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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 in Oncology and Haematology

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Volume 18 - Number 5 May 2014

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.


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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present 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, Marie-Christine Jacquemot-Perbal, Vanessa Le Berre, Anne Malo, Carol Moreau, Catherine Morel-Pair, Laurent Rassinoux, 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. The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

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Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)


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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 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 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 Adriana Zamecnikova (Kuwait) Leukaemia Section



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Volume 18, Number 5, May 2014

Table of contents

Gene Section

BYSL (Bystin-Like) 293 Michiko N Fukuda, Kazuhiro Sugihara

DBN1 (drebrin 1) 299 John Chilton

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) 301 Nayden G Naydenov, Andrei I Ivanov

AUTS2(autism susceptibility candidate 2) 306 Jean-Loup Huret

AVEN (apoptosis, caspase activation inhibitor) 311 Inga Maria Melzer, Martin Zörnig

FKBP5 (FK506 binding protein 5) 314 Katarzna Anna Ellsworth, Liewei Wang

ITGA9 (integrin, alpha 9) 321 Carla Molist, Ana Almazán-Moga, Isaac Vidal, Aroa Soriano, Luz Jubierre, Miguel F Segura, Josep Sánchez de Toledo, Soledad Gallego, Josep Roma

KIAA1199 (KIAA1199) 324 Nikki Ann Evensen, Cem Kuscu, Jian Cao

MMP19 (matrix metallopeptidase 19) 327 King Chi Chan, Maria Li Lung

RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6) 330 Tuoen Liu, Shousong Cao

SIVA1 (SIVA1, Apoptosis-Inducing Factor) 334 João Agostinho Machado-Neto, Fabiola Traina

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila)) 340 Behnam Nabet, Jonathan D Licht

TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)) 346 Maria V Bogachek, Ronald J Weigel

USP1 (ubiquitin specific peptidase 1) 351 Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti

Leukaemia Section

t(3;11)(q12;p15) NUP98/LNP1 356 Jean-Loup Huret

t(7;8)(p12;q24) /MYC 358 Jean-Loup Huret



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t(2;3)(p21;q26) THADA/MECOM 359 Jean-Loup Huret

Deep Insight Section

Adiponectin and cancer 361 Maria Dalamaga, Vassiliki Koumaki



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Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5) 293


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BYSL (Bystin-Like) Michiko N Fukuda, Kazuhiro Sugihara

Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA (MNF), Department of Gynecology and Obstetrics, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka, Japan (KS)

Published in Atlas Database: September 2013

Online updated version : http://AtlasGeneticsOncology.org/Genes/BYSLID857ch6p21.html DOI: 10.4267/2042/53636

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Review on BYSL, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: BYSTIN

HGNC (Hugo): BYSL

Location: 6p21.1

Local order: In human chromosome, BYSL gene localizes in chromosome 6, between TRFP encoding a transcription mediator, and CCND3 encoding cyclin D3 (Figure 1).

DNA/RNA Description BYSL locates on 6 chromosome 6p21.1 (Pack et al., 1998). It contains 8 exons spanning 10.7 kb of genomic DNA.

Protein Description Human bystin is a 49.6 kDa cytoplasmic protein composed of 437 amino acid residues. Bystin is a basic protein with isoelectric point 8.10.

Figure 1. Genomic organization of BYSL.

BYSL (Bystin-Like) Fukuda MN, Sugihara K


Figure 2. Blastocyst-dependent localization of bystin protein in the mouse endometrial epithelia. Above: mouse endometrium with implanting blastocyst (Bl) shows bystin protein (red) on the apical side of epithelia. below: mouse endometrium from pseudopregnant female shows bystin at abluminal side of epithelia. Glandular epithelia (ge); luminal epithelia (le). Bystin protein contains many potential protein kinase phosphorylation sites, suggesting an active role of bystin in signal transduction. However, no known structural motif is found in bystin protein.

Expression BYSL is expressed in trophectoderm cells and endometrial epithelial cells during embryo implantation in human (Aoki and Fukuda, 2000; Nakayama et al., 2003; Suzuki et al., 1999; Suzuki et al., 1998). The expression pattern of mouse bystin at peri-implantation (Aoki et al., 2006) is similar to that of mouse trophinin (Nadano et al., 2002). In the mouse, bystin protein was found in the blastocyst embryo and endometrial epithelial cells during peri-implantation period (Aoki et al., 2006). Bystin is expressed in mouse endometrial luminal and glandular epithelial cells throughout hormonal cycles (Aoki et al., 2006). Bystin in the luminal epithelia showed a distinct blastocyst-dependent pattern: in the presence of blastocysts, bystin

proteins localized to the apical side of the epithelia, whereas in their absence bystin protein was localized to the abluminal or basal side of the epithelia (Figure 2). This observation suggests the existence of an embryonic factor affecting in a way determining the localization of bystin in the maternal epithelia. The molecular basis underlying apical or basal localization of bystin is presently unknown. Bysl is strongly expressed in the adult rat brain after injury (Ma et al., 2006; Sheng et al., 2004). Bystin is expressed after optic nerve injury in zebra fish (Neve et al., 2012). Bystin protein was found in mature sperm, of which function is implicated to sperm motility (Hatakeyama et al., 2008). Bystin is overexpressed in hepatocellular carcinoma, suggesting its function in cell proliferation in liver cancer (Wang et al., 2009). In the Drosophila embryo, bys expression is ubiquitous but relatively weak at early stages, but at later stages bys expression is strong and specifically localized to larval imaginal discs, suggesting a role



of bys in cell adhesion. In particular, bys expression is strong in the region of the wing pouch giving rise to two epithelial sheets of the adult wing that adhere to one another after the disc everts (Stewart and Nordquist, 2005).

Localisation In 6 weeks human placenta, bystin protein was found in the cytoplasm of the syncytiotrophoblast and cytotrophoblast in the chorionic villi, and in endometrial decidual cells at the utero placental interface. In 10 weeks placenta, bystin was exclusively in the nucli of cytotrophoblast (Suzuki et al., 1999). In cultured cells, bystin localizes to both the nucleus and cytoplasm (Aoki et al., 2006; Miyoshi et al., 2007). In the nucleus, bystin was often found in the nucleoli.

Function Bystin function in human embryo implantation: Bystin was originally identified as a cytoplasmic protein that forms a complex with trophinin and tastin in human trophoblastic embryonal carcinoma HT-H cells (Fukuda and Nozawa, 1999; Suzuki et al., 1998). While genes encoding trophinin and tastin are only found in mammals, the bystin gene is conserved across a wide range of eukaryotes, including yeast, nematodes, insects, snakes, and mammals (Roos et al., 1997; Stewart and Denell, 1993; Stewart and Nordquist, 2005; Trachtulec and Forejt, 2001). Trophinin is an intrinsic membrane protein that mediates cell adhesion by homophilic trophinin-trophinin binding (Fukuda et al., 1995). Tastin and bystin are cytoplasmic proteins required for trophinin to function efficiently as a cell adhesion molecule. In humans, trophinin, tastin and bystin are expressed at the utero-placental interface or at implantation sites (Suzuki et al., 1999). These proteins are expressed in human placenta at early stages of pregnancy but disappear from the placenta after 10 weeks of pregnancy (Aoki and Fukuda, 2000; Fukuda and Nozawa, 1999; Suzuki et al., 1999). In trophoblastic HT-H cells, bystin protein associates with trophinin and ErbB4 in the cytoplasm (Sugihara et al., 2007). When trophinin-mediated cell adhesion takes place on the cell surface, bystin dissociates from trophinin and tyrosine phosphorylation of ErbB4 takes place, suggesting the mechanism underlying the trophectoderm cell activation upon human embryo implantation (Figure 3). Bystin functions as molecular switch in trophinin-mediated signal transduction in trophoblastic cells (Fukuda and Sugihara, 2007; Fukuda and Sugihara,2008; Fukuda and Sugihara,2012). Bystin function in mouse embryo: Bystin null mouse embryos implanted successfully but died soon after implantation (Aoki et al., 2006),

suggesting that bystin is essential for mouse embryo survival after implantation. However, as described below, Bysl gene knockdown experiments show that bystin is also required for survival of pre-implantation stage mouse embryos (Adachi et al., 2007). In the knockout mouse, it is likely that maternally derived Bysl mRNA masks loss of Bysl at pre-implantation stages. When Bysl siRNAs were microinjected into fertilized eggs, compaction at the eight-cell stage occurred normally in vitro (Adachi et al., 2007). Bysl siRNA-injected embryos showed slightly reduced expression of cytokeratin 8 (EndoA), an early trophectoderm marker (Oshima et al., 1983). While control blastocysts showed assembled cytokeratin structures in the trophectoderm layer, no organized structures were detected in Bysl siRNA-injected embryos. Consequently, blastocyst formation was completely inhibited. These embryos failed to hatch from the zona pellucida and could not outgrow in culture, suggesting that the bystin functions in trophectoderm differentiation. Bysl knockdown also inhibited embryonic stem cell proliferation (Adachi et al., 2007). Bystin function in stem cells: Mouse bystin gene Bysl has been identified as the stem cell marker commonly expressed in embryonal, neuronal and hematopoietic stem cells (Ramalho-Santos et al., 2002). BYSL is also identified as the major target of MYC in B-cells (Basso et al., 2005). Since MYC is one of essential genes for converting somatic cells into induced pluripotent stem cell (iPS) (Takahashi and Yamanaka, 2006), these observations suggest strongly an essential role of bystin in pluripotent stem cells. Bysl is included in a gene cluster of stem cell markers found on mouse chromosome 16 (Ramalho-Santos et al., 2002). Bystin function in human sperm motility: Bystin regulates sperm motility (Hatakeyama et al., 2008). Trophinin plays multiple roles in each cell type under different conditions. Bystin function in ribosomal biogenesis: The yeast bystin homologue ENP1 is essential for budding yeast to survive (Roos et al., 1997). A temperature-sensitive ENP1-null mutant showed defective processing of ribosomal RNA (rRNA) (Chen et al., 2003). Studies of ribosomal biogenesis in yeast indicate that Enp1 is required to synthesize 40S ribosomal subunits by functioning in their nuclear export (Schafer et al., 2003). Eukaryotic ribosome formation occurs predominantly in nucleoli, but late maturation steps occur in both the nucleoplasm and cytoplasm. Location of bystin in the cytoplasm during G1 and its nuclear localization prior to mitosis suggest that bystin plays dual roles in cell growth and proliferation in mammalian cells. Although bystin exhibits activities similar to Enp1, human bystin cannot rescue the lethal phenotype of



Enp1-null yeast mutant, suggesting that ribosomal RNA processing pathways in multicellular organisms differ from those in yeast and that bystin's activities may have been modified during evolution. Recent studies reveal that maturation of the 40S ribosomal subunit precursors in mammals includes an additional step during processing of the internal transcribed spacer 1 (ITS1), and that coordination between maturation and nuclear export of pre-40S particles has evolved differently in yeast and mammalian cells (Carron et al., 2011). In higher organisms, it was long believed that rRNA processing is completed within the nucleus. However, maturation of the 40S subunit, including final processing of 18S rRNA, occurs in the cytoplasm in human cells (Zemp and Kutay, 2007). Since part of cytoplasmic bystin is associated with

the 40S subunit before translation in human cells (Miyoshi et al., 2007), bystin may also function in the final step of 40S subunit synthesis in the cytoplasm. Bystin associates with undefined nuclear particles following actinomycin D treatment of HeLa cells (Miyoshi et al., 2007). Soluble proteins involved in ribosome biogenesis may shuttle between the nucleolus and nucleoplasm (Dez and Tollervey, 2004). Given the dependence of cell proliferation on ribosome biogenesis, when biogenesis is halted by nucleolar stress this system may allow rapid ribosome re-synthesis following relief from stress (Phipps et al., 2011).

