript is 2974 bp, 1041 bp are Other names: FRP-4; sFRP-4; FRPHE; MGC26498; coding sequence. Ensembl data predicts a second LOC6424 transcript from the SFRP4 gene, lacking the 81 bp exon HGNC (Hugo): SFRP4 2, although this has not been demons-trated. Location: 7p14.1 Local order: According to NCBI, SFRP4 is telomeric Protein to EPDR1 (7p14.1) ependymin related protein 1 Description (zebrafish) and STARD3NL (7p14-p13) StAR-related lipid transfer domain containing 3 N-terminal like and SFRP4 protein is comprised of 346 amino acids with a centromeric to TXNDC3 (7p14.1) thioredoxin domain predicted molecular weight of 39.9 kDa and an actual containing 3 (spermatozoa) and GPR141 (7p14.1) G molecular weight of approximately 50-55 kDa. protein-coupled receptor 141. SFRP4 belongs to a family of five SFRPs; these proteins fold into two independent domains. The N- DNA/RNA terminus contains a secretion signal peptide followed by a ~120 amino acid cysteine-rich domain (CRD). The Description CRD is 30-50% identical to the extracellular putative Wnt-binding domain of frizzled (Fzd) receptors and is The SFRP4 gene spans 10.99 kb on the short arm of characterized by the presence of ten cysteine residues at and is transcribed from the minus strand conserved positions. in the centromere-to-telomere orientation. The gene is encoded by six exons with the trans-lation initiation codon in the first exon.

Diagram illustrates SFRP4 gene that contains a total of six exons.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 296 SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS

Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain (CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.

These cysteines form a pattern of disulfide bridges. The adult uterine morphology and function. SFRP4 has C-terminal portion of the SFRP protein is characterized been shown to increase apoptosis during ovulation. by segments of positively charged residues that appear Transgenic studies have found that SFRP4 decreases to confer heparin-binding properties in at least two bone formation and inhibits osteoblast proliferation by SFRPs (SFRP1 and SFRP3) and contains a netrin- attenuating canonical/beta-catenin-Wnt signaling. related motif (NTR) with six cysteine residues that SFRP4 reportedly exhibits phospha-turic effects by most likely form three disulfide bridges. NTR domains specifically inhibiting sodium-dependent phosphate with similar features are found in a wide range of uptake. unrelated proteins, including Netrin-1, tissue inhibitors Homology of metallo-proteinases (TIMPs), complement proteins and type I procollagen C-proteinase enhancer proteins Of the five human SFRPs (SFRP1, SFRP2, SFRP3, (PCOLCEs). The six conserved cysteines in the NTR SFRP4, SFRP5), SFRP4 shares most significant of SFRP4 share a similar spacing to SFRP3, whereas homology with SFRP3. those of the SFRP1/SFRP2/SFRP5 subgroup are distinctively different, indicating a disparity in disulfide Mutations bond formation. Uniquely, SFRP4 contains two Note additional cysteine residues. The overall function of the It was reported that the T allele of the SFRP4 gene NTR is unknown, yet there is some evidence that the polymorphism ARG262 (CGC to CGT) of exon4 is NTR may also play a role in Wnt binding. This implies associated with decreased bone mineral density in post- that multiple Wnt binding sites may exist on SFRP menopausal Japanese women. molecules and/or that SFRPs exhibit differential affinities for Wnt ligands according to the different SFRP conformational and post-translational Implicated in modifications. Endometrial Carcinoma Expression Note SFRP4 is expressed in various normal tissues including SFRP4 was more frequently down-regulated in endometrium (specifically stromal cells with higher (microsatellite instability). MSI cancers as compared expression during proliferative phase of menstrual with (microsatellite stable) MSS endo-metrioid cycle), ovary, kidney, heart, brain, mammary gland, endometrial cancers. Expression of SFRP4 is decreased cervix, pancreas, stomach, colon, lung, skeletal muscle, in both low-grade endometrial stromal sarcoma and testis, eye, bone, prostate, and liver. undifferentiated endometrial sarcoma. Localisation Malignant Pleural Mesothelioma Secreted from cell; extracellular matrix; bound to Note plasma membrane. SFRP4 promoter is frequently methylated in this cancer Function leading to inhibition of expression and is associated with abnormal growth; restoration of SFRP4 results in Since SFRPs share a similar CRD with the Fzd family growth suppression and apoptosis in mesothelioma cell of receptors; it is believed that SFRPs may act as lines. soluble modulators that compete with Fzd to bind the Wnt ligands, thereby altering the Wnt signal. Individual Tumor-induced osteomalacia SFRPs also have distinct binding specificity for distinct Note Wnt ligands. Reports have demonstrated that SFRP4 Tumor-induced osteomalacia is a disorder in which binds Wnt7a and there is conflicting data for SFRP4 there is an increase in renal phosphate excretion and a binding to Wnt3a. SFRP4 expression is regulated by reduction in serum phosphate levels leading to estrogen and progesterone and may act as a regulator of hyperphosphaturia, hypophosphatemia and rickets.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 297 SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS

CLUSTAL alignment of the 5 human SFRPs.

SFRP4 is highly expressed in such tumors and tumors of cancer patients versus matched adjacent functions as a circulating phosphaturic factor that tissue controls. antagonizes renal Wnt-signaling. Gastric Carcinoma Breast Cancer Note Note The SFRP4 was highly methylated in gastric carcinoma Studies have found evidence for SFRP4 overexpression samples with greater instance in H. pylori positive in breast cancer. patients. Pancreatic Cancer Prostate Cancer Note Note SFRP4 found to be significantly hypermethylated in the SFRP4 is overexpressed in prostate cancers and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 298 SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS

functions to inhibit cell proliferation and metastatic Yamaguchi TP. Heads or tails: Wnts and anterior-posterior potential. patterning. Curr Biol. 2001 Sep 4;11(17):R713-24 Prognosis Chong JM, Uren A, Rubin JS, Speicher DW. Disulfide bond assignments of secreted Frizzled-related protein-1 provide Increased expression of membranous SFRP4 is insights about Frizzled homology and netrin modules. J Biol associated with a good prognosis in human localized Chem. 2002 Feb 15;277(7):5134-44 androgen-dependent prostate cancer, suggesting a role Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi for sFRP4 in early stage disease. O, Ouchi Y, Inoue S. Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy. J B-cell chronic lymphocytic leukemia Mol Endocrinol. 2002 Jun;28(3):213-23 Note Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, SFRP4 was found to be frequently methylated and Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted downregulated in CLL samples. frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003 Sep;112(5):785-94 Colorectal Carcinoma Drake JM, Friis RR, Dharmarajan AM. The role of sFRP4, a Note secreted frizzled-related protein, in ovulation. Apoptosis. 2003 SFRP4 expression was shown to be up-regulated in Aug;8(4):389-97 colorectal cancer. Ace CI, Okulicz WC. Microarray profiling of progesterone- regulated endometrial genes during the rhesus monkey Esophageal Adenocarcinoma secretory phase. Reprod Biol Endocrinol. 2004 Jul 7;2:54 Note Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi SFRP4 mRNA and protein expression were T, Orimo H, Ouchi Y, Inoue S.. Association of a single significantly decreased due to hypermethylation in nucleotide polymorphism in the secreted frizzled-related esophageal adenocarcinoma and Barrett's esophagus protein 4 (sFRP4) gene with bone mineral density. Ger. Geront. Int. 2004; 4 (3): 175-180. patients. Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD, References Grygiel JJ, Sutherland RL. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu in localized prostate cancer and inhibits PC3 cellular NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS. proliferation in vitro. Clin Cancer Res. 2004 Jan 15;10(2):615- Purification and molecular cloning of a secreted, Frizzled- 25 related antagonist of Wnt action. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6770-5 Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D, Lax S, Moinfar F, Tabrizi AD, Isadi-Moud N, Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Zatloukal K, Denk H. Inverse correlation of secreted frizzled- Sokol SY, Kocher O. Differential expression of frpHE: a novel related protein 4 and beta-catenin expression in endometrial human stromal protein of the secreted frizzled gene family, stromal sarcomas. J Pathol. 2004 Sep;204(1):19-27 during the endometrial cycle and malignancy. Lab Invest. 1999 Apr;79(4):439-47 Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM. Expression of the secreted Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson frizzled-related protein gene family is downregulated in human SA. Interaction of frizzled related protein (FRP) with Wnt mesothelioma. Oncogene. 2004 Aug 26;23(39):6672-6 ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem. He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, 1999 Jun 4;274(23):16180-7 Mazieres J, Mikami I, McCormick F, Jablons DM. Secreted frizzled-related protein 4 is silenced by hypermethylation and Bányai L, Patthy L. The NTR module: domains of netrins, induces apoptosis in beta-catenin-deficient human secreted frizzled related proteins, and type I procollagen C- mesothelioma cells. Cancer Res. 2005 Feb 1;65(3):743-8 proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases. Protein Sci. 1999 Risinger JI, Maxwell GL, Chandramouli GV, Aprelikova O, Litzi Aug;8(8):1636-42 T, Umar A, Berchuck A, Barrett JC. Gene expression profiling of microsatellite unstable and microsatellite stable endometrial Dennis S, Aikawa M, Szeto W, d'Amore PA, Papkoff J. A cancers indicates distinct pathways of aberrant signaling. secreted frizzled related protein, FrzA, selectively associates Cancer Res. 2005 Jun 15;65(12):5031-7 with Wnt-1 protein and regulates wnt-1 signaling. J Cell Sci. 1999 Nov;112 ( Pt 21):3815-20 Zou H, Molina JR, Harrington JJ, Osborn NK, Klatt KK, Romero Y, Burgart LJ, Ahlquist DA. Aberrant methylation of Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro secreted frizzled-related protein genes in esophageal DP, Cumberledge S, Rubin JS. Secreted frizzled-related adenocarcinoma and Barrett's esophagus. Int J Cancer. 2005 protein-1 binds directly to Wingless and is a biphasic modulator Sep 10;116(4):584-91 of Wnt signaling. J Biol Chem. 2000 Feb 11;275(6):4374-82 Berndt TJ, Bielesz B, Craig TA, Tebben PJ, Bacic D, Wagner Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy CA, O'Brien S, Schiavi S, Biber J, Murer H, Kumar R. Secreted DJ. Insights into Wnt binding and signalling from the structures frizzled-related protein-4 reduces sodium-phosphate co- of two Frizzled cysteine-rich domains. Nature. 2001 Jul transporter abundance and activity in proximal tubule cells. 5;412(6842):86-90 Pflugers Arch. 2006 Jan;451(4):579-87 Roszmusz E, Patthy A, Trexler M, Patthy L. Localization of Feng Han Q, Zhao W, Bentel J, Shearwood AM, Zeps N, disulfide bonds in the frizzled module of Ror1 receptor tyrosine Joseph D, Iacopetta B, Dharmarajan A. Expression of sFRP-4 kinase. J Biol Chem. 2001 May 25;276(21):18485-90

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 299 SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS

and beta-catenin in human colorectal carcinoma. Cancer Lett. Carmon KS, Loose DS. Secreted frizzled-related protein 4 2006 Jan 8;231(1):129-37 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol Cancer Res. 2008 Liu TH, Raval A, Chen SS, Matkovic JJ, Byrd JC, Plass C. Jun;6(6):1017-28 CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, leukemia. Cancer Res. 2006 Jan 15;66(2):653-8 Weisenberger DJ, Campan M, Laird PW. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA Turashvili G, Bouchal J, Burkadze G, Kolar Z. Wnt signaling methylation analysis. Lab Invest. 2008 Feb;88(2):161-70 pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73(5):213-23 Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T. Osteoblast-targeted expression of Wawrzak D, Métioui M, Willems E, Hendrickx M, de Genst E, Sfrp4 in mice results in low bone mass. J Bone Miner Res. Leyns L. Wnt3a binds to several sFRPs in the nanomolar 2008 Feb;23(2):271-7 range. Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23 This article should be referenced as such: Bu XM, Zhao CH, Zhang N, Gao F, Lin S, Dai XW. Carmon KS, Loose DS. SFRP4 (Secreted Frizzled-Related Hypermethylation and aberrant expression of secreted frizzled- Protein 4). Atlas Genet Cytogenet Oncol Haematol. 2010; related protein genes in pancreatic cancer. World J 14(3):296-300. Gastroenterol. 2008 Jun 7;14(21):3421-4