Homology None.

Figure 3. Role of bystin protein in signal transduction. Prior to trophinin-mediated cell adhesion or in silent trophectoderm cells, ErbB4 is arrested by trophinin-bystin complex. When trophinin-mediated cell adhesion occurs or trophinin-binding GWRQ peptide mimics trophinin-mediated cell adhesion, bystin dissociates from trophinin leading into tyrosine phosphorylation of ErbB4 (Sugihara et al., 2007).

Figure 4. Ribosomal biogenesis and rRNA processing in eukaryotic cells. The initial pre-rRNA transcript is first transcribed from repetitive ribosomal DNA genes by RNA polymerase I in the nucleolus. rRNA precursors are then processed, chemically modified, and folded in the nucleolus, and ribosomal proteins, which are translated in the cytoplasm and imported into this organelle, concomitantly assemble with pre-rRNAs. There are two alternative pathways for rRNA processing in human HeLa cells. Bystin is likely involved in processing of a 21S intermediate, of which the final product, 18S rRNA, is included in the 40S small subunit. Bystin is involved in 18S rRNA processing.



Implicated in Various cancers Note Cancer progression depends on cell growth and cell cycle progression. Upregulation of BYSL is implicated to following cancers.

Gastric cancer Note Genome-wide genomic copy aberration analysis of gastric cancer revealed several genes and BYSL was identified as one of them along with CDC6, SEC61G, ANP32E, BYSL and FDFT1 (Tsukamoto et al., 2008).

Hepatocellular carcinoma (HCC) Note Expression levels of BYSL mRNA and protein in human HCC specimens were markedly increased compared with those seen in adjacent non-cancerous tissue (Wang et al., 2009). BYSL shRNA decreased HCC cell proliferation in vitro, induced apoptosis and partially arrested the cell cycle in the G2/M phase. In vivo, HCC cells treated with BYSL siRNA failed to form tumors in nude mice after subcutaneous implantation. BYSL was found at multiple stages during nucleologenesis, including in nucleolus-derived foci (NDF), perichromosomal regions and the prenucleolar body (PNB) during mitosis. BYSL depletion remarkably suppressed NDF and PNB formation, and disrupted nucleoli assembly after mitosis, resulting in increased apoptosis and reduced tolerance of HCC cells to serum starvation.

Prostate cancers Note In prostate cancer cells, which adhere to neurons, bystin protein is expressed in a manner suggesting a role in cell-cell contact and cell growth (Ayala et al., 2006).

B cell lymphoma Note Indeed BYSL and CCND3 are both elevated in B cell lymphoma (Bea, 2010; Kasugai et al., 2005), which is consistent with close proximity of BYSL and CCND3 encoding cyclin D3 (Figure 1) suggesting their co-ordinated role in normal and malignant cells.

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Stewart MJ, Denell R. Mutations in the Drosophila gene encoding ribosomal protein S6 cause tissue overgrowth. Mol Cell Biol. 1993 Apr;13(4):2524-35

Fukuda MN, Sato T, Nakayama J, Klier G, Mikami M, Aoki D, Nozawa S. Trophinin and tastin, a novel cell adhesion molecule complex with potential involvement in embryo implantation. Genes Dev. 1995 May 15;9(10):1199-210

Roos J, Luz JM, Centoducati S, Sternglanz R, Lennarz WJ. ENP1, an essential gene encoding a nuclear protein that is highly conserved from yeast to humans. Gene. 1997 Jan 31;185(1):137-46

Pack SD, Pak E, Tanigami A, Ledbetter DH, Fukuda MN. Assignment1 of the bystin gene BYSL to human chromosome band 6p21.1 by in situ hybridization. Cytogenet Cell Genet. 1998;83(1-2):76-7

Suzuki N, Zara J, Sato T, Ong E, Bakhiet N, Oshima RG, Watson KL, Fukuda MN. A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin and may be involved in trophinin-mediated cell adhesion between trophoblast and endometrial epithelial cells. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5027-32

Fukuda MN, Nozawa S. Trophinin, tastin, and bystin: a complex mediating unique attachment between trophoblastic and endometrial epithelial cells at their respective apical cell membranes. Semin Reprod Endocrinol. 1999;17(3):229-34

Suzuki N, Nakayama J, Shih IM, Aoki D, Nozawa S, Fukuda MN. Expression of trophinin, tastin, and bystin by trophoblast and endometrial cells in human placenta. Biol Reprod. 1999 Mar;60(3):621-7

Aoki R, Fukuda MN. Recent molecular approaches to elucidate the mechanism of embryo implantation: trophinin, bystin, and tastin as molecules involved in the initial attachment of blastocysts to the uterus in humans. Semin Reprod Med. 2000;18(3):265-71

Trachtulec Z, Forejt J. Synteny of orthologous genes conserved in mammals, snake, fly, nematode, and fission yeast. Mamm Genome. 2001 Mar;12(3):227-31

Nadano D, Sugihara K, Paria BC, Saburi S, Copeland NG, Gilbert DJ, Jenkins NA, Nakayama J, Fukuda MN. Significant differences between mouse and human trophinins are revealed by their expression patterns and targeted disruption of mouse trophinin gene. Biol Reprod. 2002 Feb;66(2):313-21

Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA. "Stemness": transcriptional profiling of embryonic and adult stem cells. Science. 2002 Oct 18;298(5593):597-600

Chen W, Bucaria J, Band DA, Sutton A, Sternglanz R. Enp1, a yeast protein associated with U3 and U14 snoRNAs, is required for pre-rRNA processing and 40S subunit synthesis. Nucleic Acids Res. 2003 Jan 15;31(2):690-9

Nakayama J, Aoki D, Suga T, Akama TO, Ishizone S, Yamaguchi H, Imakawa K, Nadano D, Fazleabas AT, Katsuyama T, Nozawa S, Fukuda MN. Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy. Am J Pathol. 2003 Dec;163(6):2211-9

Schäfer T, Strauss D, Petfalski E, Tollervey D, Hurt E. The path from nucleolar 90S to cytoplasmic 40S pre-ribosomes. EMBO J. 2003 Mar 17;22(6):1370-80



Dez C, Tollervey D. Ribosome synthesis meets the cell cycle. Curr Opin Microbiol. 2004 Dec;7(6):631-7

Sheng J, Yang S, Xu L, Wu C, Wu X, Li A, Yu Y, Ni H, Fukuda M, Zhou J. Bystin as a novel marker for reactive astrocytes in the adult rat brain following injury. Eur J Neurosci. 2004 Aug;20(4):873-84

Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla-Favera R, Califano A. Reverse engineering of regulatory networks in human B cells. Nat Genet. 2005 Apr;37(4):382-90

Kasugai Y, Tagawa H, Kameoka Y, Morishima Y, Nakamura S, Seto M. Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma. Clin Cancer Res. 2005 Dec 1;11(23):8265-72

Stewart MJ, Nordquist EK. Drosophila Bys is nuclear and shows dynamic tissue-specific expression during development. Dev Genes Evol. 2005 Feb;215(2):97-102

Aoki R, Suzuki N, Paria BC, Sugihara K, Akama TO, Raab G, Miyoshi M, Nadano D, Fukuda MN. The Bysl gene product, bystin, is essential for survival of mouse embryos. FEBS Lett. 2006 Nov 13;580(26):6062-8

Ayala GE, Dai H, Li R, Ittmann M, Thompson TC, Rowley D, Wheeler TM. Bystin in perineural invasion of prostate cancer. Prostate. 2006 Feb 15;66(3):266-72

Ma L, Yin M, Wu X, Wu C, Yang S, Sheng J, Ni H, Fukuda MN, Zhou J. Expression of trophinin and bystin identifies distinct cell types in the germinal zones of adult rat brain. Eur J Neurosci. 2006 May;23(9):2265-76

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76

Adachi K, Soeta-Saneyoshi C, Sagara H, Iwakura Y. Crucial role of Bysl in mammalian preimplantation development as an integral factor for 40S ribosome biogenesis. Mol Cell Biol. 2007 Mar;27(6):2202-14

Miyoshi M, Okajima T, Matsuda T, Fukuda MN, Nadano D. Bystin in human cancer cells: intracellular localization and function in ribosome biogenesis. Biochem J. 2007 Jun 15;404(3):373-81

Sugihara K, Sugiyama D, Byrne J, Wolf DP, Lowitz KP, Kobayashi Y, Kabir-Salmani M, Nadano D, Aoki D,

Nozawa S, Nakayama J, Mustelin T, Ruoslahti E, Yamaguchi N, Fukuda MN. Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3799-804

Zemp I, Kutay U. Nuclear export and cytoplasmic maturation of ribosomal subunits. FEBS Lett. 2007 Jun 19;581(15):2783-93

Hatakeyama S, Sugihara K, Lee SH, Nadano D, Nakayama J, Ohyama C, Fukuda MN. Enhancement of human sperm motility by trophinin binding peptide. J Urol. 2008 Aug;180(2):767-71

Tsukamoto Y, Uchida T, Karnan S, Noguchi T, Nguyen LT, Tanigawa M, Takeuchi I, Matsuura K, Hijiya N, Nakada C, Kishida T, Kawahara K, Ito H, Murakami K, Fujioka T, Seto M, Moriyama M. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82

Wang H, Xiao W, Zhou Q, Chen Y, Yang S, Sheng J, Yin Y, Fan J, Zhou J. Bystin-like protein is upregulated in hepatocellular carcinoma and required for nucleologenesis in cancer cell proliferation. Cell Res. 2009 Oct;19(10):1150-64

Bea S. Amplifications and target genes in diffuse large B-cell lymphoma: real targets or consequences of structural features of the genome? Leuk Lymphoma. 2010 May;51(5):743-4

Carron C, O'Donohue MF, Choesmel V, Faubladier M, Gleizes PE. Analysis of two human pre-ribosomal factors, bystin and hTsr1, highlights differences in evolution of ribosome biogenesis between yeast and mammals. Nucleic Acids Res. 2011 Jan;39(1):280-91

Phipps KR, Charette J, Baserga SJ. The small subunit processome in ribosome biogenesis—progress and prospects. Wiley Interdiscip Rev RNA. 2011 Jan-Feb;2(1):1-21

Neve LD, Savage AA, Koke JR, García DM. Activating transcription factor 3 and reactive astrocytes following optic nerve injury in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol. 2012 Mar;155(2):213-8

This article should be referenced as such:

Fukuda MN, Sugihara K. BYSL (Bystin-Like). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):293-298.

Gene Section Short Communication



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DBN1 (drebrin 1) John Chilton

Biomedical Neuroscience Research Group, University of Exeter Medical School, Hatherly Laboratories, Prince of Wales Road, Exeter EX4 4PS, UK (JC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/DBN1ID51520ch5q35.html DOI: 10.4267/2042/53637


Abstract Review on DBN1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: D0S117E

HGNC (Hugo): DBN1

Location: 5q35.3

DNA/RNA Description 14 exons.

Transcription Two alternatively spliced isoforms: - NCBI LOCUS NM_004395 2942 bp corresponds to DBN1a variant, - NCBI LOCUS NM_080881 3058 bp corresponds to DBN1b variant.

Protein Description DBN1 encodes a 71 kDa protein of ~650 amino

acids (DBN1a has 649 amino acids, DBN1b has 651 amino acids). The N-terminus contains an ADF/Cofilin homology domain (Poukkula et al., 2011) followed by a coiled-coil and a helical domain which each contain an actin-binding site (Worth et al., 2013). The C-terminus contains no identifiable domain structure apart from two Homer binding motifs and can provide intramolecular regulation of F-actin binding (Worth et al., 2013). In some species (chick, rat) developmental regulation of the protein occurs such that at the earliest stages of development an embryonic 'E1' isoform is expressed. This is then downregulated in favour of an 'E2' isoform containing a 43 amino acid insertion which itself is subsequently superseded by the adult 'A' isoform containing a further 46 amino acids insertion adjacent to the previous one (Kojima et al., 1993). In humans E2 appears to be the predominant isoform.

Expression DBN1 is widely expressed in the nervous system and is also found in other organs, predominantly kidney, stomach, lung and skin (Dun and Chilton, 2010).

DBN1 (drebrin 1) Chilton J


Localisation DBN1 localises to actin-rich structures within cells such as the leading edge of neuronal growth cones (Geraldo et al., 2008; Dun et al., 2012) and intercellular junctions (Butkevich et al., 2004; Rehm et al., 2013).

Function At the molecular level, DBN1 stabilises actin filaments (Mikati et al., 2013). It may provide a link between the actin and microtubule networks (Geraldo et al., 2008) and is required for neuronal migration (Dun et al., 2012). Drebrin function can be regulated by the phosphorylation state of distinct serine residues due to the actions of Cdk5 (Worth et al., 2013) and PTEN (Kreis et al., 2013).

Homology Drebrin is conserved across vertebrates, especially in the first 300 amino acids containing the ADF/Cofilin homology, coiled-coil and helical domains. The closest relative in invertebrate species is actin-binding protein 1 (ABP1).

Implicated in Mantle cell lymphoma Note Drebrin is a direct target of Sox11 in primary mantle cell lymphomas (Wang et al., 2010).

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) Note High levels of drebrin protein expression in BCP-ALL (Vaskova et al., 2011).

Skin tumours (varied) Note Drebrin levels are increased compared to control skin samples in basal cell carcinoma, squamous cell carcinoma, melanoma and leiomyosarcoma (Peitsch et al., 2005).

References Kojima N, Shirao T, Obata K. Molecular cloning of a developmentally regulated brain protein, chicken drebrin A and its expression by alternative splicing of the drebrin gene. Brain Res Mol Brain Res. 1993 Jul;19(1-2):101-14

Butkevich E, Hülsmann S, Wenzel D, Shirao T, Duden R,

Majoul I. Drebrin is a novel connexin-43 binding partner that links gap junctions to the submembrane cytoskeleton. Curr Biol. 2004 Apr 20;14(8):650-8

Peitsch WK, Hofmann I, Bulkescher J, Hergt M, Spring H, Bleyl U, Goerdt S, Franke WW. Drebrin, an actin-binding, cell-type characteristic protein: induction and localization in epithelial skin tumors and cultured keratinocytes. J Invest Dermatol. 2005 Oct;125(4):761-74

Geraldo S, Khanzada UK, Parsons M, Chilton JK, Gordon-Weeks PR. Targeting of the F-actin-binding protein drebrin by the microtubule plus-tip protein EB3 is required for neuritogenesis. Nat Cell Biol. 2008 Oct;10(10):1181-9

Dun XP, Chilton JK. Control of cell shape and plasticity during development and disease by the actin-binding protein Drebrin. Histol Histopathol. 2010 Apr;25(4):533-40

Wang X, Björklund S, Wasik AM, Grandien A, Andersson P, Kimby E, Dahlman-Wright K, Zhao C, Christensson B, Sander B. Gene expression profiling and chromatin immunoprecipitation identify DBN1, SETMAR and HIG2 as direct targets of SOX11 in mantle cell lymphoma. PLoS One. 2010 Nov 22;5(11):e14085

Poukkula M, Kremneva E, Serlachius M, Lappalainen P. Actin-depolymerizing factor homology domain: a conserved fold performing diverse roles in cytoskeletal dynamics. Cytoskeleton (Hoboken). 2011 Sep;68(9):471-90

Vaskova M, Kovac M, Volna P, Angelisova P, Mejstrikova E, Zuna J, Brdicka T, Hrusak O. High expression of cytoskeletal protein drebrin in TEL/AML1pos B-cell precursor acute lymphoblastic leukemia identified by a novel monoclonal antibody. Leuk Res. 2011 Aug;35(8):1111-3

Dun XP, Bandeira de Lima T, Allen J, Geraldo S, Gordon-Weeks P, Chilton JK. Drebrin controls neuronal migration through the formation and alignment of the leading process. Mol Cell Neurosci. 2012 Mar;49(3):341-50

Kreis P, Hendricusdottir R, Kay L, Papageorgiou IE, van Diepen M, Mack T, Ryves J, Harwood A, Leslie NR, Kann O, Parsons M, Eickholt BJ. Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN. PLoS One. 2013;8(8):e71957

Mikati MA, Grintsevich EE, Reisler E. Drebrin-induced stabilization of actin filaments. J Biol Chem. 2013 Jul 5;288(27):19926-38

Rehm K, Panzer L, van Vliet V, Genot E, Linder S. Drebrin preserves endothelial integrity by stabilizing nectin at adherens junctions. J Cell Sci. 2013 Aug 15;126(Pt 16):3756-69

Worth DC, Daly CN, Geraldo S, Oozeer F, Gordon-Weeks PR. Drebrin contains a cryptic F-actin-bundling activity regulated by Cdk5 phosphorylation. J Cell Biol. 2013 Sep 2;202(5):793-806


Chilton J. DBN1 (drebrin 1). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):299-300.

Gene Section Review



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OPEN ACCESS JOURNAL

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) Nayden G Naydenov, Andrei I Ivanov

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA (NGN), Department of Human and Molecular Genetics, Virginia Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA (AII)


Online updated version : http://AtlasGeneticsOncology.org/Genes/NAPAID44025ch19q13.html DOI: 10.4267/2042/53638


Abstract Review on NAPA, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: SNAPA

HGNC (Hugo): NAPA

Location: 19q13.32

Local order: The human NAPA gene maps on 19q13 between the ZNF541 (zing finger protein 541) and the KPTN, (kaptin) (actin binding protein) loci.

Note: No translocations reported.

DNA/RNA Description The NAPA gene spans 27,61 kb on chromosome

19q13 and consists of 11 exons and 10 introns (fig. 1) with an open reading frame of 1839 bp. The NAPA promoter has not been functionally explored.

Transcription The predominant transcript variant (1) of the NAPA gene encodes a functional protein of 295 amino acids. The second transcript of 1521 bp is predicted to encode a 256 amino acid protein. This variant (2) uses an alternate splice site in the 3' terminal exon, compared to variant 1. This variant is represented as non-coding because the use of the alternate splice site renders the resulting transcript a candidate for nonsense-mediated mRNA decay (NMD). The third transcript, variant (3), is 1668 bp. Variant (3) lacks two consecutive internal exons, compared to variant 1.

Figure 1. Schematic representation of the genomic structure of human NAPA gene-transcript variant 1, (ENST00000263354). Exons are represented by red boxes while introns appear as waved black lines. The length of exons in (bp) is shown in the red boxes, and that of the introns is presented at the bottom blue boxes (not to scale). The relative position of ATG start and TAA stop codons are indicated with black arrows.

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) Naydenov NG, Ivanov AI


Figure 2. A model depicting vesicle fusion events according to the SNARE hypothesis. During the initial docking step, v-SNARE and t-SNARE bind creating a complex that drives pore formation and fusion of the two opposing membranes. After the fusion step, NAPA is recruited to the cys-SNARE complex allowing NSF binding. Next the ATPase activity of NSF and conformational changes of both NSF and NAPA disassemble the cys-SNARE complex, and release its components for recycling in subsequent fusion events.