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 300

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Stephen Hiscox Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, UK (SH)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/SRCID448ch20q11.html DOI: 10.4267/2042/44715 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: ASV (Avian Sarcoma Virus); SRC1; c- Note SRC; p60-Src; pp60c-Src Src can be phosphorylated on Tyr-530 by CSK (c-Src HGNC (Hugo): SRC kinase). The phosphorylated form is termed pp60c-src. Phosphorylation of this tyrosine allows facilitates Location: 20q11.23 interaction between the C-terminal tail and the SH2 Note domain, maintaining Src in an inactive formation. The Src kinase proto-oncogene has a high degree of Protein Translation: similarity to the v-src gene of Rous sarcoma virus, MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFP although the C-terminal domain of v-Src is trunca-ted ASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGF and lacks the regulatory Tyr527 and therefore is not NSSDTVTSPQRAGPLAGGVTTFVALYDYESRTET subjected to downregulation by Csk. Src kinase is DLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGY implicated in the regulation of embryonic development, IPSNYVAPSDSIQAEEWYFGKITRREGQGCFGEV cell differentiation and proliferation. Src has been WMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQV suggested to play a key role in cancer, where it may MKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLL facilitate tumour spread through promotion of tumour DFLKGETGKYLRLPQLVDMAAQIASGMAYVER cell invasion. MNYVHRDLRAANILVGENLVCKVADFGLARLIE DNEYTARQGAKFPIKWTAPEAALYGRFTIKSDV DNA/RNA WSFGILLTELTTKGRVPYPGMVNREVLDQVERG YRMPCPPECPESLHDLMCQCWRKEPEERPTFEYL Note QAFLEDYFTSTEPQYQPGENL The gene consists of 14 exons. Two isoforms have been Note: This variant (isoform 1) represents the longer Src described differing in their 5' UTRs. Variant 1 transcript although both isoforms 1 and 2 encode the represents the longer transcript although both isoforms same protein as the difference is in the 5' UTR. 1 and 2 encode the same protein. Description Size: 61.33 Kb, 14 exons. mRNA: 4145 bases.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 301 SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S

Linear representation of the protein structure of human Src family members, showing the six distinct domains. N and C denote N- and C- termini respectively. Location of major regulatory phosphorylation sites and the myristolation signal sequence are shown. Description transcription events. The ability of Src to function as both an effector and regulator of receptor-induced Size: 536 amino acids; 59.835 KDa. signalling allows it to mediate cross-talk between Src is 59.6 KDa in size and has a domain structure normally distinct signalling pathways and thus regulate comprised of six distinct functional regions (see figure a wide variety of both normal and oncogenic processes, above). These include an N-terminal SH4 domain that including proliferation, differentiation, survival, contains a lipid-modification sequence allowing adhesion, motility, invasion and angiogenesis. targeting of Src to cellular membranes, and an adjacent, poorly-conserved region thus being unique to each Src Homology family member. SH3 and SH2 domains adjacent to the c-Src is the prototypic member of a family of nine non- N-terminus facilitate protein-protein interactions receptor tyrosine kinases which share the same domain between Src and its interacting proteins whilst the SH1 structure (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr and domain allows ATP and substrate binding and has Frk) (Erpel and Courtneidge, 1995) and are expressed tyrosine kinase activity; autophosphorylation of Y419 in vertebrates. All Src family members have the same within this domain is required for the maximum kinase basic structure of an N-terminal, unique domain activity of Src. The negative regulatory tail of Src containing a myristylation site and frequently a contains a tyrosine at 530, the phosphorylation of palmitoylation site; regulatory SH3 and SH2 domains; which promotes a conformational change to produce an a catalytic domain that has its active site wedged inactive Src molecule. Sequences within the C- between the two lobes of the molecule, and a C- terminus of Src have been recently identified to terminal regulatory tail that contains the hallmark facilitate protein-protein interactions have been shown regulatory tyrosine residue (Tyr527 in Src). The to regulate Src function in addition to its kinase activity of Src family kinases is suppressed upon activity. phosphorylation of Tyr527, allowing binding of the C- Expression terminal domain to the SH2 domain. The SH2 and SH3 domains bind phosphotyrosine and proline-rich Ubiquitously expressed but with particularly high peptides, respectively; through these interactions, they levels in brain tissue, osteoclasts and platelets. participate in intra- and intermolecular regulation of Localisation kinase activity, as well as localization and substrate recognition. Differences in the SH2 linker sequences Predominantly cytoplasmic and/or plasma mem-brane, within Src family kinases correlate with the division of the latter due to myristolation of the N-terminus. the Src kinase family into two separate subfamilies: Activated Src has also been reported in the cell nucleus Group A: Src, Fyn, Yes, Fgr and Group B: Lyn, Hck, in some tumour tissues. Lck and Blk. Frk forms a separate but linked subfamily Function but with homologues also found in invertebrates. Src Src can interact with a diverse array of cellular factors family members, with the exception of Src, Fyn and allowing it to regulate a variety of normal and Yes, exhibit tissue-restricted distribution, being found oncogenic processes that ultimately result in cell primarily in cells of a haematopoietic nature. Below is proliferation, differentiation, survival, adhe-sion, a table constructed from Src homology analysis motility, invasion and angiogenesis (Thomas and performed by CluSTr: Brugge, 1997; Summy and Gallick, 2003). Such Src family interacting partners include receptor tyrosine kinases % identity* % similarity** (e.g. the EGF receptor family (Biscardi et al., 1998)), member integrins (Galliher and Schiemann, 2006; Huveneers et Fyn 75 10 al., 2007), cell-cell adhesion molecules (Giehl and Yes 73 9 Menke, 2008), in addition to STATs (Silva, 2004), FAK (Brunton and Frame, 2008), the adaptor protein Fgr 66 11 p130Cas (Chang et al., 2008) and GPCRs (McGarrigle Lck 60 17 and Huang, 2007). Importantly, Src can also interact with the oestrogen receptor (Weatherman, 2008), where Lyn 60 17 it has been shown to be pivotal in both non-genomic Hck 57 17 ER activation of signalling pathways and gene

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 302 SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S

Blk 62 13 family allowing Src to regulate signal-ling pathways that may contribute to aggressive breast cancer cell *Percent identity between Src and protein; defined as: (Same behaviour. Src is also intimately involved with Her2 AAs/Length of Protein 1) X100% pathway signalling in breast cancer, the result of which **Percent similarity between Src and protein; defined as: (Sim. is the promotion of an invasive phenotype (Vadlamudi AAs/Length of Protein 1) X100% et al., 2003; Tan et al., 2005). Mutations Oestrogenic signalling plays a critical role in promoting breast cancer cell growth where ligand-induced Somatic activation of oestrogen receptors (ERs) results in gene transcription mediated by the ER, in complex with The SRC family of kinases is rarely mutated in primary various co-activators/co-repressor molecules. In such human tumours, although apparently scarce, a cases, Src is able to potentiate ER-mediated, AF-1 truncating and activating mutation in Src (at aa 531) dependent gene transcription through indirect has been described for a small subset of advanced-stage phosphorylation of nuclear ER via ERK1/ERK2 (Feng colorectal cancers (Irby et al., 1999). et al., 2001) and Akt (Campbell et al., 2001; Shah et al.,

2005) and through regulation of FAK-p130CAS-JNK Implicated in signalling pathway activity and the subsequent activation of co-activator molecules including CBP Cancer (PAG1) and GRIP1 (NCOA2). Furthermore, Src Note appears to mediate non-genomic ER signalling through Elevated Src expression and/or activity has been ERK and Akt pathways (Castoria et al., 2001; Wessler reported in many different cancer types, where it may et al., 2006) to regulate cellular proliferation and associate with poor clinical prognosis (Irby and survival (Castoria et al., 1999; Migliaccio et al., 2000). Yeatman, 2000). Increased Src kinase activity in cancer That Src is involved in both EGFR/Her2 and ER is likely to arise from the deregulation of Src signalling has led to Src being implicated in growth expression and/or activation mechanisms rather than factor-ER cross talk mechanisms in breast cancer and the presence of activating mutations, since genetic the development of endocrine resistance (Arpino et al., mutations of this kind are rarely reported for Src (see 2008; Massarweh and Schiff, 2006; Hiscox et al., 2006; above). Whereas constitutively activated forms of Src Hiscox et al., 2009). are transforming, wild-type Src has a relatively low Hematopoietic cancers transformation potential suggesting that Src may act to facilitate intracellular signalling through regulation, Disease either directly or indirectly, of other signalling proteins. The majority of Src family kinases are highly expressed in cells of a hematopoietic origin where they are Colorectal cancer suggested to regulate growth and prolifera-tion. Src Disease itself is, along with related family kinase members, are Increased Src activity has been widely described in implicated in imatinib-resistant, BCR-ABL-expressing colorectal tumour tissue compared with normal CML (Li, 2008). epithelia and within colon polyps, particularly those Other tumour types displaying a malignant phenotype (DeSeau et al., 1987; Cartwright et al., 1994). In colorectal cancer tissue Disease studies, elevated Src kinase activity is associated with a Src protein and activity have been identified as being poor clinical outcome (Aligayer et al., 2002). In vitro increased in a number of other tumour types including studies suggest that in colon cancer, Src may contribute gastric, pancreatic, lung and ovarian tumours compared more to disease spread than to increased proliferation to normal tissue suggesting a possible role for Src in (Jones et al., 2002). these tumours. Breast cancer References Disease DeSeau V, Rosen N, Bolen JB. Analysis of pp60c-src tyrosine Src kinase activity is increased in breast cancer tissue kinase activity and phosphotyrosyl phosphatase activity in compared to normal tissues (Verbeek et al., 1996). In human colon carcinoma and normal human colon mucosal vivo animal models suggest that Src activity is elevated cells. J Cell Biochem. 1987 Oct;35(2):113-28 in breast tumours over-expressing HER2 and Cartwright CA, Coad CA, Egbert BM. Elevated c-Src tyrosine interaction between Src and erbB family members may kinase activity in premalignant epithelia of ulcerative colitis. J promote the develop-ment of a more aggressive disease Clin Invest. 1994 Feb;93(2):509-15 clinically (Biscardi et al., 2000; Tan et al., 2005). Erpel T, Courtneidge SA. Src family protein tyrosine kinases Physical interactions between Src and growth factor and cellular signal transduction pathways. Curr Opin Cell Biol. receptors are reported in breast cancer tissues and cells, 1995 Apr;7(2):176-82 particularly with receptor tyrosine kinases of the EGFR

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 303 SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S

Verbeek BS, Vroom TM, Adriaansen-Slot SS, Ottenhoff-Kalff Shah YM, Rowan BG. The Src kinase pathway promotes AE, Geertzema JG, Hennipman A, Rijksen G. c-Src protein tamoxifen agonist action in Ishikawa endometrial cells through expression is increased in human breast cancer. An phosphorylation-dependent stabilization of estrogen receptor immunohistochemical and biochemical analysis. J Pathol. 1996 (alpha) promoter interaction and elevated steroid receptor Dec;180(4):383-8 coactivator 1 activity. Mol Endocrinol. 2005 Mar;19(3):732-48 Thomas SM, Brugge JS. Cellular functions regulated by Src Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y, Fang D, Jing T, family kinases. Annu Rev Cell Dev Biol. 1997;13:513-609 Yu D. ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer Biscardi JS, Belsches AP, Parsons SJ. Characterization of metastasis. Cancer Res. 2005 Mar 1;65(5):1858-67 human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol Carcinog. 1998 Galliher AJ, Schiemann WP. Beta3 integrin and Src facilitate Apr;21(4):261-72 transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano Breast Cancer Res. 2006;8(4):R42 D, Migliaccio A, Auricchio F. Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. EMBO J. Hiscox S, Morgan L, Green T, Nicholson RI. Src as a 1999 May 4;18(9):2500-10 therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer. Endocr Relat Cancer. 2006 Dec;13 Suppl Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, 1:S53-9 Karl R, Fujita DJ, Jove R, Yeatman TJ. Activating SRC mutation in a subset of advanced human colon cancers. Nat Massarweh S, Schiff R. Resistance to endocrine therapy in Genet. 1999 Feb;21(2):187-90 breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer. 2006 Dec;13 Suppl Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ. Tyrosine 1:S15-24 kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Wessler S, Otto C, Wilck N, Stangl V, Fritzemeier KH. Res. 2000;2(3):203-10 Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak Irby RB, Yeatman TJ. Role of Src expression and activation in transcriptional activity. J Steroid Biochem Mol Biol. 2006 human cancer. Oncogene. 2000 Nov 20;19(49):5636-42 Jan;98(1):25-35 Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio Huveneers S, van den Bout I, Sonneveld P, Sancho A, A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Sonnenberg A, Danen EH. Integrin alpha v beta 3 controls Abbondanza C, Auricchio F. Steroid-induced androgen activity and oncogenic potential of primed c-Src. Cancer Res. receptor-oestradiol receptor beta-Src complex triggers prostate 2007 Mar 15;67(6):2693-700 cancer cell proliferation. EMBO J. 2000 Oct 16;19(20):5406-17 McGarrigle D, Huang XY. GPCRs signaling directly through Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Src-family kinases. Sci STKE. 2007 Jun 26;2007(392):pe35 Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of : a new model for anti- Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk estrogen resistance. J Biol Chem. 2001 Mar 30;276(13):9817- between the estrogen receptor and the HER tyrosine kinase 24 receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008 Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco Apr;29(2):217-33 A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F. PI3-kinase in concert with Src promotes the S- Brunton VG, Frame MC. Src and focal adhesion kinase as phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. therapeutic targets in cancer. Curr Opin Pharmacol. 2008 2001 Nov 1;20(21):6050-9 Aug;8(4):427-32 Feng W, Webb P, Nguyen P, Liu X, Li J, Karin M, Kushner PJ. Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP. Src Potentiation of estrogen receptor activation function 1 (AF-1) family kinase oncogenic potential and pathways in prostate by Src/JNK through a serine 118-independent pathway. Mol cancer as revealed by AZD0530. Oncogene. 2008 Oct Endocrinol. 2001 Jan;15(1):32-45 23;27(49):6365-75 Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Giehl K, Menke A. Microenvironmental regulation of E- Gallick GE. Activation of Src kinase in primary colorectal cadherin-mediated adherens junctions. Front Biosci. 2008 May carcinoma: an indicator of poor clinical prognosis. Cancer. 1;13:3975-85 2002 Jan 15;94(2):344-51 Li S. Src-family kinases in the development and therapy of Jones RJ, Avizienyte E, Wyke AW, Owens DW, Brunton VG, Philadelphia chromosome-positive chronic myeloid leukemia Frame MC. Elevated c-Src is linked to altered cell-matrix and acute lymphoblastic leukemia. Leuk Lymphoma. 2008 adhesion rather than proliferation in KM12C human colorectal Jan;49(1):19-26 cancer cells. Br J Cancer. 2002 Nov 4;87(10):1128-35 Weatherman RV. Sensing estrogen's many pathways. ACS Summy JM, Gallick GE. Src family kinases in tumor Chem Biol. 2008 Jun 20;3(6):338-40 progression and metastasis. Cancer Metastasis Rev. 2003 Dec;22(4):337-58 Hiscox S, Jordan NJ, Smith C, James M, Morgan L, Taylor KM, Green TP, Nicholson RI. Dual targeting of Src and ER prevents Vadlamudi RK, Sahin AA, Adam L, Wang RA, Kumar R. acquired antihormone resistance in breast cancer cells. Breast Heregulin and HER2 signaling selectively activates c-Src Cancer Res Treat. 2009 May;115(1):57-67 phosphorylation at tyrosine 215. FEBS Lett. 2003 May 22;543(1-3):76-80 This article should be referenced as such: Silva CM. Role of STATs as downstream signal transducers in Hiscox S. SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral Src family kinase-mediated tumorigenesis. Oncogene. 2004 oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Oct 18;23(48):8017-23 Haematol. 2010; 14(3):301-304.