This variant is also represented as non-coding because the use of the 5'-most expected translational start codon, as used in variant 1, also makes this transcript a candidate for NMD. Additionally, 2 alternative transcribed variants are predicted to exist via the automatic annotation program, Havana. However, these predicted transcripts need to be experimentally confirmed.

Pseudogene None discovered.

Protein Description The sequence of the predicted 295-amino acid; 33233 Da human protein encoded by NAPA shares 37%, 60%, and 81% identity with sequences in yeast (Sacharomyces cerevisiae), Drosophila melanogaster, and zebrafish (Danio rerio). NAPA belongs to a protein family comprised of, in higher eukaryotes, three homologues named NAPA, soluble NSF attachment protein beta (NAPB), and soluble NSF attachment protein gamma (NAPG) (Clary et al., 1990). Amino acid sequence comparison of bovine proteins show that NAPA and NAPB are most related to each other with 83% amino acid identity (Whiteheart et al., 1993). In

contrast, NAPA and NAPG have only about 25% sequence identity. Structural information is available for the yeast homolog of NAPA, Sec17 (Rice and Brunger, 1999), and zebrafish NAPG (Bitto et al., 2008). Both homologs represent elongated proteins comprised of an extended twisted sheet of α-helical hairpins and a helical-bundle domain at the carboxy-terminal end.

Expression NAPA is ubiquitously expressed in various mammalian cells and tissues. In mouse tissues, its expression level is highest in the brain, spleen, and testis (Whiteheart et al., 1993). Data from the human gene atlas has shown that NAPA is expressed at the highest level in heart, liver, lung, and placenta. Regulation of NAPA expression remains unexplored. One recent report demonstrated decreased protein levels of NAPA in brain synaptosomes of rats subjected to oxidative stress (Kaneai et al., 2013).

Localisation In polarized epithelial cells such as alveolar type II cells, T84, and SK-CO15 human colonic epithelial cells NAPA predominantly localizes in the plasma membrane with significant enrichment at the apical junctional complex (Abonyo et al., 2003; Naydenov et al., 2012a). By contrast, in contact-naïve

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha)

Naydenov NG, Ivanov AI


epithelial cells, NAPA accumulates in the perinuclear intracellular compartment that resembles the Golgi complex (Naydenov et al., 2012a).

Function One of the most-studied intracellular functions of NAPA involves regulation of NSF-dependent vesicle fusion (Andreeva et al., 2006). According to the so-called "SNARE (soluble NSF attachment protein receptor) hypothesis" vesicle fusion is driven by specific associations of complementary SNARE proteins residing on the vesicle (v-SNAREs) and target (t-SNAREs) membranes (Chen and Scheller, 2001). These proteins form a core SNARE complex consisting of a parallel four-helix bundle. This complex drives the opposing membranes to a close apposition, and subsequently to a complete fusion (fig. 2). Eukaryotic cells use an evolutionarily-conserved mechanism to disassemble and recycle the cys-SNARE complex that is formed after the fusion of two membranes (Barnard et al., 1997). This mechanism involves a hexameric ATPase, NSF, and its adaptor protein, NAPA (Vivona et al., 2013; Wilson et al., 1992; Winter et al., 2009). NAPA interacts with the SNARE complex, recruits NSF, stimulates NSF activity, and transduces a conformational change of NSF to drive SNARE disassembly (fig. 2). NAPA was implicated in the regulation of numerous trafficking/fusion events in different cellular compartments (Andreeva et al., 2006). Examples of this regulation include ER-Golgi transport, intra-Golgi vesicle fusion, trafficking from the trans-Golgi network to the plasma membrane, neuromediator exocytosis, and synaptic vesicle fusion (Barnard et al., 1997; Burgalossi et al., 2010; Clary et al., 1990; Low et al., 1998; Peter et al., 1998; Xu et al., 2002). Interestingly, recent studies discovered several NSF-independent activities of NAPA. These activities involve assembly of epithelial junctions (Andreeva et al., 2005; Naydenov et al., 2012a), suppression of cell apoptosis (Naydenov et al., 2012b; Wu and Chao, 2010), and autophagy (Naydenov et al., 2012c), as well as regulation of store-operated calcium entry (Miao et al., 2013). Such NSF-independent functions are likely to depend on NAPA interactions with different binding partners. For example, NAPA may suppress apoptosis due to its binding to the ER-resident, pro-apoptotic protein BNIP1 (Nakajima et al., 2004). Furthermore, NAPA-dependent regulation of autophagy can be mediated by its ability to interact and dephosphorylate AMP-activated protein kinase (Wang and Brautigan, 2013).

Mutations Note A missense G to A transition that leads to a change from methionine to isoleucine (M105I) has been detected in mice (Chae et al., 2004; Hong et al., 2004). This mutation leads to the appearance of the so-called hyh (hydrocephalus with hop gait) phenotype and also impairs acrosomal exocytosis in sperm (Bátiz et al., 2009). Other mutations have not been found associated with this gene potentially because of the multiple roles of NAPA in critical cellular functions which would prevent survival of cells with dysfunctional NAPA mutations.

Implicated in Colorectal cancer Note A study utilizing patients with small undifferentiated colorectal cancer revealed a significant increase of NAPA immunoreactivity in cancer cells that correlated with a more aggressive course of the disease (Grabowski et al., 2002).

Down syndrome Note One study has analyzed expression of NAPA protein in fetal cortex samples of patients with Down Syndrome. The study reported a significant decrease in NAPA expression compared to control samples that correlated with deterioration of the neuronal dendritic tree (Weitzdoerfer et al., 2001). Another study demonstrated a loss of NAPA homolog, NAPB, in brain specimens of adult patients with Down syndrome (Yoo et al., 2001).

Huntington's disease Note Marked elevation of NAPA expression was observed by Western blotting of hippocampus samples from patients with Huntington's diseases as compared to age-matched controls (Morton et al., 2001).

Atopic dermatitis Note A proteomic analysis of peripheral blood leukocytes demonstrated significant downregulation of NAPA expression in patients with atopic dermatitis as compared to control subjects (Kim et al., 2008). This decrease was validated by Western blotting analysis and NAPA level was suggested as a possible biomarker for the disease.

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha) Naydenov NG, Ivanov AI


To be noted Acknowledgments: the authors thank Alex Feygin for critical reading of the manuscript. This work was supported in part by National Institute of Health grants RO1 DK083968 and R01 DK084953 to A.I.I.

References Clary DO, Griff IC, Rothman JE. SNAPs, a family of NSF attachment proteins involved in intracellular membrane fusion in animals and yeast. Cell. 1990 May 18;61(4):709-21

Wilson DW, Whiteheart SW, Wiedmann M, Brunner M, Rothman JE. A multisubunit particle implicated in membrane fusion. J Cell Biol. 1992 May;117(3):531-8

Whiteheart SW, Griff IC, Brunner M, Clary DO, Mayer T, Buhrow SA, Rothman JE. SNAP family of NSF attachment proteins includes a brain-specific isoform. Nature. 1993 Mar 25;362(6418):353-5

Barnard RJ, Morgan A, Burgoyne RD. Stimulation of NSF ATPase activity by alpha-SNAP is required for SNARE complex disassembly and exocytosis. J Cell Biol. 1997 Nov 17;139(4):875-83

Low SH, Chapin SJ, Wimmer C, Whiteheart SW, Kömüves LG, Mostov KE, Weimbs T. The SNARE machinery is involved in apical plasma membrane trafficking in MDCK cells. J Cell Biol. 1998 Jun 29;141(7):1503-13

Peter F, Wong SH, Subramaniam VN, Tang BL, Hong W. Alpha-SNAP but not gamma-SNAP is required for ER-Golgi transport after vesicle budding and the Rab1-requiring step but before the EGTA-sensitive step. J Cell Sci. 1998 Sep;111 ( Pt 17):2625-33

Rice LM, Brunger AT. Crystal structure of the vesicular transport protein Sec17: implications for SNAP function in SNARE complex disassembly. Mol Cell. 1999 Jul;4(1):85-95

Chen YA, Scheller RH. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol. 2001 Feb;2(2):98-106

Morton AJ, Faull RL, Edwardson JM. Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease. Brain Res Bull. 2001 Sep 15;56(2):111-7

Weitzdoerfer R, Dierssen M, Fountoulakis M, Lubec G. Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure. J Neural Transm Suppl. 2001;(61):59-70

Yoo BC, Cairns N, Fountoulakis M, Lubec G. Synaptosomal proteins, beta-soluble N-ethylmaleimide-sensitive factor attachment protein (beta-SNAP), gamma-SNAP and synaptotagmin I in brain of patients with Down syndrome and Alzheimer's disease. Dement Geriatr Cogn Disord. 2001 May-Jun;12(3):219-25

Grabowski P, Schönfelder J, Ahnert-Hilger G, Foss HD, Heine B, Schindler I, Stein H, Berger G, Zeitz M, Scherübl H. Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum. Virchows Arch. 2002 Sep;441(3):256-63

Xu J, Xu Y, Ellis-Davies GC, Augustine GJ, Tse FW. Differential regulation of exocytosis by alpha- and beta-SNAPs. J Neurosci. 2002 Jan 1;22(1):53-61

Abonyo BO, Wang P, Narasaraju TA, Rowan WH 3rd, McMillan DH, Zimmerman UJ, Liu L. Characterization of

alpha-soluble N-ethylmaleimide-sensitive fusion attachment protein in alveolar type II cells: implications in lung surfactant secretion. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):273-82

Chae TH, Kim S, Marz KE, Hanson PI, Walsh CA. The hyh mutation uncovers roles for alpha Snap in apical protein localization and control of neural cell fate. Nat Genet. 2004 Mar;36(3):264-70

Hong HK, Chakravarti A, Takahashi JS. The gene for soluble N-ethylmaleimide sensitive factor attachment protein alpha is mutated in hydrocephaly with hop gait (hyh) mice. Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1748-53

Nakajima K, Hirose H, Taniguchi M, Kurashina H, Arasaki K, Nagahama M, Tani K, Yamamoto A, Tagaya M. Involvement of BNIP1 in apoptosis and endoplasmic reticulum membrane fusion. EMBO J. 2004 Aug 18;23(16):3216-26