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TACC3 (transforming, acidic coiled-coil containing protein 3) Melissa R Eslinger, Brenda Lauffart, Ivan H Still Department of Chemistry and Life Science Bartlett Hall, United States Military Academy, West Point, New York 10996, USA (MRE), Department of Physical Sciences, Arkansas Tech University, 1701 N Boulder Ave, Russellville, AR 72801, USA (BL), Department of Biological Sciences, Arkansas Tech University, 1701 N Boulder Ave, Russellville, AR 72801, USA (IHS)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/TACC3ID42458ch4p16.html DOI: 10.4267/2042/44716 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Other names: ERIC1; MGC117382; MGC133242 HGNC (Hugo): TACC3 Location: 4p16.3

exons between exon 1 and the first coding exon (exon DNA/RNA 2), based on NM_006342, is indicated based on several Description cDNAs that may however be from suspect cDNA libraries (see UCSC Genome Bioinformatics Site The gene is composed of 16 verified exons spanning (http://genome.ucsc.edu)). Four additional transcripts 23.6 kb. variants are suggested based on singleton Expressed Transcription sequence tags in tumor cell lines (AW516785, Encodes a single confirmed 2788 nt transcript BE552327, BX331864) and/or stem cell progenitors (NM_006342) (Still et al., 1999), although one (AV761182, CX872433). additional transcript with two additional small 5' coding Pseudogene None.

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SDS-PAGE. Additional variants are suggested based Protein on singleton cDNAs (see above) but their predicted Description protein isoforms have not been confirmed. TACC3 encodes a single protein of 838 amino acids Expression with a molecular mass of 90 kDa (Still et al., 1999). High levels during early (mouse) embryogenesis, in The protein is heavily phosphorylated based on direct particular during early differentiation of specific tissues evidence and based on predictions from the Xenopus (Sadek et al., 2003). In adult tissues, expression is and mouse orthologs (Beausoleil et al., 2004; relatively limited, with high levels noted in Beausoleil et al., 2008; Kinoshita et al., 2005; Yu et al., hematological tissues such as the thymus, spleen and 2007; Cantin et al., 2008; Dephoure et al., 2008). Thus, leukocytes, and reproductive tissues, especially meiotic human TACC3 migrates at approxi-mately 150 kDa in cells of the testes and ovary (Still et al., 1999; Sadek et al., 2003).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 306 TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.

Epithelial layers of the lung, mammary gland and ovary targets for cyclin dependent kinases in mitotic HeLa express TACC3 and alterations in expression are noted cells (Yu et al., 2007; Cantin et al., 2008; Dephoure et during tumorigenesis (see below). Expression in human al., 2008). By homology, Ser558 phosphorylation by adult tissues is summarized in Lauffart et al. 2006. TPX2 is required for nucleation of microtubules in Localisation meiotic oocytes (Brunet et al., 2008). TACC3 also has a defined role in interphase cells as a Human (and mouse) TACC3 is located in the transcriptional cofactor for the aryl-nuclear translocator interphase nucleus and/or cytosol, depending on cell protein (Sadek, 2000), FOG1 (Garriga-Canut and type and cancer type (Gergely et al., 2000; Aitola et al., Orkin, 2004; Simpson et al., 2004) and is a possible 2003; Lauffart et al., 2005; Jung et al., 2006; indirect activator of CREB via FHL family of Vettaikkorumakankauv et al., 2008). TACC3 does not coactivator/corepressor proteins (Lauffart et al., however contain a classical nuclear localisation signal 2007b). Roles in transcriptional regulation (Still et al., 1999). TACC3 associates with the centrosome in a cell cycle dependent manner (Gergely have also been proposed based on TACC3 binding to et al., 2000). Phosphorylation of TACC3 by Aurora A GAS41 (YEATS4) via the SDP repeat, histone acetyl on key serine residues is required for this interaction transferases hGCN5L2 (KAT2A), pCAF (KAT2B), (Kinoshita et al., 2005; LeRoy et al., 2007). and retinoid X-receptor beta via the TACC domain Overexpression of TACC3 from artificial constructs (Gangisetty, 2004; Lauffart et al., 2002; can result in accumulation in the cytosol of some cells Vettaikkorumakankauv et al., 2008). TACC3 resulting in oligmerisation in punctate structures functionally interacts with MBD2 bound to methylated (Gergely et al., 2000). promoters, promoting transcription by displacement of Function HDAC2 and recruitment of KAT2B (Angrisano et al., 2006). Human TACC3 may be involved in Gene knockout and knockdown studies in mouse have transcriptional termination and/or pre-mRNA splicing indicated that TACC3 is vital for embryonic through TTF2 (Leonard et al., 2003). TACC3 can development. A functionally null TACC3 mutant dies interact with BARD1, BRCA1 and p53 and has been during mid to late gestation due to excessive apoptosis shown to have some protective affects against affecting hematopoietic and other organ systems adriamycin-mediated DNA damage in ovarian cancer (Piekorz et al., 2002). Hypomorphic alleles result in cells (Lauffart et al., 2007a). Phosphorylation of the defects in mitosis affecting mesenchymal sclerotome last amino acid of the SDP repeat, Ser434, is noted in and therefore the axial skeleton (Yao et al., 2007). nuclear extracts of HeLa (Beausoleil, 2004; Beausoleil, These mutational mouse models indicate that TACC3 2006), although its functional significance is unknown. has a role in chromosomal alignment, separation and cytokinesis and that TACC3 can be associated with Homology p53-mediated apoptosis. Member of the TACC family, based on the presence of TACC3 has a well characterized function in the evolutionarily conserved approxi- microtubule dynamics, particularly during mitosis, mately 200 amino acid carboxy terminal coiled coil based on mutational analysis (see above) and physical domain (TACC domain) (Still et al., 1999; Still et al., interactions with Aurora A and Aurora B kinases, 2004). TACC3 orthologues are noted in all vertebrates CKAP5 (ch-TOG/XMAP215) and AKAP9 via the sequenced to date (Still et al., 2004 and Still TACC domain (see Peset and Vernos, 2008 for unpublished). However, the central region between the review). Interaction with CEP120 is important in conserved N-terminal region and the TACC domain is interkinetic nuclear migration and maintenance of highly variable in size and sequence. The SDP repeats neural progenitor self-renewal during the development are noted within the central region in most vertebrates of the neocortex (Xie et al., 2007). Phosphorylation of except mouse and rat (Still et al., 2004). Ser34, Ser552 and Ser558 by Aurora A are required for localization to centro-somes and is necessary for Mutations recruitment of CKAP5 and nucleation of microtubules (Kinoshita et al., 2005; LeRoy et al., 2007). Ser25, Note Thr59, Ser71, Ser317, and Ser 434 are presumed Somatic mutations noted in ovarian cancer samples (Lauffart et al., 2005; Eslinger, 2006).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 307 TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.

See legend for normal protein.

Implicated in Oncogenesis TACC3 is located close to the MMSET gene that is Ovarian cancer rearranged in t(4;14) translocation (Still et al., 1999). Prognosis This rearrangement upregulates the TACC3 gene Overexpression of TACC3 is associated with (Stewart et al., 2004). chemoresistance in ovarian tumors (L'Esperance et al., Thyroid cancer 2006). Prognosis Oncogenesis Reduction of expression associated with increased Total cellular expression or nuclear localization lost in malignancy in cell line models (Ulisse et al., 2007). ovarian cancer (Lauffart et al., 2005). Oncogenesis Non-small cell lung cancer Analysis of differentiated thyroid cancers indicates that Prognosis TACC3 mRNA levels were either upregulated (44%) High TACC3 expression is an independent prognostic or downregulated (56%) in tumors, in some cases indicator associated with significantly shorter median correlation was observed between TACC3 and Aurora- survival time. TACC3 expression was correlated with A kinase (Ulisse et al., 2007). However protein analysis p53 expression and poor prognosis (Jung et al., 2006). was not reported. Oncogenesis Breakpoints A high level of TACC3 expression was observed in 14.8% of cases of non small cell lung cancer, Note predominantly of the squamous cell carcinoma type Rearrangements of the human TACC3 gene have not (Jung et al., 2006). been described. However, translocation breakpoints in Breast cancer the WHSC1 gene, associated with multiple myeloma upregulate the intact TACC3 promoter (Stewart et al., Prognosis 2004). Tacc3 in the mouse genome is a site of proviral Loss of TACC3 is observed as a predictor of poor integration of MoMuLV transmitted via milk from prognosis in breast cancer (Conte et al., 2002). infected mothers. This leads to upregulation of the gene Oncogenesis and leads to the development of lymphomas TACC3 protein downregulated in breast cancer (Conte (Chakraborty et al., 2008). et al., 2002). Multiple myeloma References Prognosis Still IH, Vince P, Cowell JK. The third member of the transforming acidic coiled coil-containing gene family, TACC3, TACC3 overexpression correlates with the t(4;14) maps in 4p16, close to translocation breakpoints in multiple translocation that is associated with poor prognosis myeloma, and is upregulated in various cancer cell lines. (Stewart et al., 2004). Genomics. 1999 Jun 1;58(2):165-70