Andreeva AV, Kutuzov MA, Vaiskunaite R, Profirovic J, Meigs TE, Predescu S, Malik AB, Voyno-Yasenetskaya T. G alpha12 interaction with alphaSNAP induces VE-cadherin localization at endothelial junctions and regulates barrier function. J Biol Chem. 2005 Aug 26;280(34):30376-83

Andreeva AV, Kutuzov MA, Voyno-Yasenetskaya TA. A ubiquitous membrane fusion protein alpha SNAP: a potential therapeutic target for cancer, diabetes and neurological disorders? Expert Opin Ther Targets. 2006 Oct;10(5):723-33

Bitto E, Bingman CA, Kondrashov DA, McCoy JG, Bannen RM, Wesenberg GE, Phillips GN Jr. Structure and dynamics of gamma-SNAP: insight into flexibility of proteins from the SNAP family. Proteins. 2008 Jan 1;70(1):93-104

Kim WK, Cho HJ, Ryu SI, Hwang HR, Kim DH, Ryu HY, Chung JW, Kim TY, Park BC, Bae KH, Ko Y, Lee SC. Comparative proteomic analysis of peripheral blood mononuclear cells from atopic dermatitis patients and healthy donors. BMB Rep. 2008 Aug 31;41(8):597-603

Bátiz LF, De Blas GA, Michaut MA, Ramírez AR, Rodríguez F, Ratto MH, Oliver C, Tomes CN, Rodríguez EM, Mayorga LS. Sperm from hyh mice carrying a point mutation in alphaSNAP have a defect in acrosome reaction. PLoS One. 2009;4(3):e4963

Winter U, Chen X, Fasshauer D. A conserved membrane attachment site in alpha-SNAP facilitates N-ethylmaleimide-sensitive factor (NSF)-driven SNARE complex disassembly. J Biol Chem. 2009 Nov 13;284(46):31817-26

Burgalossi A, Jung S, Meyer G, Jockusch WJ, Jahn O, Taschenberger H, O'Connor VM, Nishiki T, Takahashi M, Brose N, Rhee JS. SNARE protein recycling by αSNAP and βSNAP supports synaptic vesicle priming. Neuron. 2010 Nov 4;68(3):473-87

Wu ZZ, Chao CC. Knockdown of NAPA using short-hairpin RNA sensitizes cancer cells to cisplatin: implications to overcome chemoresistance. Biochem Pharmacol. 2010 Sep 15;80(6):827-37

Naydenov NG, Brown B, Harris G, Dohn MR, Morales VM, Baranwal S, Reynolds AB, Ivanov AI. A membrane fusion protein αSNAP is a novel regulator of epithelial apical junctions. PLoS One. 2012a;7(4):e34320

Naydenov NG, Harris G, Brown B, Schaefer KL, Das SK, Fisher PB, Ivanov AI. Loss of soluble N-ethylmaleimide-sensitive factor attachment protein α (αSNAP) induces

NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha)

Naydenov NG, Ivanov AI


epithelial cell apoptosis via down-regulation of Bcl-2 expression and disruption of the Golgi. J Biol Chem. 2012b Feb 17;287(8):5928-41

Naydenov NG, Harris G, Morales V, Ivanov AI. Loss of a membrane trafficking protein αSNAP induces non-canonical autophagy in human epithelia. Cell Cycle. 2012c Dec 15;11(24):4613-25

Kaneai N, Fukui K, Koike T, Urano S. Vitamin E prevents hyperoxia-induced loss of soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor proteins in the rat neuronal cytoplasm. Biol Pharm Bull. 2013;36(9):1500-2

Miao Y, Miner C, Zhang L, Hanson PI, Dani A, Vig M. An essential and NSF independent role for α-SNAP in store-operated calcium entry. Elife. 2013;2:e00802

Vivona S, Cipriano DJ, O'Leary S, Li YH, Fenn TD, Brunger AT. Disassembly of all SNARE complexes by N-ethylmaleimide-sensitive factor (NSF) is initiated by a conserved 1:1 interaction between α-soluble NSF attachment protein (SNAP) and SNARE complex. J Biol Chem. 2013 Aug 23;288(34):24984-91

Wang L, Brautigan DL. α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro. Nat Commun. 2013;4:1559


Naydenov NG, Ivanov AI. NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):301-305.

Gene Section Review



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OPEN ACCESS JOURNAL

AUTS2 (autism susceptibility candidate 2) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: October 2013

Online updated version : http://AtlasGeneticsOncology.org/Genes/AUTS2ID51794ch7q11.html DOI: 10.4267/2042/53639


Abstract Review on AUTS2, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: FBRSL2

HGNC (Hugo): AUTS2

Location: 7q11.22

Local order: AUTS2 is close to (about 2.1 Mb) –

and proximal to- POM121 (another gene involved in PAX5 translocations in leukemia), and to the Williams-Beuren syndrome critical region.

DNA/RNA Description The gene spans 1.19 Mb. 19 coding exons.

Transcription There are 16 transcripts (splice variants). Six transcripts contains an open reading frame.

AUTS2 protein and domains.

AUTS2 (autism susceptibility candidate 2) Huret JL


Protein Description 1259 amino acids (aa); from N-term to C-term, AUTS2 contains: nuclear localization sequences (aa: 11-27; 70-79; 120-141); Pro-rich regions (aa: 288-471; 544-646); a Dwarfin consensus sequence (aa: 325-453); a Ser-rich region (aa: 383-410); a PY motif (aa: 515-519); a hexanucleotide repeat (aa: 524-540; (cagcac/cagcac/cagcac/cagcac/acc/cac/cagcac/cagcac/cagcac) at nucleotide 1901-1949 (exon 9)); His-rich regions (aa: 525-548, 1122-1181); a Fibrosin homology region (aa: 645-798); a topoisomerase homology region (aa: 880-920); a trinucleotide repeat (aa: 1126-1133 (cac)8, at nucleotide 3701-3732 (exon 19)), and also N-glycosylation sites (aa 395-398, 785-788, 955-958, 1009-1012), cAMP and cGMP- dependent protein kinase phosphorylation sites (aa: 13-16, 77-80, 116-119, 832-835, 849-852, 975-978, 1235-1238), SH3 interaction domains (P67, P72, P73, P266, P332, P361, P364, P467, P468, P471, P638, P806, P1234), and a SH2 interaction domain (Y971) (Sultana et al., 2002; Bedogni et al., 2010b; Oksenberg and Ahituv, 2013).

Expression AUTS2 is primarily expressed in the central nervous system, and also in skeletal muscle and kidney, and with lower expression in other tissues (placenta, lung, and leukocytes) (Sultana et al., 2002). AUTS2 is highly expressed in the embryo, and in more restricted areas in the adult (Oksenberg and Ahituv, 2013). Auts2 in the mouse embryo is expressed in the cortical preplate, in frontal cortex, hippocampus and cerebellum, including Purkinje cells and deep nuclei, in developing dorsal thalamus, olfactory bulb, inferior colliculus and substantia nigra (Bedogni et al., 2010a).

Localisation AUTS2 is a nuclear protein.

Function TBR1, a postmitotic projection-neuron specific transcription factor, binds the AUTS2 promoter and activates AUTS2 in developing neocortex in vivo (Bedogni et al., 2010b; Srinivasan et al., 2012). Suppression of auts2 in zebrafish embryos caused microcephaly, and a reduction in developing midbrain neurons and also in sensory and motor neurons (Beunders et al., 2013; Oksenberg et al., 2013). ZMAT3 (a target gene of TP53) downregulation produced significant reductions in AUTS2 mRNA levels (Sedaghat et al., 2012).

Enhancers that were mutated in patients with dyslexia or with autism spectrum disorder were described; AUTS2 has been found as a rapidly evolving gene in homo sapiens sapiens, compared to Neanderthals, and non-human primates. It is suggested that AUTS2 has an important role in the evolution of human cognitive traits (Oksenberg et al., 2013).

Implicated in t(7;9)(q11;p13) PAX5/AUTS2 Note PAX5 is involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Medvedovic et al., 2011).

Disease Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Prognosis Three cases to date, two boys and one girl, aged 0.6, 2.8, and 3.1 years (Kawamata 2008; Coyaud et al., 2010; Denk et al., 2012). Two patients presented with a high WBC, and also had a central nervous system involvement at a time during course of the disease. Patients were assigned to different risk arms of the respective clinical trials, as noted by Denk et al., 2012. The three patients achieved complete remission (CR), but two (those with high risk features) relapsed and died at 1.7 and 3.4 years after diagnosis, indicating a rather poor outcome (Denk et al., 2012). Only one patient is still in CR and well 2.2 years after diagnosis.

Cytogenetics The t(7;9)(q11;p13) was the sole abnormality in one case. Unbalanced translocation in two cases, due to the loss of the der(7)t(7;9).

Hybrid/Mutated gene 5' PAX5-3' AUTS2. Fusion of PAX5 exon 6 to AUTS2 exon 4 or 6.

Abnormal protein 1289 or 1311 amino acids depending on whether exon 6 or 4 of AUTS2 is fused to PAX5. The predicted fusion protein contains the paired domain, the octapeptide, and the homeodomain of PAX5 and the proline rich, the Dwarfin consensus sequence, the serine rich, the PY motif, the hexanucleotide repeat, the histidine rich, the fibrosin homology region, the topoisomerase homology region, and the trinucleotide repeat of AUTS2.



Fusion protein PAX5/AUTS2.

Other cancers Disease Loss of heterozygocity was found in an adenocarcinoma of the lung, but more data is needed (Weir et al., 2007). Copy number variation was found in a single case of mixed germ cell tumor containing yolk sac tumor and teratoma (Stadler et al., 2012).

Syndromic phenotype, mental retardation, neurodevelopmental and psychiatric disorders, including autism spectrum disorder A review in Oksenberg and Ahituv, 2013 shows a map of the gene with the structural variants and abnormalities in relation to the various phenotypes described.

Disease Syndromic phenotype: A study on 24 patients with deletions of part of AUTS2 allowed the identification of a variable syndromic phenotype including intellectual disability, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The authors delineated an "AUTS2 syndrome severity score" of the phenotypic diversity, that correlated with genotypic data: individuals with deletions in the 5' part of the gene showed a milder phenotype than those with a deletion in the 3' part of the gene (Beunders et al., 2013).