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Gergely F, Karlsson C, Still I, Cowell J, Kilmartin J, Raff JW. phosphorylation of TACC3/maskin is required for centrosome- The TACC domain identifies a family of centrosomal proteins dependent microtubule assembly in mitosis. J Cell Biol. 2005 that can interact with microtubules. Proc Natl Acad Sci U S A. Sep 26;170(7):1047-55 2000 Dec 19;97(26):14352-7 Lauffart B, Vaughan MM, Eddy R, Chervinsky D, DiCioccio RA, Sadek CM, Jalaguier S, Feeney EP, Aitola M, Damdimopoulos Black JD, Still IH. Aberrations of TACC1 and TACC3 are AE, Pelto-Huikko M, Gustafsson JA. Isolation and associated with ovarian cancer. BMC Womens Health. 2005 characterization of AINT: a novel ARNT interacting protein May 26;5:8 expressed during murine embryonic development. Mech Dev. 2000 Oct;97(1-2):13-26 Angrisano T, Lembo F, Pero R, Natale F, Fusco A, Avvedimento VE, Bruni CB, Chiariotti L. TACC3 mediates the Lauffart B, Howell SJ, Tasch JE, Cowell JK, Still IH. Interaction association of MBD2 with histone acetyltransferases and of the transforming acidic coiled-coil 1 (TACC1) protein with relieves transcriptional repression of methylated promoters. ch-TOG and GAS41/NuBI1 suggests multiple TACC1- Nucleic Acids Res. 2006;34(1):364-72 containing protein complexes in human cells. Biochem J. 2002 Apr 1;363(Pt 1):195-200 Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP. A probability-based approach for high-throughput protein Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, phosphorylation analysis and site localization. Nat Biotechnol. Sexl V, Snyder L, Rehg J, Ihle JN. The centrosomal protein 2006 Oct;24(10):1285-92 TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J. Eslinger MR.. Molecular Analysis of TACC3 in ovarian cancer. 2002 Feb 15;21(4):653-64 MS thesis, Department of Natural Science, Roswell Park Division, SUNY Buffalo 2006. 106p. Aitola M, Sadek CM, Gustafsson JA, Pelto-Huikko M. Aint/Tacc3 is highly expressed in proliferating mouse tissues Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY. during development, spermatogenesis, and oogenesis. J Expression of transforming acidic coiled-coil containing protein Histochem Cytochem. 2003 Apr;51(4):455-69 3 is a novel independent prognostic marker in non-small cell lung cancer. Pathol Int. 2006 Sep;56(9):503-9 Leonard D, Ajuh P, Lamond AI, Legerski RJ. hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing. Lauffart B, Dimatteo A, Vaughan MM, Cincotta MA, Black JD, Biochem Biophys Res Commun. 2003 Sep 5;308(4):793-801 Still IH. Temporal and spatial expression of TACC1 in the mouse and human. Dev Dyn. 2006 Jun;235(6):1638-47 Sadek CM, Pelto-Huikko M, Tujague M, Steffensen KR, Wennerholm M, Gustafsson JA. TACC3 expression is tightly L'Espérance S, Popa I, Bachvarova M, Plante M, Patten N, Wu regulated during early differentiation. Gene Expr Patterns. L, Têtu B, Bachvarov D. Gene expression profiling of paired 2003 May;3(2):203-11 ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Int J Oncol. 2006 Jul;29(1):5-24 Li J, Cohn MA, Cantley LC, Gygi SP. Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc Lauffart B, Gangisetty O, Still IH.. Evolutionary conserved Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5 interaction of TACC2/TACC3 with BARD1 and BRCA1: potential implications for DNA damage response in breast and Gangisetty O, Lauffart B, Sondarva GV, Chelsea DM, Still IH. ovarian cancer. Cancer Therapy. 2007a Dec;5(2):409-416. The transforming acidic coiled coil proteins interact with nuclear histone acetyltransferases. Oncogene. 2004 Apr Lauffart B, Sondarva GV, Gangisetty O, Cincotta M, Still IH. 1;23(14):2559-63 Interaction of TACC proteins with the FHL family: implications for ERK signaling. J Cell Commun Signal. 2007 Jun;1(1):5-15 Garriga-Canut M, Orkin SH. Transforming acidic coiled-coil protein 3 (TACC3) controls friend of GATA-1 (FOG-1) LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J, subcellular localization and regulates the association between Bowman D, Galvin K, Ecsedy JA. Localization of human GATA-1 and FOG-1 during hematopoiesis. J Biol Chem. 2004 TACC3 to mitotic spindles is mediated by phosphorylation on May 28;279(22):23597-605 Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res. 2007 Jun Simpson RJ, Yi Lee SH, Bartle N, Sum EY, Visvader JE, 1;67(11):5362-70 Matthews JM, Mackay JP, Crossley M. A classic zinc finger from friend of GATA mediates an interaction with the coiled-coil Ulisse S, Baldini E, Toller M, Delcros JG, Guého A, Curcio F, of transforming acidic coiled-coil 3. J Biol Chem. 2004 Sep De Antoni E, Giacomelli L, Ambesi-Impiombato FS, Bocchini S, 17;279(38):39789-97 D'Armiento M, Arlot-Bonnemains Y. Transforming acidic coiled- coil 3 and Aurora-A interact in human thyrocytes and their Stewart JP, Thompson A, Santra M, Barlogie B, Lappin TR, expression is deregulated in thyroid cancer tissues. Endocr Shaughnessy J Jr. Correlation of TACC3, FGFR3, MMSET Relat Cancer. 2007 Sep;14(3):827-37 and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. Br J Haematol. 2004 Jul;126(1):72-6 Xie Z, Moy LY, Sanada K, Zhou Y, Buchman JJ, Tsai LH. Cep120 and TACCs control interkinetic nuclear migration and Still IH, Vettaikkorumakankauv AK, DiMatteo A, Liang P. the neural progenitor pool. Neuron. 2007 Oct 4;56(1):79-93 Structure-function evolution of the transforming acidic coiled coil genes revealed by analysis of phylogenetically diverse Yao R, Natsume Y, Noda T. TACC3 is required for the proper organisms. BMC Evol Biol. 2004 Jun 18;4:16 mitosis of sclerotome mesenchymal cells during formation of the axial skeleton. Cancer Sci. 2007 Apr;98(4):555-62 Jacquemier J, Ginestier C, Rougemont J, Bardou VJ, Charafe- Jauffret E, Geneix J, Adélaïde J, Koki A, Houvenaeghel G, Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD. Hassoun J, Maraninchi D, Viens P, Birnbaum D, Bertucci F. Improved titanium dioxide enrichment of phosphopeptides from Protein expression profiling identifies subclasses of breast HeLa cells and high confident phosphopeptide identification by cancer and predicts prognosis. Cancer Res. 2005 Feb cross-validation of MS/MS and MS/MS/MS spectra. J 1;65(3):767-79 Proteome Res. 2007 Nov;6(11):4150-62 Kinoshita K, Noetzel TL, Pelletier L, Mechtler K, Drechsel DN, Brunet S, Dumont J, Lee KW, Kinoshita K, Hikal P, Gruss OJ, Schwager A, Lee M, Raff JW, Hyman AA. Aurora A Maro B, Verlhac MH. Meiotic regulation of TPX2 protein levels

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governs cell cycle progression in mouse oocytes. PLoS One. Peset I, Vernos I. The TACC proteins: TACC-ling microtubule 2008 Oct 3;3(10):e3338 dynamics and centrosome function. Trends Cell Biol. 2008 Aug;18(8):379-88 Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd. Combining protein-based IMAC, peptide-based IMAC, and Vettaikkorumakankauv AK, Lauffart B, Gangisetty O, Cincotta MudPIT for efficient phosphoproteomic analysis. J Proteome MA, Hawthorne LA, Cowell JK, Still IH.. The TACC proteins are Res. 2008 Mar;7(3):1346-51 coregulators of the Retinoid-X Receptor Beta. Cancer Therapy. 2008 Dec;6(2):805-816. Chakraborty J, Okonta H, Bagalb H, Lee SJ, Fink B, Changanamkandat R, Duggan J. Retroviral gene insertion in This article should be referenced as such: breast milk mediated lymphomagenesis. Virology. 2008 Jul 20;377(1):100-9 Eslinger MR, Lauffart B, Still IH. TACC3 (transforming, acidic coiled-coil containing protein 3). Atlas Genet Cytogenet Oncol Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE, Haematol. 2010; 14(3):305-310. Elledge SJ, Gygi SP. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7

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Gene Section Mini Review

TP53INP1 (tumor protein p53 inducible nuclear protein 1) Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti INSERM U.624, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France (MS, AC, JI, ND)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/TP53INP1ID42672ch8q22.html DOI: 10.4267/2042/44717 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Expression In mouse: TP53INP1 is expressed in thymus, spleen Other names: SIP; TEAP; p53DINP1; TP53INP1A; and bone marrow. It is also expressed at low levels in TP53INP1B; TP53DINP1 heart, stomach, liver, intestine, testis, kidney and HGNC (Hugo): TP53INP1 pancreas. TP53INP1 expression is highly induced Location: 8q22.1 during the acute phase of mouse experimental pancreatitis (caerulein induced). DNA/RNA In cells lines: TP53INP1 is transcriptionally induced in response to stress in a p53-dependent and independent Description manner. Examples: in mouse fibroblast, it is induced Gene is ~24 kb, with 5 exons. upon adriamycin, methyl-methane sulfonate, ethanol, H2O2, UV exposure and heat shock treatment; in Transcription neuronal cells by copper treatment; in pancreatic cancer Alternative splicing: 2 transcripts: TP53INP1alpha cell lines by gemcitabine; in pro-B cells by IL-3 (exons 1, 2, 3, 4 and 5 with a stop codon in the fourth deprivation or treatement with staurosporine, cisplatin, exon) and TP53INP1beta (exons 1, 2, 3 and 5 with a campto-thecin, methotrexate and paclitaxel; in mouse stop codon in the fifth exon). embryonic fibroblast (MEF), human fibroblasts and MCF7 by gamma irradiation; in melanoma cells by UV Protein mimetic compound (4NQ). TP53INP1 expression is regulated by different Description transcriptional regulators: p53, E2F1, (in p53-/- 2 isoforms: TP53INP1alpha, 18 kDa (164 amino acids) cells), myc (in neuroblastoma cell lines) and PLZF (in and TP53INP1beta, 27 kDa (240 amino acids). Both hematopoietic cell lines). isoforms contain a PEST domain (sequence rich in Localisation proline, glutamic acid, serine and threonine between amino acids 26 and 62 found in proteins with half-lives Nuclear when over-expressed and in PML-bodies of less than 2 h). (Promyelocytic leukemia protein) upon PML-IV over- expression.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 311 TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.

Green boxes: exons, black lines: introns, alternative splicing for TP53INP1beta in black and TP53INP1alpha in red.

Function Disease TP53INP1 is a tumor suppressor gene induced with Mainly in female (only 1% in male). Genetic disorders different stress conditions. TP53INP1 overexpres-sion known: loss of HER2 and ER expression, mutations in leads to cell cycle arrest (G1 phase) and p53-dependent p53 and BRCA1. or independent apoptosis. TP53INP1 interacts with p53 Prognosis and two kinases (HIPK2, and PKCd). These kinases Mortality rate: 25%. phosphorylate p53 on serine 46 modifying the p53 Gastric cancer activity. TP53INP1 can modulate the p53 and p73 transcriptional activity to potentiate pro-apoptotic Note pathways. Colitis and colitis-associated cancer are TP53INP1 expression is lost during cancer exacerbated in mice deficient for TP53INP1. development. The decreased expression of TP53INP1 protein may reflect the malignant grade of gastric Homology cancer. TP53INP1 is conserved between species (from fly to Disease human). In vertebrates, one paralog has been identified, 10% are familial. Mutations in APC, p53, Bcl-2. TP53INP2 localized on chromosome 20q11.2. TP53INP2 is involved in autophagy. Prognosis The 5-year survival after surgical resection is 30-50% Mutations for patients with stage II and 10-25% for patients with stage III. Note Anaplastic carcinoma of the thyroid No mutation identified. (ATC) Implicated in Note TP53INP1 is overexpressed in anaplastic thyroid Pancreatic Adenocarcinoma carcinoma. Note Disease TP53INP1 is lost early during pancreatic cancer ATC is less than 2% of total thyroid cancer but progression (from the neoplasia stages PanIN2). This represents 40% of death by thyroid cancer. It is a very downregulation seems to be important for tumour aggressive cancer with early dissemination. development. TP53INP1 expression is down regulated Prognosis by the oncogenic micro-RNA miR-155 during 5-year survival rate is less than 10%. pancreatic cancer progression. Disease References Sporadic cancer, very aggressive, epigenetic disease with known mutations/deletions of p53, K-Ras, Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y. p53DINP1, a p53-inducible gene, SMAD4, p16, BRCA2, EGFR and HER2. regulates p53-dependent apoptosis. Mol Cell. 2001 Jul;8(1):85- Prognosis 94 Very bad, with only 20% of patients reaching two years Nowak J, Tomasini R, Mattei MG, Azizi Samir LA, Dagorn JC, of survival, and 3% after 5 years. Dusetti N, Iovanna JL, Pébusque MJ. Assignment of tumor protein p53 induced nuclear protein 1 (TP53INP1) gene to Breast cancer human chromosome band 8q22 by in situ hybridization. Cytogenet Genome Res. 2002;97(1-2):140E Note TP53INP1 expression is lost during breast cancer Tomasini R, Samir AA, Pebusque MJ, Calvo EL, Totaro S, development. Dagorn JC, Dusetti NJ, Iovanna JL. P53-dependent expression

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 312 TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.

of the stress-induced protein (SIP). Eur J Cell Biol. 2002 genes in primary human fibroblasts. Int J Radiat Oncol Biol May;81(5):294-301 Phys. 2006 Dec 1;66(5):1506-14 Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Bell E, Lunec J, Tweddle DA. Cell cycle regulation targets of Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ. MYCN identified by gene expression microarrays. Cell Cycle. TP53INP1s and homeodomain-interacting protein kinase-2 2007 May 15;6(10):1249-56 (HIPK2) are partners in regulating p53 activity. J Biol Chem. 2003 Sep 26;278(39):37722-9 Bernardo MV, Yelo E, Gimeno L, Campillo JA, Parrado A. Identification of apoptosis-related PLZF target genes. Biochem Hershko T, Chaussepied M, Oren M, Ginsberg D. Novel link Biophys Res Commun. 2007 Jul 27;359(2):317-22 between and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ. 2005 Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux Apr;12(4):377-83 J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L, Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC, Tomasini R, Seux M, Nowak J, Bontemps C, Carrier A, Dagorn Iovanna JL, Carrier A, Pébusque MJ, Dusetti NJ. Tumor JC, Pébusque MJ, Iovanna JL, Dusetti NJ. TP53INP1 is a protein 53-induced nuclear protein 1 expression is repressed novel p73 target gene that induces cell cycle arrest and cell by miR-155, and its restoration inhibits pancreatic tumor death by modulating p73 transcriptional activity. Oncogene. development. Proc Natl Acad Sci U S A. 2007 Oct 2005 Dec 8;24(55):8093-104 9;104(41):16170-5 Vanlandingham JW, Tassabehji NM, Somers RC, Levenson Gommeaux J, Cano C, Garcia S, Gironella M, Pietri S, Culcasi CW. Expression profiling of p53-target genes in copper- M, Pébusque MJ, Malissen B, Dusetti N, Iovanna J, Carrier A. mediated neuronal apoptosis. Neuromolecular Med. Colitis and colitis-associated cancer are exacerbated in mice 2005;7(4):311-24 deficient for tumor protein 53-induced nuclear protein 1. Mol Cell Biol. 2007 Mar;27(6):2215-28 Ito Y, Motoo Y, Yoshida H, Iovanna JL, Nakamura Y, Kuma K, Miyauchi A. High level of tumour protein p53-induced nuclear Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, protein 1 (TP53INP1) expression in anaplastic carcinoma of Barelier S, Vasseur S, Spoto RP, Pébusque MJ, Dusetti NJ, the thyroid. Pathology. 2006 Dec;38(6):545-7 Iovanna JL, Carrier A. Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Ito Y, Motoo Y, Yoshida H, Iovanna JL, Takamura Y, Miya A, Cancer Res. 2009 Jan 1;69(1):219-26 Kuma K, Miyauchi A. Decreased expression of tumor protein p53-induced nuclear protein 1 (TP53INP1) in breast Nowak J, Archange C, Tardivel-Lacombe J, Pontarotti P, carcinoma. Anticancer Res. 2006 Nov-Dec;26(6B):4391-5 Pébusque MJ, Vaccaro MI, Velasco G, Dagorn JC, Iovanna JL. The TP53INP2 protein is required for autophagy in mammalian Jiang PH, Motoo Y, Garcia S, Iovanna JL, Pébusque MJ, cells. Mol Biol Cell. 2009 Feb;20(3):870-81 Sawabu N. Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer. World J Nowak J, Iovanna JL. TP53INP2 is the new guest at the table Gastroenterol. 2006 Feb 7;12(5):691-6 of self-eating. Autophagy. 2009 Apr;5(3):383-4