Mental retardation: A patient with developmental delay had an intragenic deletion within AUTS2 (Jolley et al., 2013). Three unrelated mentally disabled patients were found to carry a balanced translocation that truncates AUTS2. Patients were borderline or severely mentally retarded and carried different deletions in AUTS2 (Kalscheuer et al., 2007). AUTS2 has been found disrupted in balanced chromosomal abnormality in patients with abnormal neurodevelopment (Huang et al., 2010; Talkowski et al., 2012). Autism spectrum disorder (ASD): Small copy-number variations (CNVs) that disrupt AUTS2 (duplications or deletions of exons) were found in two patients with developmental delay, and two with autism spectrum disorder (Nagamani et al., 2013). AUTS2 has been found disrupted in a monozygotic twin pair concordant for autism (Sultana et al., 2002). Duplication in the AUTS2 gene was identified in a family with ASD (Ben-David et al., 2011). Pathological behaviour: A variant in AUTS2 was associated with excessive alcohol consumption (Edenberg and Foroud, 2013; Kapoor et al., 2013). AUTS2 variants (rs6943 allele A) are correlated with heroin dependence, and reduced AUTS2 gene expression might confer increased susceptibility (Chen et al., 2013). rs6943555 A allele was also found associated with alcohol consumption (Schumann et al., 2011), and with suicide committed after drinking (Chojnicka et al., 2013).



Amino acids sequence variant in AUTS2 were found in a large family with high risk for suicide, but also with a significant co-morbidity for affective disorders, alcohol disorders, psychotic disorders, and drug abuse disorders (Coon et al., 2013). Epilepsy: AUTS2 deletions were identified in one patient with juvenile myoclonic epilepsy and in another patient with an unclassified 'non-lesional epilepsy with features of atypical benign partial epilepsy' (Mefford et al., 2010).

References Sultana R, Yu CE, Yu J, Munson J, Chen D, Hua W, Estes A, Cortes F, de la Barra F, Yu D, Haider ST, Trask BJ, Green ED, Raskind WH, Disteche CM, Wijsman E, Dawson G, Storm DR, Schellenberg GD, Villacres EC. Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics. 2002 Aug;80(2):129-34

Kalscheuer VM, FitzPatrick D, Tommerup N, Bugge M, Niebuhr E, Neumann LM, Tzschach A, Shoichet SA, Menzel C, Erdogan F, Arkesteijn G, Ropers HH, Ullmann R. Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum Genet. 2007 May;121(3-4):501-9

Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007 Dec 6;450(7171):893-8

Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Stocking C, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Bartram CR, Koeffler HP. Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11921-6

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Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Beyer RP, Bammler TK, Rubenstein JL, Hevner RF. Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proc Natl Acad Sci U S A. 2010b Jul 20;107(29):13129-34

Coyaud E, Struski S, Dastugue N, Brousset P, Broccardo C, Bradtke J. PAX5-AUTS2 fusion resulting from t(7;9)(q11.2;p13.2) can now be classified as recurrent in B cell acute lymphoblastic leukemia. Leuk Res. 2010 Dec;34(12):e323-5

Huang XL, Zou YS, Maher TA, Newton S, Milunsky JM. A de novo balanced translocation breakpoint truncating the autism susceptibility candidate 2 (AUTS2) gene in a patient with autism. Am J Med Genet A. 2010 Aug;152A(8):2112-4

Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse K, Baker C, Franke A, Malafosse A, Genton P, Thomas P, Gurnett CA, Schreiber S, Bassuk AG, Guipponi M, Stephani U, Helbig I, Eichler EE. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010 May 20;6(5):e1000962

Ben-David E, Granot-Hershkovitz E, Monderer-Rothkoff G, Lerer E, Levi S, Yaari M, Ebstein RP, Yirmiya N, Shifman S. Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum Mol Genet. 2011 Sep 15;20(18):3632-41

Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a master regulator of B cell development and leukemogenesis. Adv Immunol. 2011;111:179-206

Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivières S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proença C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernández-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Núñez A, Nyholt DR, Onland-Moret CN, Oostra BA, O'Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tönjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A, Doering A, Scott J, Spector TD, Loos RJ, Boomsma DI, Mooser V, Peltonen L, Stefansson K, van Duijn CM, Vineis P, Sommer WH, Kooner JS, Spanagel R, Heberlein UA, Jarvelin MR, Elliott P. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7119-24

Denk D, Nebral K, Bradtke J, Pass G, Möricke A, Attarbaschi A, Strehl S. PAX5-AUTS2: a recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia. Leuk Res. 2012 Aug;36(8):e178-81

Srinivasan K, Leone DP, Bateson RK, Dobreva G, Kohwi Y, Kohwi-Shigematsu T, Grosschedl R, McConnell SK. A network of genetic repression and derepression specifies projection fates in the developing neocortex. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19071-8

Sedaghat Y, Mazur C, Sabripour M, Hung G, Monia BP. Genomic analysis of wig-1 pathways. PLoS One. 2012;7(2):e29429

Stadler ZK, Esposito D, Shah S, Vijai J, Yamrom B, Levy D, Lee YH, Kendall J, Leotta A, Ronemus M, Hansen N, Sarrel K, Rau-Murthy R, Schrader K, Kauff N, Klein RJ, Lipkin SM, Murali R, Robson M, Sheinfeld J, Feldman D, Bosl G, Norton L, Wigler M, Offit K. Rare de novo germline



copy-number variation in testicular cancer. Am J Hum Genet. 2012 Aug 10;91(2):379-83

Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y, Neale B, Shaffer LG, Daly MJ, Morton CC, Gusella JF. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell. 2012 Apr 27;149(3):525-37

Beunders G, Voorhoeve E, Golzio C, Pardo LM, Rosenfeld JA, Talkowski ME, Simonic I, Lionel AC, Vergult S, Pyatt RE, van de Kamp J, Nieuwint A, Weiss MM, Rizzu P, Verwer LE, van Spaendonk RM, Shen Y, Wu BL, Yu T, Yu Y, Chiang C, Gusella JF, Lindgren AM, Morton CC, van Binsbergen E, Bulk S, van Rossem E, Vanakker O, Armstrong R, Park SM, Greenhalgh L, Maye U, Neill NJ, Abbott KM, Sell S, Ladda R, Farber DM, Bader PI, Cushing T, Drautz JM, Konczal L, Nash P, de Los Reyes E, Carter MT, Hopkins E, Marshall CR, Osborne LR, Gripp KW, Thrush DL, Hashimoto S, Gastier-Foster JM, Astbury C, Ylstra B, Meijers-Heijboer H, Posthuma D, Menten B, Mortier G, Scherer SW, Eichler EE, Girirajan S, Katsanis N, Groffen AJ, Sistermans EA. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet. 2013 Feb 7;92(2):210-20

Chen YH, Liao DL, Lai CH, Chen CH. Genetic analysis of AUTS2 as a susceptibility gene of heroin dependence. Drug Alcohol Depend. 2013 Mar 1;128(3):238-42

Chojnicka I, Gajos K, Strawa K, Broda G, Fudalej S, Fudalej M, Stawiński P, Pawlak A, Krajewski P, Wojnar M, Płoski R. Possible association between suicide committed under influence of ethanol and a variant in the AUTS2 gene. PLoS One. 2013;8(2):e57199

Coon H, Darlington T, Pimentel R, Smith KR, Huff CD, Hu

H, Jerominski L, Hansen J, Klein M, Callor WB, Byrd J, Bakian A, Crowell SE, McMahon WM, Rajamanickam V, Camp NJ, McGlade E, Yurgelun-Todd D, Grey T, Gray D. Genetic risk factors in two Utah pedigrees at high risk for suicide. Transl Psychiatry. 2013 Nov 19;3:e325

Edenberg HJ, Foroud T. Genetics and alcoholism. Nat Rev Gastroenterol Hepatol. 2013 Aug;10(8):487-94

Jolley A, Corbett M, McGregor L, Waters W, Brown S, Nicholl J, Yu S. De novo intragenic deletion of the autism susceptibility candidate 2 (AUTS2) gene in a patient with developmental delay: a case report and literature review. Am J Med Genet A. 2013 Jun;161A(6):1508-12

Kapoor M, Wang JC, Wetherill L, Le N, Bertelsen S, Hinrichs AL, Budde J, Agrawal A, Bucholz K, Dick D, Harari O, Hesselbrock V, Kramer J, Nurnberger JI Jr, Rice J, Saccone N, Schuckit M, Tischfield J, Porjesz B, Edenberg HJ, Bierut L, Foroud T, Goate A. A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks. Hum Genet. 2013 Oct;132(10):1141-51

Nagamani SC, Erez A, Ben-Zeev B, Frydman M, Winter S, Zeller R, El-Khechen D, Escobar L, Stankiewicz P, Patel A, Cheung SW. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet. 2013 Mar;21(3):343-6

Oksenberg N, Ahituv N. The role of AUTS2 in neurodevelopment and human evolution. Trends Genet. 2013 Oct;29(10):600-8

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Huret JL. AUTS2 (autism susceptibility candidate 2). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5): 306-310.




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AVEN (apoptosis, caspase activation inhibitor) Inga Maria Melzer, Martin Zörnig

Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany (IMM, MZ)


Online updated version : http://AtlasGeneticsOncology.org/Genes/AVENID43158ch15q14.html DOI: 10.4267/2042/53640


Abstract Review on AVEN, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: PDCD12

HGNC (Hugo): AVEN

Location: 15q14

DNA/RNA Description The human AVEN gene is located on the reverse strand of chromosome 15 (bases 34158428 to 34331303; according to NCBI RefSeq gene database (gene ID: 57099; Refseq ID: NM_020371.2), genome assembly GRCh37 from February 2009) of the human genome and is comprised of 172876 bp. AVEN consists of 6

exons, ranging in length between 70 and appr. 500 bp and 5 introns varying largely in size (from few 100 bp to some Mb). According to the Ensembl genome browser database (ENSG00000169857), there are three transcript variants of AVEN of which only one leads to the translation of a functional protein whereas the other two are degraded by nonsense-mediated decay or do not encode for a functional protein product.

Transcription According to the NCBI database, the human AVEN gene encodes for a 1551 bp mRNA transcript, the coding sequence ranging from bp 57 to 1145. The CDS in the Ensembl genome browser database (ENSG00000169857) is identical to the NCBI CDS (NM_020371.2). The transcript NM_020371.2 is also included in the human CCDS set and encodes for a protein of 362 aa.