Jiang PH, Motoo Y, Sawabu N, Minamoto T. Effect of This article should be referenced as such: gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells. World J Gastroenterol. 2006 Seux M, Carrier A, Iovanna J, Dusetti N. TP53INP1 (tumor Mar 14;12(10):1597-602 protein p53 inducible nuclear protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):311-313. Kis E, Szatmári T, Keszei M, Farkas R, Esik O, Lumniczky K, Falus A, Sáfrány G. Microarray analysis of radiation response

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Leukaemia Section Mini Review del(5q) in myeloid neoplasms Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke FACMG, Cytogenetics Laboratory, Mayo Clinic, Rochester, Minnesota, USA (KK, RPK, DLV)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del5qID1092.html DOI: 10.4267/2042/44718 This article is an update of: Charrin C. del(5q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol 1998;2(3):88-90

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Identity Note Interstitial del(5q) was first reported as a type of refractory anemia with characteristic clinical features; female predominance (unlike other MDS), macrocytosis, erythroid hypoplasia, frequent thrombocytosis and dysmegakaryopoiesis. It is one of the most common structural rearrangements in MDS (10%), seen as an isolated abnormality or with additional karyotypic anomalies. It is also observed in AML, with important prognostic significance.

del(5q) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center (1 and 5 from the left), Kazunori Kanehira, Rhett P. Ketterling, Daniel L. Van Dyke (2, 4, 6, and 7), and Jean-Luc Lai (3); R-banding (bottom), Courtesy Christiane Charrin (1 and 3), Editor (2).

syndrome as a specific type of MDS, restricting Clinics and pathology diagnosis to the cases with isolated interstitial del(5q), Disease without excess blasts in the bone marrow (<5%). It also defined a new category, therapy-related MDS/AML, 5q- syndrome excluding cases with a history of previous Note chemotherapy from 5q- syndrome MDS. The World Health Organization (WHO) defined the 5q-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 314 del(5q) in myeloid neoplasms Kanehira K, et al.

Clinics Cytogenetics As described above, cases of MDS with isolated del(5q) show female predominance (M:F=1:1.5-4), Cytogenetics morphological anemia, macrocytosis, normal or moderately decreased The most commonly observed interstitial deletions are WBC, normal or moderately decreased platelet count, del(5)(q13q31), del(5)(q13q33), and del(5)(q22q33), and dysmegakaryopoiesis. forming a commonly deleted region (CDR) at 5q31- Treatment q32. Supportive care including RBC transfusion for anemia Cytogenetics molecular is the mainstay of treatment. It is not infrequent that The CDR is the approximately 1.5 Mb interval between transfusions are needed for years, causing iron D5S413 and GLRA1 gene, containing around 40 genes. overload, and increasing the risk of blood-borne No cases of 5q- syndrome have been reported to have infections. Anemia of 5q- syndrome does not respond biallelic deletion within the CDR, and no point well to erythropoietin. Leanalidomide, a Thalidomide mutations have been found in the genes in the region. derivative, has been investigated for treatment of MDS Recently, it is suggested that haploinsufficienty (a gene with 5q-. Lenalidomide has immunomodulatory dosage effect) of one or more of the genes mapping to properties, including the suppression of pro- the CDR is the pathogenetic basis of the 5q- syndrome. inflammatory cytokine production by monocytes, Ebert et al. demonstrated that impaired function of the enhancement of T-cell and NK-cell activation, and ribosomal subunit protein RPS14 recapitulated the inhibition of angiogenesis. In Phase II trials in characteristic phenotype of the 5q- syndrome, a severe transfusion-dependent MDS with 5q-, 168 patients decrease in the production of erythroid cells with were enrolled, of whom 76% had isolated 5q- and 29% relative preservation of megakaryocytic cells, in normal had the 5q- syndrome. Transfusion independence was CD34+ human hematopoietic progenitor cells. In obtained in 67%. A complete cytogenetic response was addition, forced expression of RPS14 rescued the achieved in 45% of patients. Cytogenetic response rate disease phenotype in patient-derived bone marrow was not significantly different in isolated del(5q), cells. del(5q) + 1 and del(5q) + >1 additional chromosome Germline heterozygous mutations for two other abnormalities. Although the results of lenalidomide ribosomal proteins, RPS19 and RPS24, have recently treatment seem promising, it is not yet clear if the been described in the congenital disorder known as treatment will affect the natural disease course and Diamond-Blackfan anemia. The conge-nital anemia is prolongs survival. characterized by sever anemia, macrocytosis, relative Prognosis preservation of the platelet and neutrophil count, erythroid hypoplasia in the bone marrow and an The impact of lenalidomide on the prognosis of MDS increased risk of leukemia. The erythroid specificity of patients with 5q- is unknown at this point. Progression 5q- syndrome and Diamond-Blackfan anemia in to AML is rare (10%). With the supportive therapy, the ribosomal expression is noteworthy. prognosis of 5q- syndrome is favorable, with reported median survival ranging from 53 to 146 months. MDS Additional anomalies patients with 5q- plus one additional chromosome By definition, an interstitial deletion of 5q must be the abnormality seem to have significantly shorter survival sole abnormality for 5q- syndrome. However, 5q (with exception of loss of the Y chromosome). MDS deletion can be seen with other accompanying with 5q- as part of a complex karyotype (3 or more abnormalities. Review of the recent Mayo Clinic cases abnormalities) have an unfavorable prognosis. shows that major abnormalities include -7, +8, -20, Disease 20q-, -13/13q-, and abnormalities in 12p, in the descending order. AML (Acute Myeloid Leukemia). Clinics References Deletion of 5q can be observed in both de novo and Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux therapy related AML. It is also seen as monosomy 5. In JL, Sokal G. Distinct haematological disorder with deletion of AML, 5q deletion is usually associated with a complex long arm of no. 5 chromosome. Nature. 1974 Oct karyotype. 4;251(5474):437-8 Pedersen B, Jensen IM. Clinical and prognostic implications of Prognosis chromosome 5q deletions: 96 high resolution studied patients. Prognosis of AML with 5q-/-5 is generally unfavorable, Leukemia. 1991 Jul;5(7):566-73 associated with rapid disease progression and poor Rubin CM, Arthur DC, Woods WG, Lange BJ, Nowell PC, outcome and survival, especially when it is seen as a Rowley JD, Nachman J, Bostrom B, Baum ES, Suarez CR. part of complex karyotype. Therapy-related myelodysplastic syndrome and acute myeloid leukemia in children: correlation between chromosomal abnormalities and prior therapy. Blood. 1991 Dec 1;78(11):2982-8

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 315 del(5q) in myeloid neoplasms Kanehira K, et al.

Neuman WL, Rubin CM, Rios RB, Larson RA, Le Beau MM, Bernasconi P, Boni M, Cavigliano PM, Calatroni S, Giardini I, Rowley JD, Vardiman JW, Schwartz JL, Farber RA. Rocca B, Zappatore R, Dambruoso I, Caresana M. Clinical Chromosomal loss and deletion are the most common relevance of cytogenetics in myelodysplastic syndromes. Ann mechanisms for loss of heterozygosity from chromosomes 5 N Y Acad Sci. 2006 Nov;1089:395-410 and 7 in malignant myeloid disorders. Blood. 1992 Mar 15;79(6):1501-10 Cherian S, Bagg A. The genetics of the myelodysplastic syndromes: classical cytogenetics and recent molecular Baranger L, Szapiro N, Gardais J, Hillion J, Derre J, Francois insights. Hematology. 2006 Feb;11(1):1-13 S, Blanchet O, Boasson M, Berger R. Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone associated with a myeloid disorder with eosinophilia. Br J RM, Ritz J, Alyea EP, Antin JH, Soiffer RJ. Impact of Haematol. 1994 Oct;88(2):343-7 cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood. Transplant. 2007 Jun;13(6):655-64 1994 Nov 15;84(10):3253-60 Haase D. Cytogenetic features in myelodysplastic syndromes. Boultwood J, Fidler C. Chromosomal deletions in Ann Hematol. 2008 Jul;87(7):515-26 myelodysplasia. Leuk Lymphoma. 1995 Mar;17(1-2):71-8 Kelaidi C, Eclache V, Fenaux P. The role of lenalidomide in the Fenaux P. Syndromes myelodysplasiques et deletion 5q. management of myelodysplasia with del 5q. Br J Haematol. Hematologie. 1995; 1: 35-43. 2008 Feb;140(3):267-78 Van den Berghe H, Michaux L. 5q-, twenty-five years later: a Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein synopsis. Cancer Genet Cytogenet. 1997 Mar;94(1):1-7 H, Thiele J, Vardiman JW.. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Classification of Giagounidis AA, Germing U, Wainscoat JS, Boultwood J, Aul Tumours of Haematopoietic and Lymphoid Tissues, 4th C. The 5q- syndrome. Hematology. 2004 Aug;9(4):271-7 Edition; 2008;102. Nishino HT, Chang CC. Myelodysplastic syndromes: clinicopathologic features, pathobiology, and molecular This article should be referenced as such: pathogenesis. Arch Pathol Lab Med. 2005 Oct;129(10):1299- Kanehira K, Ketterling RP, Van Dyke DL. del(5q) in myeloid 310 neoplasms. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):314-316.

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Leukaemia Section Mini Review t(11;11)(q13;q23) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1111q13q23ID1541.html DOI: 10.4267/2042/44719 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Cytogenetics Epidemiology Cytogenetics morphological The involvement of MLL in 11q23 and ARHGEF17 in The t(11;11) was apparently the sole anomaly in 3 of 11q13 was ascertained in only 1 case (Teuffel et al., the 4 cases; a complex karyotype with del(5q), a 2005). It was an unusual case of treatment-related MLL marker chromosome, and other anomalies was found in rearrangement in the absence of leukemia. the case reported by Mackinnon and Campbell, 2007. Clinics Genes involved and proteins The case reported by Teuffel et al. (2005), was a five- year-old girl, who experienced an acute myeloid ARHGEF17 leukemia (AML) with a variant t(8;21) and achieved Location remission under treatment. Four years later, a follow-up 11q13 control of her karyotype revealed a t(11;11)(q13;q23), in the absence of any sign of leukemia in the bone Protein marrow, over a period of 30 months following the Guanine nucleotide exchange factor (GEF) for RhoA discover of the t(11;11). GTPases. Involved in transduction of various signals Other cases of t(11;11)(q13;q23) were: into downstream signaling cascades. A 13-year-old girl, who have had a M4eo AML with MLL inv(16)(p13q22). Eleven month later, a t(11;11)(q13;q23) was found, but bone marrow Location remained normal; however, an overt M5b AML was 11q23 diagnosed 6 months later (Leblanc et al., 1994). This DNA/RNA case resembles the case of Teuffel. 36 exons, multiple transcripts 13-15 kb. There was also the case of a 69-year-old male patient Protein with a primary M4 AML, who died 5 months after 3969 amino acids; 431 kDa; contains two DNA binding diagnosis, and an AML (not classified) female patient motifs (a AT hook and a CXXC domain), a DNA (Testa et al., 1985; Mackinnon and Campbell, 2007). methyl transferase motif, a bromodomain. MLL is Cytology cleaved by taspase 1 into 2 proteins before entering the In the case reported by Teuffel, the MLL-ARHGEF17 nucleus, called MLL-N and MLL-C. was only seen in the myeloid lineage. The myeloid The FYRN and FRYC domains of native MLL differentiation was not perturbed by the presence of the associate MLL-N and MLL-C in a stable complex; they chimeric protein, and normal mature myeloid cells form a multiprotein complex with transcription factor carrying the chimeric protein were found in normal TFIID. MLL is a transcriptional regulatory factor. MLL amounts. can be associated with more than 30 proteins, including

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 317 t(11;11)(q13;q23) Huret JL

the core components of the SWI/SNF chromatin remodeling complex and the transcription complex References TFIID. MLL binds pro-motors of HOX genes through Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH. acetylation and methylation of histones. MLL is a Chromosomal alterations in acute leukemia patients studied with improved culture methods. Cancer Res. 1985 major regulator of hematopoesis and embryonic Jan;45(1):430-4 development. Leblanc T, Hillion J, Derré J, Le Coniat M, Baruchel A, Daniel MT, Berger R. Translocation t(11;11)(q13;q23) and HRX gene Result of the chromosomal rearrangement associated with therapy-related leukemia in a child previously treated with VP16. Leukemia. 1994 anomaly Oct;8(10):1646-8 Hybrid gene Teuffel O, Betts DR, Thali M, Eberle D, Meyer C, Schneider B, Marschalek R, Trakhtenbrot L, Amariglio N, Niggli FK, Schäfer Description BW. Clonal expansion of a new MLL rearrangement in the The fusion between MLL and ARHGEF17 occurred in absence of leukemia. Blood. 2005 May 15;105(10):4151-2 introns 12 and 1 respectively. Mackinnon RN, Campbell LJ. Dicentric chromosomes and 20q11.2 amplification in MDS/AML with apparent monosomy 20. Cytogenet Genome Res. 2007;119(3-4):211-20 This article should be referenced as such:

Huret JL. t(11;11)(q13;q23). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):317-318.

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Leukaemia Section Short Communication t(11;19)(q23;p13.3) MLL/ACER1 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1119q23p13ID1540.html DOI: 10.4267/2042/44720 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology ACER1 Location Disease 19p13.3 Acute lymphocytic leukemia (ALL) Protein Epidemiology ACER1 is the alkaline ceramidase 1. Ceramidases Only one case to date, a case of congenital leukemia catalyze hydrolysis of ceramide to generate sphingosine (Lo Nigro et al., 2002). (SPH), which is phosphorylated to form sphingosine-1- phosphate (S1P). Ceramide, SPH, and S1P are Genes involved and proteins bioactive lipids that mediate cell proliferation, differentiation, apoptosis, adhesion and migration (Mao MLL and Obeid, 2008). Location Result of the chromosomal 11q23 DNA/RNA anomaly 36 exons, multiple transcripts 13-15 kb. Hybrid gene Protein Description 3969 amino acids; 431 kDa; contains two DNA binding 5' MLL - 3' ACER1; fusion of MLL intron 8 to motifs (a AT hook and a CXXC domain), a DNA ACER1. methyl transferase motif, a bromodomain. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus, called MLL-N and MLL-C. The FYRN and References FRYC domains of native MLL associate MLL-N and Lo Nigro L, Slater DJ, Rappaport EF, Biondi A, Maude S, MLL-C in a stable complex; they form a multiprotein Megnigal MD, Bungaro S, Schiliro G, Felix CA.. Two partner complex with transcription factor TFIID. MLL is a genes of MLL and additional heterogeneity in t(11;19)(q23;p13) translocations. Blood 2002; 2080 p531a. transcriptional regulatory factor. MLL can be associated with more than 30 proteins, including the Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and core components of the SWI/SNF chromatin sphingosine-1-phosphate. Biochim Biophys Acta. 2008 remodeling complex and the transcription complex Sep;1781(9):424-34 TFIID. MLL binds pro-motors of HOX genes through acetylation and methylation of histones. MLL is a This article should be referenced as such: major regulator of hematopoesis and embryonic Huret JL. t(11;19)(q23;p13.3) MLL/ACER1. Atlas Genet development. Cytogenet Oncol Haematol. 2010; 14(3):319.

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Leukaemia Section Short Communication t(2;5)(p21;q33) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0205p21q33ID1511.html DOI: 10.4267/2042/44721 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

domains, a transmembrane domain, and an intracellular Clinics and pathology part with a tyrosine kinase domain (made of two Disease tyrosine kinase subdomains) for transduction of the Atypical myeloproliferative disease with eosino-philia signal. Receptor tyrosine kinase; receptor for PDGFB and PDGFD (Bergsten et al., 2001); forms Epidemiology homodimers, or heterodimer with PDGFRA; upon One case to date, a 73-year-old female patient dimerization, subsequent activa-tion by (Gallagher et al., 2008). autophosphorylation of the tyrosine kinase intracellular Prognosis domains occurs. The patient was alive and well after 3 years of therapy Result of the chromosomal with imatinib. anomaly Cytogenetics Fusion protein Cytogenetics morphological Description The t(2;5) was the sole anomaly. Constitutive activation of the PDGFRB tyrosine kinase Genes involved and proteins domain. SPTBN1 References Location Winkelmann JC, Forget BG. Erythroid and nonerythroid spectrins. Blood. 1993 Jun 15;81(12):3173-85 2p16.2 is the exact location Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: Protein metazoan inventions for integrating cells into tissues. Physiol SPTBN1 (spectrin beta1 non erythrocytic), also called Rev. 2001 Jul;81(3):1353-92 beta-fodrin, is a cytoskeleton protein. Forms dimers Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, with alpha-fodrin (SPTAN1, 9q34), which self- Alitalo K, Eriksson U. PDGF-D is a specific, protease-activated associates head-to-head into tetramers. Mem-brane ligand for the PDGF beta-receptor. Nat Cell Biol. 2001 skeleton protein associated with ion channels and May;3(5):512-6 pumps (Winkelmann and Forget, 1993); Stabilizes cell Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of surface membranes; role in mitotic spindles assembly PRKG2 and SPTBN1 to the platelet-derived growth factor (Bennett and Baines, 2001). receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders. Cancer Genet Cytogenet. 2008 PDGFRB Feb;181(1):46-51 Location This article should be referenced as such: 5q33 Huret JL. t(2;5)(p21;q33). Atlas Genet Cytogenet Oncol Protein Haematol. 2010; 14(3):320. Comprises an extracellular part with 5 Ig-like C2 type

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Solid Tumour Section Review

Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Rodney C Diaz Department of Otolaryngology-Head and Neck Surgery, University of California Davis Medical Center, Sacramento, California 95817, USA (RCD)

Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Tumors/EndolymphaticSacTumID5096.html DOI: 10.4267/2042/44722 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Clinics and pathology Alias Disease Low Grade Papillary Adenocarcinoma of the Endolymphatic sac tumors are rare. As a recognized, Endolymphatic Sac, Papillary Adenoma of the distinct entity, ELSTs are relatively new. Endolymphatic Sac. The first reported case of a tumor arising from the Note endolymphatic sac was discovered during Endolymphatic sac tumors (ELSTs) are rare tumors of decompression of the endolymphatic sac for presumed the petrous temporal bone. Classified as mastoid unilateral Ménière's Disease in 1984. papillary tumors of unknown origin, these tumors were Although benign, ELSTs can be locally destructive. synthesized into a new, distinct clinico-pathological They present with hearing loss, tinnitus, facial nerve entity by Heffner in 1989. Initially described as a low weakness or paralysis, vertigo, and can be lethal. CT grade papillary adenocarcinoma, their histologic imaging demonstrates erosion of the posterior petrous appearance and apparent lack of metastatic potential temporal bone with occasional intratumoral has since persuaded most practitioners to reclassify calcification. MRI tumor signal is isointense to brain them as papillary adenomas. ELSTs can arise and demonstrates gadolinium enhancement and sporadically or in association with von Hippel-Lindau heterogeneous signal intensity from intratumoral (VHL) disease. calcification and vascularity. Classification Etiology The synthesis of sporadic temporal bone papillary Note tumors into a distinct clinicopathological entity was The differential diagnosis for ELSTs includes all proposed in 1989 by Heffner, with the anatomic origin intrinsic temporal bone neoplasms (most commonly of these tumors being the endolymphatic sac. paraganglioma) as well as metastatic papillary thyroid Knowledge of this tumor has grown, expedited in part carcinoma, metastatic renal cell carcinoma, and choroid by its association with VHL disease, yet many aspects plexus papilloma, the latter three of which are similar are still poorly understood. in appearance to ELSTs histologically.

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MRI T1 weighted axial images of the brain at the level of the endolymphatic sac and internal auditory canal. The top view without gadolinium contrast shows moderate expansion of the endolymphatic sac and duct on the right. The bottom view with gadolinium contrast shows contrast enhancement of the endolymphatic sac on the right.

CT axial image of the temporal bones at the level of the endolymphatic sac and internal auditory canals. The vestibular aqueduct on the right is markedly widened directly behind the internal auditory canal and vestibule, in contrast to the appearance of the vestibular aqueduct on the left, which is thin and nondescript. The bony erosion and widening of the vestibular aqueduct on the right is highly suggestive of a neoplastic or otherwise destructive process within the endolymphatic sac, consistent with an ELST.

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Initially described as a low grade papillary tumor. Large glomus tumors as well as large ELSTs adenocarcinoma, the histologic appearance and can both present as pink or purple masses encroaching apparent lack of metastatic potential of these tumors on the middle ear and external auditory canal. Glomus has convinced some to reclassify them as benign tumors exhibit a characteristic "salt and pepper" tumor papillary adenomatous tumors. The high overall appearance on MRI, but this heterogeneity in signal survival following surgical resection, despite locally reflects the vascularity of such tumors and is not aggressive behavior, is likely due to the underlying pathognomonic. The heterogeneity in signal seen in benign histology of the tumor. large ELSTs - arising from hypervascularity as well as Epidemiology intra-tumoral hemorrhage and/or calcification - can often mimic glomus tumors in this respect. This is not Over 175 case reports of ELSTs have now been necessarily problematic, as management would proceed reported in the literature. The majority of these are similarly for either histologic type of tumor: pre- single case reports of a practice group or university. operative embolization followed by total tumor As the majority of these case reports do not disclose the resection via the appropriate lateral skull base population size of their patient base, it is difficult to approach. assess the true incidence of these tumors. ELSTs tend to afflict women more than men with an overall female Pathology to male ratio of 2:1 in a review of the literature. ELSTs are highly vascular and are comprised of Clinics papillary cystic structures lined with a simple cuboidal or columnar epithelium. Siderophages and cholesterol The most common presenting complaints were aural, clefts are seen, as are clear, vacuolated cells. Nuclear with hearing loss occurring in neary every reported pleomorphism is not pronounced, and mitoses are rare. patient, followed by tinnitus, aural fullness, and Immunohistochemistry and special staining may aid in imbalance. The symptoms of pulsatile tinnitus, otalgia, differentiation of papillary tumors of question-able otorrhea, vertigo, and facial paresis were also present in origin. ELSTs usually stain positive for cytokeratin, some patients. Cranial neuropathies were also vimentin, and epithelial membrane antigen, as well as diagnosed either at the time of presentation or stain on Periodic acid-Schiff (diastase sensitive). Some following treatment. The most commonly involved papers have also reported sensitivity to glial fibrillary nerve was the facial nerve, with preoperative facial acid protein; however, most authors have had poor paresis or paralysis in 43% of patients. In patients with tumor reactivity to glial fibrillary acid protein. Papillary larger tumors or in those who delayed presentation for thyroid metastasis to the temporal bone may be decades after onset of initial symptoms, multiple differentiated by positive reaction to thyroglobulin cranial neuropathies were present including trigeminal, immunohisto-chemistry. glossopharyngeal, and vagal nerves. Transthyretin has been shown to exhibit differential From a statistical standpoint, a vascular tumor eroding expression in choroid plexus papillomas with little to the temporal bone and cranial base is likely to be a no expression in ELSTs. paraganglioma, and likely a glomus jugulare

MRI T1 weighted images of the brain, showing a very large ELST of the left temporal bone, in axial view on the left and coronal view on the right. There has been complete erosion of the petrous temporal bone by the tumor, with significant brainstem and cerebellar compression.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 323 Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC

Histological appearance of ELST. HE stain, low power magnification, demonstrating the characteristic papillary cystic architecture of these tumors.