Pseudogene None known.

AVEN protein: 1-362 aa. Cathepsin D cleavage sites: L144 and L196; putative BH3 domain: aa141-153; NES: aa282-293. ATM kinase phosphorylation sites: S 135 and S 308.

AVEN (apoptosis, caspase activation inhibitor) Melzer IM, Zörnig M


Protein Description The AVEN protein possesses no predicted domains according to the NCBI database. However, a sequential proteolytic processing of AVEN by the lysosomal protease cathepsin D has been published (Melzer et al., 2012), leading to the cleavage of AVEN at aa 144 and 196 and the generation of a shorter isoform (deltaN Aven) that is supposed to be associated with the antiapoptotic function. Moreover, AVEN is able to bind to the DNA damage response regulating kinase ATM (ataxia telangiectasia mutated) and is phosphorylated by ATM at S135 and S308 (Guo et al., 2008). In addition, a potential nuclear export sequence (NES) to exists between aa 282-293 (Esmaili et al., 2010) and a putative BH3 motif (for binding to Bcl-xL) has been predicted to be located between aa 141-153 (Hawley et al., 2012).

Expression Widely expressed throughout the human organism (Chau et al., 2000).

Localisation Mostly cytosolic, punctuate, reticular pattern (associated with intracellular membrane localization, lysosomal?) in the cytosol (Chau et al., 2000), diffuse nuclear staining (Esmaili et al., 2010).

Function Antiapoptotic: AVEN was first discovered as an interactor of the antiapoptotic BCl-xL protein by Chau et al. (2000). It was also shown to bind to the proapoptotic APAF-1 protein and postulated to prevent the oligomerization of APAF-1 (apoptosome formation) in the intrinsic apoptosis pathway and to stabilize the Bcl-xL protein by binding to it (Kutuk et al., 2010). Putative binding sites in Bcl-xL are predicted to be located in the Bcl-xL BH1 and BH4 domains (Hawley et al., 2012). Recently, it was shown that AVEN can be processed by the lysosomal protease Cathepsin D at aa 144 and 196, and that this processing is neccessary to activate AVEN's antiapoptotic function (Melzer et al., 2012). It is still unclear whether it is the stabilization of Bcl-xL, the interference with apoptosome assembly or another feature of AVEN that is responsible for the antiapoptotic capacity of this protein. DNA damage repair: It was shown by Guo et al. (2008) that AVEN, in addition to binding to the apoptotic machinery, is also able to bind one of the key players in DNA damage repair, the ataxia telangiectasia mutated (ATM) kinase. Overexpression of AVEN in

Xenopus laevis egg extracts induced a cell cycle arrest at G2/M which is in large part ATM dependent, whereas the absence of AVEN impaired ATM-mediated checkpoint function. An intrinsic loop of activation exists between AVEN and ATM: AVEN binds to the kinase domain of ATM (appr. aa 2500-3000) and, in turn, is phosphorylated by ATM at S135 and S308. This phosphorylation seems to enhance AVEN's activating influence on ATM. Esmaili et al. (2010) were able to demonstrate that AVEN possesses a nuclear export signal (NES) which is located between aa 282 and 293. Under normal physiological conditions, AVEN is shuttled outside of the nucleus by Exportin-1/CRM1 whereas inhibition of CRM1 by leptomycin or mutation of the AVEN NES leads to nuclear accumulation of the protein. The NES/nuclear-cytosolic shuttling of AVEN might be important for its cell cycle regulatory functions and its role in DNA damage repair. Depending on the degree of DNA damage, AVEN is possibly a multifunctional protein, finetuning the cellular decisions of cell cycle arrest and apoptosis in the DNA damage response.

Homology No close orthologs of AVEN in humans are known. However, Hawley et al. (2010) note homology to Bik (58% homology over a 77 aa region encompassing the putative BH3 homology domain). Homologs of AVEN can be found in several species, like mouse (NCBI acc. Nr. NP_083120), Drosophila (NP_572817), rat (NP_001101227), chicken (NP_001005791; Vezyri et al., 2011) and Xenopus (NP_001090621; Guo et al., 2008). Of note, two isoforms are postulated to exist in mouse, the second one (NP_001159407) possessing a distinctly shorter N-terminus than the full length protein. However, nothing is known about the function or biological relevance of this predicted second isoform. Functional similarity to the human protein in its cell cycle regulatory properties has been published for the Drosophila (Zou et al., 2011) and the Xenopus homologs (Guo et al., 2008).

Implicated in Acute leukemias Note AVEN is a putative oncogene which is overexpressed in T- cell acute lymphoblastic leukemia. First reports that AVEN is overexpressed on mRNA level in acute leukemias were published by Paydas et al. in 2003. The authors investigated a study group consisting of 37 acute myeloblastic leukemias (AML) and 28 acute lymphoblastic leukemia (ALL) patients.

AVEN (apoptosis, caspase activation inhibitor) Melzer IM, Zörnig M


Details regarding the number of ALL patients who were either of the frequent B-cell type or had developed T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) were not given. In this study, elevated Aven mRNA expression levels were noted in acute leukemias, and the authors suggest that AVEN could be a new prognostic marker in this cancer entity. Choi et al. (2006) describe a positive correlation between Aven mRNA overexpression and poor prognosis in childhood ALL. A recent study by Eissmann et al. (2013) shows proof that overexpression of AVEN contributes to increased malignancy in hematopoietic neoplasms. Here, the authors confirm overexpression of AVEN in T-ALL patient samples compared to healthy T cells on protein level. Furthermore, using a transgenic mouse model with T-cell specific overexpression of AVEN, an oncogenic cooperation of AVEN with heterozygous loss of p53 is shown. Additionally, in subcutaneous mouse xenograft models, the authors show that downregulation of AVEN expression via shRNA leads to significantly decreased, if not halted, tumor growth indicating AVEN as a putative novel therapy target for T-ALL and AML.

Breast cancer Note Two other studies implicate AVEN in breast cancer (Kutuk et al., 2010; Ouzounova et al., 2013). Kutuk et al. describe decreased nuclear expression of AVEN in breast cancer tissue microarrays, in particular in infiltrative ductal carcinoma and papillary carcinoma compared to non-neoplastic breast tissue and infiltrating lobular breast cancer. They suggest that AVEN might be an important mediator in DNA damage-induced apoptotic signalling and its nuclear downregulation in breast cancer can lead to genomic instability. A recent study by Ouzounova et al. shows that AVEN is an inversely regulated downstream target of the miR-30 family which is important for regulation of breast cancer cells under non-attachment conditions. Overexpression of miR-30 family members reduces breast tumor progression and tumorsphere formation (and AVEN expression), an effect which could be partially rescued by AVEN re-/overexpression, suggesting, in contrast to the other study, that rather overexpression (than downregulation or nuclear depletion) of AVEN is important for breast tumor growth.

References Chau BN, Cheng EH, Kerr DA, Hardwick JM. Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Mol Cell. 2000 Jul;6(1):31-40

Paydas S, Tanriverdi K, Yavuz S, Disel U, Sahin B, Burgut R. Survivin and aven: two distinct antiapoptotic signals in acute leukemias. Ann Oncol. 2003 Jul;14(7):1045-50

Choi J, Hwang YK, Sung KW, Kim DH, Yoo KH, Jung HL, Koo HH. Aven overexpression: association with poor prognosis in childhood acute lymphoblastic leukemia. Leuk Res. 2006 Aug;30(8):1019-25

Guo JY, Yamada A, Kajino T, Wu JQ, Tang W, Freel CD, Feng J, Chau BN, Wang MZ, Margolis SS, Yoo HY, Wang XF, Dunphy WG, Irusta PM, Hardwick JM, Kornbluth S. Aven-dependent activation of ATM following DNA damage. Curr Biol. 2008 Jul 8;18(13):933-42

Esmaili AM, Johnson EL, Thaivalappil SS, Kuhn HM, Kornbluth S, Irusta PM. Regulation of the ATM-activator protein Aven by CRM1-dependent nuclear export. Cell Cycle. 2010 Oct 1;9(19):3913-20

Kutuk O, Temel SG, Tolunay S, Basaga H. Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL. Eur J Cancer. 2010 Sep;46(13):2494-505

Vezyri E, Mikrou A, Athanassiadou A, Zarkadis IK. Molecular cloning and expression of Aven gene in chicken. Protein J. 2011 Jan;30(1):72-6

Zou S, Chang J, LaFever L, Tang W, Johnson EL, Hu J, Wilk R, Krause HM, Drummond-Barbosa D, Irusta PM. Identification of dAven, a Drosophila melanogaster ortholog of the cell cycle regulator Aven. Cell Cycle. 2011 Mar 15;10(6):989-98

Hawley RG, Chen Y, Riz I, Zeng C. An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates. Open Biol J. 2012 May 4;5:6-16

Melzer IM, Fernández SB, Bösser S, Lohrig K, Lewandrowski U, Wolters D, Kehrloesser S, Brezniceanu ML, Theos AC, Irusta PM, Impens F, Gevaert K, Zörnig M. The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential. Cell Death Differ. 2012 Sep;19(9):1435-45

Eißmann M, Melzer IM, Fernández SB, Michel G, Hrabě de Angelis M, Hoefler G, Finkenwirth P, Jauch A, Schoell B, Grez M, Schmidt M, Bartholomae CC, Newrzela S, Haetscher N, Rieger MA, Zachskorn C, Mittelbronn M, Zörnig M. Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms. Oncogene. 2013 May 16;32(20):2586-91

Ouzounova M, Vuong T, Ancey PB, Ferrand M, Durand G, Le-Calvez Kelm F, Croce C, Matar C, Herceg Z, Hernandez-Vargas H. MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells. BMC Genomics. 2013 Feb 28;14:139


Melzer IM, Zörnig M. AVEN (apoptosis, caspase activation inhibitor). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):311-313.

Gene Section Review



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FKBP5 (FK506 binding protein 5) Katarzyna Anna Ellsworth, Liewei Wang

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA (KAE, LW)


Online updated version : http://AtlasGeneticsOncology.org/Genes/FKBP5ID40578ch6p21.html DOI: 10.4267/2042/53641


Abstract Review on FKBP5, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: AIG6, FKBP51, FKBP54, P54, PPIase, Ptg-10

HGNC (Hugo): FKBP5

Location: 6p21.31

DNA/RNA Description FKBP5 gene is located on short arm of chromosome 6 (6p21.31). FKBP5 gene ranges from 35541362 to 35696360 on reverse strand with a total length of 154999 bp including 10 coding exons.