Treatment conservation procedures while 68% underwent hearing ablative procedures. In patients with excellent Surgical resection is the primary modality of treatement preoperative hearing and a small ELST, such a hearing for ELSTs. Despite the benign histologic nature of conservation approach may be warranted. However, the these tumors, complete resection appears crucial for completeness of tumor resection should not be ensuring success. Total tumor resection is clearly the compromised for the sake of hearing conservation. Half treatment of choice, as only one patient with reported of patients undergoing hearing conservation approaches complete resection had subsequent recurrence. with subtotal resection followed by adjuvant radiation Although the most common presenting symptom was therapy had regrowth of tumor. sensorineural hearing loss, many patients, particularly In some tumors, total resection cannot be achieved those with VHL disease, present with small ELSTs and without risk of catastrophic loss of function or death, consequently present with serviceable hearing. VHL and in these patients subtotal resection may be patients are unique in that all undergo active warranted. Patients who have subtotal resection may surveillance and cranial imaging for hemangioblastoma benefit from postoperative radiotherapy, but there still as part of their VHL disease management. remains a roughly 50% risk of tumor regrowth and Subsequently, ELSTs in these patients are frequently therefore close surveillance is warranted as re-resection diagnosed early, with relatively little delay between may be necessary. Stereotactic radiotherapy has shown onset of audio-vestibular symptoms and identification no increased benefit above standard fractionated of tumor. This significantly affected surgical decision radiotherapy in survival or recurrence rates, and making, as 32% of patients underwent hearing

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subtotal resection followed by stereotactic radiotherapy hemangioblastomas, retinal hemangioblas-tomas, has uniformly resulted in tumor regrowth. There are no pheochromocytomas, and cysts of the kidneys, reported cases of radiation therapy and/or stereotactic pancreas, and epididymis. radiotherapy used as the primary modality of treatment The gene responsible for VHL disease is a tumor for ELSTs. suppressor and it has been mapped to chromosome Evolution 3p25. The VHL gene product pVHL forms a multi- protein complex that contains elongin B, elongin C, There are currently no reported cases of spontaneous Cul-2, and Rbx1. metastatic dissemination of ELSTs in the literature. The pVHL complex has a role in oxygen sensing. The Recently however, two reports have surfaced VHL gene regulates vascular endothelial growth factor describing metastatic disease following subtotal VEGF, and inactivation of the gene promotes VEGF resection. The first was a reported case of ELST drop overexpression and angiogenesis. In addition, its loss of metastasis with dissemination onto the ipsilateral function mutation can increase expression of hypoxia- cerebellar convexity beyond the original tumor site in a inducible factor HIF1, stimulating angiogenesis and patient who had undergone previous subtotal resection tumorigenesis. In VHL disease, it is believed that and radiotherapy. A second case of drop metastasis of tumors arise when both an inherited germline mutation ELST involved the spine, manifesting after multiple and a loss-of-function mutation of the wild-type VHL subtotal resections and three courses of stereotactic gene are present. radiosurgery. In addition, it has been shown that somatic mutations to These seminal reports serve to illustrate the importance the VHL gene locus at 3p25/26 are detected even in of complete tumor removal on initial resection in order cases of sporadic ELSTs, that is, in non-VHL patients. to minimize both recurrence and metastatic seeding. Genetic sequencing analysis of the 3p25 VHL gene The oncologic principle of complete tumor extirpation locus in both sporadic and VHL-associated ELSTs on primary resection is certainly applicable to ELSTs, demonstrates nucleotide substitution as well as despite their benign histology and absence of deletion/frameshift errors. spontaneous metastasis. Even though temporal bone lesions were described in Prognosis patients by Lindau in 1926, the association of these tumors with VHL disease was not made until recently. Overall survival characteristics for all reported cases of This clinical association has been confirmed at the ELSTs are: 74% no evidence of disease, 20% alive molecular level with mutations in the VHL gene with disease, and 4% died of disease, for the reporting identified in endolymphatic sac tumors in VHL periods. patients. Approximately 10% of patients with VHL ELSTs are histologically benign yet sometimes disease have ELSTs, and approximately 30% of VHL destructive, highly aggressive lesions. They show patients with ELSTs have bilateral tumors. This excellent response to primary surgical resection, with variable phenotypic expression may be a reflection of or without adjuvant radiotherapy. Complete tumor VHL gene function secondary to the type of mutation removal on initial resection is crucial. Hearing present. preservation should not take precedence over complete Indeed, VHL disease has been found to have tumor removal, as adjuvant radiotherapy does not phenotypic expression consistent within members of a ensure against tumor recurrence, which can be family, thus implying a singular, conserved mutation devastating and lethal. In addition, drop metastases within affected families. VHL disease is categorized following subtotal tumor resection have now been into two familial types, with type 1 being without reported. In patients with VHL disease, regularly pheochromocytomas and type 2 being with scheduled audiometry and surveillance MRI are vital to pheochromocytomas. There is further subclassification early detection of ELSTs, which can optimize the of type 2 into type 2a, low risk for developing renal cell opportunity for hearing preservation without carcinoma, and type 2b, high risk for developing renal compromising tumor control. cell carcinoma. Clinical presentation type correlates Genetics with genetic mutation type: type 1 families usually have deletion or truncation mutations, whereas type 2 Note families usually have missense mutations. The current literature suggests that approximately one If a family history of VHL disease exists, or if the third of all ELSTs are associated with VHL disease. diagnosis of VHL disease is made in the absence of an VHL disease is an autosomal dominant familial cancer ELST, then early routine audiologic screening can syndrome. VHL disease affects approximately 1 in allow for early tumor detection and the possibility of 39,000 people. It encompasses a variety of neoplasia hearing preservation surgery should ELST develop. both benign and malignant including renal cell Positive identification of tumor on MRI with carcinomas, central nervous system gadolinium is necessary prior to surgery: to date,

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surgical exploration in VHL patients with endolymphatic sac tumor. J Natl Cancer Inst. 1997 Jul audiovestibular symptoms but without MRI abnor- 2;89(13):970-2 mallities has not been documented and is not Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP, Wang recommended. AM. Paraganglioma of the temporal bone: role of magnetic resonance imaging versus computed tomography. Top Magn Genes involved and proteins Reson Imaging. 2000 Apr;11(2):108-22 Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman VHL RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von Hippel-Lindau gene mutations detected in sporadic Location endolymphatic sac tumors. Cancer Res. 2000 Nov 3p25.3 1;60(21):5963-5 DNA / RNA Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K, Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor The VHL gene is a tumor suppressor gene mapped to suppressor gene in a sporadic endolymphatic sac tumor. Hum chromosome 3p25/26. Pathol. 2001 Nov;32(11):1272-6 Protein Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons The VHL gene product, pVHL, forms a multi-protein SW, Preul MC. Endolymphatic sac tumor: unique features of complex that contains elongin B, elongin C, Cul-2, and two cases and review of the literature. Acta Neurochir (Wien). 2002 Oct;144(10):1047-53 Rbx1. Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ, Glasscock ME 3rd. Hearing preservation surgery for small References endolymphatic sac tumors in patients with von Hippel-Lindau Schindler RA. Histopathology of the human endolymphatic sac. syndrome. Otol Neurotol. 2002 May;23(3):378-87 Am J Otol. 1981 Oct;3(2):139-43 Bambakidis NC, Megerian CA, Ratcheson RA. Differential Hassard AD, Boudreau SF, Cron CC. Adenoma of the grading of endolymphatic sac tumor extension by virtue of von endolymphatic sac. J Otolaryngol. 1984 Aug;13(4):213-6 Hippel-Lindau disease status. Otol Neurotol. 2004 Sep;25(5):773-81 Heffner DK. Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases. Kim WY, Kaelin WG. Role of VHL gene mutation in human Cancer. 1989 Dec 1;64(11):2292-302 cancer. J Clin Oncol. 2004 Dec 15;22(24):4991-5004 Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Lonser RR, Kim HJ, Butman JA, Vortmeyer AO, Choo DI, Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the Oldfield EH. Tumors of the endolymphatic sac in von Hippel- von Hippel-Lindau disease tumor suppressor gene. Science. Lindau disease. N Engl J Med. 2004 Jun 10;350(24):2481-6 1993 May 28;260(5112):1317-20 Kim HJ, Butman JA, Brewer C, Zalewski C, Vortmeyer AO, Lo WW, Applegate LJ, Carberry JN, Solti-Bohman LG, House Glenn G, Oldfield EH, Lonser RR. Tumors of the JW, Brackmann DE, Waluch V, Li JC. Endolymphatic sac endolymphatic sac in patients with von Hippel-Lindau disease: tumors: radiologic appearance. Radiology. 1993 implications for their natural history, diagnosis, and treatment. Oct;189(1):199-204 J Neurosurg. 2005 Mar;102(3):503-12 Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diagnosis Gnarra JR, Orcutt ML, Duh FM, Glenn G. Germline mutations of endolymphatic sac tumors. Laryngoscope. 2006 in the von Hippel-Lindau disease tumor suppressor gene: Jan;116(1):40-6 correlations with phenotype. Hum Mutat. 1995;5(1):66-75 Santarpia L, Lapa D, Benvenga S. Germline mutation of von Megerian CA, McKenna MJ, Nuss RC, Maniglia AJ, Ojemann Hippel-Lindau (VHL) gene 695 G>A (R161Q) in a patient with a RG, Pilch BZ, Nadol JB Jr. Endolymphatic sac tumors: peculiar phenotype with type 2C VHL syndrome. Ann N Y Acad histopathologic confirmation, clinical characterization, and Sci. 2006 Aug;1073:198-202 implication in von Hippel-Lindau disease. Laryngoscope. 1995 Skalova A, Síma R, Bohus P, Curík R, Lukás J, Michal M. Aug;105(8 Pt 1):801-8 Endolymphatic sac tumor (aggressive papillary tumor of middle Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, ear and temporal bone): report of two cases with analysis of Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan the VHL gene. Pathol Res Pract. 2008;204(8):599-606 WM, Oldfield EH. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997 This article should be referenced as such: May 14;277(18):1461-6 Diaz RC. Head and Neck: Ear: Endolymphatic Sac Tumor Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von (ELST). Atlas Genet Cytogenet Oncol Haematol. 2010; Hippel-Lindau disease gene alterations associated with 14(3):321-326.

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Solid Tumour Section Mini Review

Lymphangioleiomyoma Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss Translational Medicine Branch, NHLBI, NIH, Building 10, Room 6D05, MSC 1590, Bethesda, Maryland 20892-1590, USA (CGG, AMTD, JM) Published in Atlas Database: April 2009 Online updated version: http://AtlasGeneticsOncology.org/Tumors/LymphangioleiomyomaID5868.html DOI: 10.4267/2042/44723 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

result from pulmonary or extrapulmonary lesions. Classification Pulmonary LAM is characterized by thin-walled cysts, Note which are diffused throughout the lungs. Patients with Lymphangioleiomyoma is a benign neoplasm of these lesions experience deterioration of lung function lymphatic vessels characterized as a PEComa that can lead to oxygen depen-dency, lung (perivascular epithelioid cell tumour), involving the transplantation or death. Extrapul-monary LAM proliferation of epithelioid cells, with mutations in the involves the axial lymphatics of the abdomen and tuberous sclerosis complex (TSC) genes TSC1 and thorax (lymphangioleiomyomas, adenopathy), and TSC2. abdominal organs, especially the kidneys (angiomyolipomas). Clinics and pathology Abdomino-pelvic lymphangioleiomyomas may present with abdominal pain as an acute abdomen, with a Note neuropathy or with abdominal bloating. Thoraco- Lymphangioleiomyomas are commonly associated with abdominal lymphadenopathy and lymph- lymphangioleiomyomatosis (LAM), a multi-system angioleiomyomas, along with chylothorax (Figure 1) or disorder primarily affecting women of child-bearing ascites may suggest the presence of a malignant age. Initial presentation of LAM may lymphoproliferative disease.

Figure 1: Large left chylous pleural effusion (white arrow) in a patient with LAM.

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Figure 2 A, B, C, D, and E. Histological characterization of extrapulmonary LAM. LAM cells form fascicles separated by lymphatic channels (A). (HE, original magnification x 100) An example of LAM cells arranged in trabecular bundles and irregular papillary patterns (B). (H&E, original magnification x 250) Image representing morphological heterogeneity of LAM cells; large epithelioid LAM cells (asterik) and smaller, round to oval cells (arrows) (C). (H&E, original magnification x 1,000) Positive reactivity of LAM cells to HMB-45 (D). (immunoperoxidase with hematoxylin counterstain, original magnification x 400) Positive reactivity of LAM cells to SMMHC (E). (original magnification x 400). (from Matsui et al., Hum Pathol. 2000 October;31(10):1242-1248).

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Etiology leakage and intractable chylothorax and ascites. Chylous effusions including pleural effusions are LAM results from proliferation of an abnormal cell, particularly difficult to treat. Repeated thora-centeses termed the LAM cell. LAM occurs in 30-40% of lead to malnutrition and may result in infectious patients with tuberous sclerosis complex, an autosomal complications. Low fat diet with medium-chain dominant disorder associated with mutations in the triglycerides and therapeutic thora-centesis should be TSC1 or TSC2 genes. Sporadic LAM is caused attempted initially. However, most patients require presumably by cells with mutations of the TSC2 gene. pleurodesis, which may be effective if the rate of chyle Lymphatic involvement (including generation can be reduced. Patients should be placed on lymphangioleiomyomas) occurs less frequently in a fat-free parenteral nutrition regimen prior to, during, patients with LAM/TSC, than in patients with sporadic and after surgery. It is essential that good lung LAM. expansion be obtained to ensure complete apposition of Epidemiology the visceral and parietal pleura to avoid residual pleural Lymphangioleiomyomas are present in about 16-21% pockets. After a successful pleurodesis, a low fat diet of patients with LAM. with mid-chain trigly-cerides is recommended. A peritoneal-venous shunt may be considered for most Pathology severe cases when the ascites is disabling and is Histological examination of the cells lining the walls of causing mechanical/ nutritional problems, but little the extrapulmonary lesions reveal common experience with this therapeutic modality in LAM is characteristics with pulmonary LAM cells, abnormal reported. Treatment with octreotide may be considered smooth muscle-like cells with a mixture of epithelioid for those patients with disabling ascites and large and splindle-shaped morphologies. Cells react with lymph-angioleiomyomata. Previous studies with HMB-45, a monoclonal antibody against gp100 (a somato-statin and octreotide in other clinical settings premelanosomal marker), and with antibodies against (e.g., traumatic damage to the lymphatics, yellow nail SMMHC, a smooth muscle-cell marker. Unlike the syndrome) have shown a successful reduction in nodular collections of the pulmonary LAM cells, the chylous effusions, chyluria, ascites, and peripheral extrapulmonary cells usually form fascicles or papillary lymphedema. patterns. Both types of lesions contain slit-like Sirolimus: The TSC1 and TSC2 genes encode lymphatic channels (Figure 2A, B, C, D, and E). respectively, hamartin and tuberin. Although Hamartin Radiologic Imaging: Retroperitoneal lymphangio- and tuberin may have individual functions, they are leiomyomas have a distinctive radiologic appearance also known to interact in a cytosolic complex. (Figures 3-7), and diurnal variation in size of the tumor Hamartin may play a role in the reorganization of the masses can be demonstrated by ultrasonography or actin cytoskeleton. Tuberin has roles in pathways computed tomography scans (Figure 8). controlling cell growth and proliferation. It is a Lymphangioleiomyomas are well characterized by negative regulator of cell cycle progression, and loss of either ultrasonography or computed tomography tuberin function shortens the G1 phase of the cell cycle. scanning, appearing as well-circumscribed lobular, thin Tuberin binds p27KIP1, a cyclin-dependent kinase or thick-walled masses without evidence of necrosis or inhibitor, thereby preventing its degradation and hemorrhage. Masses greater than 3 cm in diameter are leading to inhibition of the cell cycle. Tuberin also usually cystic in appearance and many contain fluid, integrates signals from growth factors and energy presumably chyle. Lesions as large as 20 cm in stores through its interaction with mTOR (mammalian diameter have been observed. In patients with LAM, target of rapamycin). Tuberin has Rheb GAP (Ras the lesions most often occur in the retroperitoneal homolog enriched in brain GTPase-activating protein) region. activity, which converts active Rheb-GTP to inactive Treatment Rheb-GDP. Rheb regulates mTOR, a serine/threonine kinase that phosphorylates at least two substrates: 4E- There is no effective treatment for lymphangio- BP1, allowing cap-dependent translation, and S6K1, leiomyomas. The lesions are usually asymptomatic, leading to translation of 5' TOP (terminal however, ascites, peripheral edema, and compres-sion oligopyrimidine tract)-containing RNAs. of the bladder, bowel, pelvic veins and other viscera by Phosphorylation of tuberin by Akt, which is activated large lymphangioleiomyomata may cause severe by growth factors, leads to inhibition of tuberin, symptomatology, including pain, obstipation, urinary resulting in cell growth and proliferation. frequency, and peripheral edema. Although surgery is Phosphorylation of tuberin by AMPK (AMP-activated sometimes contemplated to ameliorate symptoms kinase) activates tuberin and further promotes caused by visceral compression, it is contraindicated, inhibition of cell growth in conditions of energy as, in our experience; it may lead to persistent deprivation. lymphatic

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Figure 3. Mediastinal lymphangioleiomyoma (white arrow), located posteriorly to the descending thoracic aorta. A: aorta. Figure 4. Mediastinal lymphangioleiomyomas (white arrow), located posteriorly to the trachea. Figure 5. Large retroperitoneal lymphangioleiomyoma (white arrow) surrounding the aorta and inferior vena cava. A: aorta; IVC: inferior vena cava. Figure 6A and B. Black arrows point to large pelvic lymphangioleiomyoma (A). A complex lymphangioleiomyoma is shown marked by circle on panel B. Figure 7A, B and C. Evidence of bladder and bowel compression caused by the tumors. B: bladder.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 330 Lymphangioleiomyoma Glasgow CG, et al.

Figure 8A, B, C and D. Diurnal variation of lymphangioleiomyomas. Abdominal ultrasound shows that the size of a lymphangioleiomyoma is greater in the evening (panel B) that in the morning (panel A). Abdominal CT scan showing also diurnal variation in tumor size from morning (panel C) to evening (panel D).

Sirolimus, an inmmunosuppressive agent, inacti-vates with LAM, is correlated with more severe lung disease mTOR. Sirolimus has been shown to induce apoptosis assessed by computed tomography scans. of tumors in rodents and decrease the size of renal angiomyolipomas in patients with lymph- Genes involved and proteins angioleiomyomatosis or TSC. Further, sirolimus was effective in decreasing the size of chylous effusions and Note lymphangioleiomyomas in one patient with LAM and Serum levels of VEGF-D, a lymphangiogenic growth improved chylous effusions in another patient who factor, are higher in patients with LAM than those in underwent lung trans-plantation. healthy volunteers. In addition, serum levels of VEGF- D in patients with LAM who have Evolution lymphangioleiomyomas and adenopathy are higher Lymphangioleiomyomas are thought to occur due to than in patients without lymphangioleiomyomas. LAM the proliferation of LAM cells in lymphatic vessels, lung nodules demonstrate immunoreactivity for VEGF- causing obstruction and dilatation of the vessels leading D. Because of these findings and reported observations to collection of chylous material in cyst-like structures. of LAM cell clusters in lymphatic channels, it has been The cysts, when overdistended, may rupture resulting hypothesized that LAM-associated lymphangiogenesis, in chylous ascites. Lymphangioleiomyomas can exhibit driven by VEGF-D, may account for the dissemination diurnal variation, (visualized by CT or sonography) of LAM cells through the shedding of LAM cell with lesions increasing in size during the day. This clusters into the lymphatic system. phenomenon can be an aid in a differential diagnosis of a probable lymphangioleiomyoma with thick walls and References no fluid, from other mass lesions such as a lymphoma Druelle S, Aubry P, Levi-Valensi P. [Pulmonary or a sarcoma. lymphangiomyomatosis: a 3-year follow-up of Prognosis medroxyprogesterone acetate therapy. Apropos of a case]. Rev Pneumol Clin. 1995;51(5):284-7 Lymphatic involvement (defined by the presence of adenopathy and/or lymphangioleiomyomas) in patients Kimura M, Morikawa T, Takeuchi K, Furuie H, Fukimura M, Mikami R, Kakuta Y, Kawamura S, Tashiro Y.

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[Lymphangiomyomatosis with chylous ascites treatment Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, successfully by peritoneo-venous shunting]. Nihon Kyobu Hayashi S, Minami M, Uekusa T, Fukuchi Y, Suda K. Shikkan Gakkai Zasshi. 1996 May;34(5):557-62 Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Boudard C, Gamondes JP, Mornex JF, Brune J. [Pleuro- Am J Surg Pathol. 2004 Aug;28(8):1007-16 peritoneal Denver shunt in treatment of chronic pleurisy]. Ann Chir. 1998;52(2):192-6 Makrilakis K, Pavlatos S, Giannikopoulos G, Toubanakis C, Katsilambros N. Successful octreotide treatment of chylous Kehagias D, Pafiti A, Vaos N, Samanidis L. Retroperitoneal pleural effusion and lymphedema in the yellow nail syndrome. lymphangioleiomyomatosis: CT appearance. Eur Radiol. Ann Intern Med. 2004 Aug 3;141(3):246-7 1998;8(3):471-3 Ooi GC, Khong PL, Chan GC, Chan KN, Chan KL, Lam W, Ng Wójcik P, Otto TJ, Jagiełło R, Komarow I, Zaremba J, I, Ha SY. Magnetic resonance screening of iron status in Drygalska-Pozorańska A, Chudański M. [Use of pleuro- transfusion-dependent beta-thalassaemia patients. Br J peritoneal shunt in the treatment of chronic chylothorax]. Haematol. 2004 Feb;124(3):385-90 Pneumonol Alergol Pol. 1998;66(9-10):473-9 Avila NA, Dwyer AJ, Murphy-Johnson DV, Brooks P, Moss J. Widjaja A, Gratz KF, Ockenga J, Wagner S, Manns MP. Sonography of lymphangioleiomyoma in Octreotide for therapy of chylous ascites in yellow nail lymphangioleiomyomatosis: demonstration of diurnal variation syndrome. Gastroenterology. 1999 Apr;116(4):1017-8 in lesion size. AJR Am J Roentgenol. 2005 Feb;184(2):459-64 Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Lymphangioleiomyomatosis: abdominopelvic CT and US Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, Fukuchi Y, findings. Radiology. 2000 Jul;216(1):147-53 Suda K. Lymphangiogenesis-mediated shedding of LAM cell Ferrans VJ, Yu ZX, Nelson WK, Valencia JC, Tatsuguchi A, clusters as a mechanism for dissemination in Avila NA, Riemenschn W, Matsui K, Travis WD, Moss J. lymphangioleiomyomatosis. Am J Surg Pathol. 2005 Lymphangioleiomyomatosis (LAM): a review of clinical and Oct;29(10):1356-66 morphological features. J Nippon Med Sch. 2000 Almoosa KF, McCormack FX, Sahn SA. Pleural disease in Oct;67(5):311-29 lymphangioleiomyomatosis. Clin Chest Med. 2006 Johnson SR, Tattersfield AE. Clinical experience of Jun;27(2):355-68 lymphangioleiomyomatosis in the UK. Thorax. 2000 Avila NA, Dwyer AJ, Rabel A, DeCastro RM, Moss J. CT of Dec;55(12):1052-7 pleural abnormalities in lymphangioleiomyomatosis and Matsui K, Tatsuguchi A, Valencia J, Yu Z, Bechtle J, Beasley comparison of pleural findings after different types of MB, Avila N, Travis WD, Moss J, Ferrans VJ. Extrapulmonary pleurodesis. AJR Am J Roentgenol. 2006 Apr;186(4):1007-12 lymphangioleiomyomatosis (LAM): clinicopathologic features in Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, 22 cases. Hum Pathol. 2000 Oct;31(10):1242-8 Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy Avila NA, Bechtle J, Dwyer AJ, Ferrans VJ, Moss J. HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Lymphangioleiomyomatosis: CT of diurnal variation of Decastro RM, Jacobs SS, Stylianou M, Fanburg BL. The lymphangioleiomyomas. Radiology. 2001 Nov;221(2):415-21 NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Kelly J, Moss J. Lymphangioleiomyomatosis. Am J Med Sci. Jan 1;173(1):105-11 2001 Jan;321(1):17-25 Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, Mitani Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, K, Tominaga S, Fukuchi Y. Vascular endothelial growth factor- Brooks PG, Hedin CJ, Hunsberger S, Kristof AS. Prevalence D is increased in serum of patients with and clinical characteristics of lymphangioleiomyomatosis lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4(3):143- (LAM) in patients with tuberous sclerosis complex. Am J Respir 52 Crit Care Med. 2001 Aug 15;164(4):669-71 Taveira-DaSilva AM, Steagall WK, Moss J. Llopis I, Arandiga R, Real E, Estañ A, Chulia R, Pastor E, Grau Lymphangioleiomyomatosis. Cancer Control. 2006 E. Lymphangiomyomatosis mimicking an abdominal Oct;13(4):276-85 lymphoma. Haematologica. 2002 Oct;87(10):EIM23 Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic Jaiswal VR, Baird J, Fleming J, Miller DS, Sharma S, Molberg lymphangioleiomyomatosis and tuberous sclerosis complex K. Localized retroperitoneal lymphangioleiomyomatosis with lymphangioleiomyomatosis: comparison of CT features. mimicking malignancy. A case report and review of the Radiology. 2007 Jan;242(1):277-85 literature. Arch Pathol Lab Med. 2003 Jul;127(7):879-82 Taillé C, Debray MP, Crestani B. Sirolimus treatment for Lu HC, Wang J, Tsang YM, Lin MC, Li YW. pulmonary lymphangioleiomyomatosis. Ann Intern Med. 2007 Lymphangioleiomyomatosis initially presenting with abdominal May 1;146(9):687-8 pain: a case report. Clin Imaging. 2003 May-Jun;27(3):166-70 Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Ryu JH, Doerr CH, Fisher SD, Olson EJ, Sahn SA. Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Chylothorax in lymphangioleiomyomatosis. Chest. 2003 Salisbury S, Franz DN. Sirolimus for angiomyolipoma in Feb;123(2):623-7 tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140-51 Wong YY, Yeung TK, Chu WC. Atypical presentation of lymphangioleiomyomatosis as acute abdomen: CT diagnosis. Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox AJR Am J Roentgenol. 2003 Jul;181(1):284-5 JA, McCartney DL, Doyle T, Elmslie F, Saggar A, de Vries PJ, Sampson JR. Sirolimus therapy in tuberous sclerosis or Crooks DM, Pacheco-Rodriguez G, DeCastro RM, McCoy JP sporadic lymphangioleiomyomatosis. N Engl J Med. 2008 Jan Jr, Wang JA, Kumaki F, Darling T, Moss J. Molecular and 10;358(2):200-3 genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2004 Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J.. Related Dec 14;101(50):17462-7 Articles: Serum VEGF-D levels in patients with

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 332 Lymphangioleiomyoma Glasgow CG, et al.

lymphangioleiomyomatosis (LAM) reflect lymphatic Weiss SW, Goldblum JR.. Enzinger and Weiss's Soft Tissue involvement. Accepted by Chest for publication October 8, Tumors. Fourth edition; Mosby, Inc. (Elsevier) publisher 2008. 2008. in press. This article should be referenced as such: Glasgow CG, Taveira-Dasilva AM, Darling TN, Moss J. Lymphatic involvement in lymphangioleiomyomatosis. Ann N Y Glasgow CG, Taveira-DaSilva AM, Moss J. Acad Sci. 2008;1131:206-14 Lymphangioleiomyoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):327-333. Ohara T, Oto T, Miyoshi K, Tao H, Yamane M, Toyooka S, Okazaki M, Date H, Sano Y. Sirolimus ameliorated post lung transplant chylothorax in lymphangioleiomyomatosis. Ann Thorac Surg. 2008 Dec;86(6):e7-8

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