Transcription This gene has been found to have multiple polyadenylation sites. Transcription of FKBP5 gene produces 4 different transcript variants due to alternative splicing (RefSeq, Mar 2009). NM_004117 is the transcript most widely referred to, and its mRNA is 3803 bp long.

Protein Note Protein name: FK506 binding protein 51, FKBP51, Peptidyl-prolyl cis-trans isomerase (PPIase). It is encoded by the FKBP5 gene (Nair et al., 1997).

Description FKBP51 is a member of immunophilin family, proteins characterized by their ability to bind immunosuppresive drugs. Additionally, immunophilins are peptidylprolyl isomerases (PPIase) that catalyze the cis-trans conversion of peptidylprolyl bonds, a reaction important for protein folding (Fischer et al., 1984). Sinars et al. (Sinars et al., 2003) initially showed the structure of FKBP51 and the orientation of its domains. The N-terminal domain, FK1, is an active rotamase domain (peptidyl-prolyl isomerase; PPIase) which is required to bind immunosuppressive drugs, such as FK506 (tacrolimus). In addition, it is responsible for binding to the kinase Akt (Pei et al., 2009). The FK2 domain, needed for interaction with some binding partners (Figure 2), does not show measurable PPIase activity. The TRP domain consists of three highly degenerate 34 amino acid repeats TPR repeats, and is responsible for multiple protein-protein interactions (figure 2), for example with Hsp90 (Cheung-Flynn et al., 2003), progesterone receptor (PR) (Barent et al., 1998), PH domain and leucine rich repeat protein phosphatase (PHLPP) (Pei et al., 2009).

Expression FKBP5 is ubiquitously expressed with different levels of distribution in various tissues. Tissue examples include amygdala, kidney, heart, hippocampus, liver skeletal muscle, peripheral blood, placenta, thymus, testis, uterus, and others, with lower levels of expression in pancreas, spleen, and stomach (Baughman et al., 1997).

FKBP5 (FK506 binding protein 5) Ellsworth KA, Wang L


Figure 1. (A) Schematic diagram of FKBP5 location on chromosome 6. FKBP5 localizes to chromosome 6p21.31, which is represented graphically. FKBP5 gene spans over 154 kbp from 35541362 to 35696360 on reverse strand. The region surrounding FKBP5 gene is enlarged. (B) Schematic representation of FKBP5 mRNA structure, with indicated ATG translation start site in exon 2. Up to date it has been established that FKBP5 expression is regulated by glucocorticoids, progestins, and androgens (Hubler et al., 2003; Hubler and Scammell, 2004; Makkonen et al., 2009; Paakinaho et al., 2010).

Localisation FKBP5 localizes to cytoplasm and nucleus.

Function FKBP5 plays multiple important roles in cellular process. Since it has peptidyl-prolyl isomerase (PPIase) activity, it regulates protein folding (Galat, 1993; Fruman et al., 1994). In addition, FKBP5 can associate with chaperones, thus playing a role in cell trafficking (Schiene-Fischer and Yu, 2001). Also, it influences steroid receptor signaling (Denny et al., 2000; Barent et al., 1998; Ni et al.,

2010), NFκB pathway (Bouwmeester et al., 2004), as well as Akt pathway (Pei et al., 2009). Moreover, FKBP5 plays a role in regulating drug responses (Jiang et al., 2008; Li et al., 2008; Hou and Wang, 2012; Binder et al., 2004).

Mutations Note Next Generation resequencing of FKBP5 gene was performed using 96 Caucasian American samples and identified 657 single nucleotide polymorphisms (SNPs) (Ellsworth et al., 2013b). In addition, Next Generation resequencing was also performed using 60 samples from pancreatic cancer patients and identified 404 SNPs (Ellsworth et al., 2013a). All of these polymorphisms are germinal SNPs.

Figure 2. Functional domains of FKBP51. FKBP1 consists of 457 amino acids with three functional domains, as shown. FKBP51 binding proteins are indicated and listed by domain they interact with.



Figure 3. Importance of FKBP5 in regulating activity of Akt pathway. FKBP5 acts as a scaffolding protein, enhancing the interaction of PHLPP and Akt, therefore promoting de-phosphorylation of Akt's Serine residue 473. That in turn eventually leads to inactivation of Akt pathway. FKBP5 expression and interaction with PHLPP is especially important upon chemotherapy treatment, because it inactivation of Akt leads to chemotoxic stress and directs cells towards apoptosis, rather than survival pathway.

Somatic It has been reported that four confirmed somatic mutations in various cancer tissues has been identified (V37V: silent (ovary) M97I: missense (breast) (Cancer Genome Atlas Research Network, 2011), Y113Y: silent (pancreas) (Biankin et al., 2012), S309L: missense (endometrium, lung, large intestine) (Liu et al., 2012).

Implicated in Cancer and response to chemotherapy Note FKBP51 is an important protein involved in the regulation of many key signaling cascades in the cell, such as Akt (Pei et al., 2009), NFκB (Bouwmeester et al., 2004), and androgen receptor pathways (Ni et al., 2010). All of these signalling pathways are implicated in tumorigenesis and response to drug treatment. It has been suggested that the contribution of FKBP5 in tumorgenesis and antineoplastic therapy is tissue-specific. Depending on the cellular context, FKBP5 can either promote or inhibit tumor progression and chemoresistance.

Pancreatic cancer Note The Akt pathway is one of the most important signaling pathways, playing a role in regulation of many cellular processes, including cell proliferation, growth, and other processes that crucial for cell survival (Manning and Cantley, 2007). Akt is a serine/threonine kinase that in order to become fully activated needs its residues: Ser473 and Thr308 to be phosphorylated. This is facilitated by phosphoinositide 3-kinase (PIP3), as well as PDK1, and mTOR complex 2 (Alessi et al., 1996; Engelman et al., 2006; Sarbassov et al., 2005). Conversely, phosphatases, such as PP2 holoenzymes and PHLPP de-phosphorylate Akt, halting its activity (Brognard et al., 2007; Carracedo and Pandolfi, 2008; Gao et al., 2005; Padmanabhan et al., 2009). The balance in phosphorylation levels of Akt determines its pathway activity, therefore affecting all the downstream cellular events. If Akt pathway becomes highly up-regulated, it potentially could lead to tumor development, progression and eventually to chemotherapy resistance (Pei et al., 2010).



Figure 4. FKBP5 enzymatic activity regulates NF-κB pathway activation. Peptidylprolyl isomerase enzymatic activity of FKBP5 is required for IKKa activation and further phosphorylation of NFκB, which promotes cell survival and chemoresistance. Rapamycin can specifically inhibit FKBP5 enzymatic activity, which leads to decrease in NFκB pathway activation and increase in apoptosis upon chemotherapy treatment. Genome-wide association studies of cytidine analogues identified FKBP5 low expression levels to be associated with resistance to many chemotherapeutic drugs (Li et al., 2008; Pei et al., 2009). Functional studies of FKBP5 demonstrated that FKBP51 acts as a scaffolding protein increasing interaction between Akt's phosphatase - PHLPP and Akt, thus decreasing the phosphorylation of Akt-Ser473 (Pei et al., 2009). It was shown, that in pancreatic and breast cancer cells FKBP5 expression levels are decreased, while the phosphorylation of Akt-Ser473 is increased, which could lead to chemoresistance. Also, it suggested that FKBP5 might function as a tumor suppressor gene through the down-regulation of Akt activation (Pei et al., 2009, Hou and Wang, 2012).

Acute lymphoblastic leukemia, glioma, melanoma Note FKBP5 plays a pivotal role in regulating NF-κB pathway (Bouwmeester et al., 2004). Specifically, FKBP51 interacts with several members of the NF-κB pathway including inhibitors of NF-κB kinase: IKK α, IKKε, TAK1 and MEKK1. It was shown, that FKBP51 enzymatic activity is required for IKK activation, which suggested that FKBP5 plays an important role in this pathway. Avellino et al. demonstrated, that the addition of rapamycin, a known inhibitor of FKBP51 enzymatic (PPIase)

activity, to anthracycline treatment of blasts from chronic childhood acute lymphoblastic leukemia (ALL) patients would sensitize these cells to anthracyclines (Avellino et al., 2005). These experiments suggested that the combination treatment of rapamycin and doxorubicin inhibits the activation of the NF-κB pathway, which leads to an increase in apoptosis, and, in turn, an increase in sensitivity to chemotherapy (Avellino et al., 2005). Since NF-κB pathway activation leads to anti-apoptotic signals, therefore, in this case, FKBP5 plays a role in chemoresistance to drugs such as anthracyclines. In addition, in glioma cells, FKBP5 expression contributes to glioma cells growth and sensitivity to rapamycin through regulation of the NF-κB pathway (Jiang et al., 2008). FKBP5 was also described to influence radioresistance in melanoma cells (Romano et al., 2010). Specifically, it was found that in melanoma samples FKBP51 controlled radioresistance through the activation of NF-κB pathway, and by silencing expression of FKBP5 in tumors in vitro and in vivo, it contributed to an increase in apoptosis after irradiation.

Prostate cancer Note FKBP5 influences androgen receptor signaling in prostate cancer. Androgen receptor (AR) is a transcription factor, regulating expression of multiple genes, including FKBP5 (Makkonen et al., 2009).



Figure 5. Prostate cancer cell growth promotion under low-androgen conditions. Formation of ATP-bound Hsp90-FKBP5-p23 superchaperone complex allows for increased androgen and androgen receptor binding which promotes cell growth.

Additionally, FKBP5 is a part of a positive feedback loop that not only is having its expression regulated by AR and androgen binding, but it also facilitates androgen-dependent transcription. Ni et al. (Ni et al., 2010) reported that FKBP5 forms a superchaperone complex with ATP-bound Hsp90 and p23 that increases binding of androgen to its receptor. This allows for androgen-dependent gene transcription activation and promotes cell growth, which is especially important during prostate cancer progression to the androgen-independent state during disease progression and tumor growth (Ni et al., 2010).

Depression, post-traumatic stress disorder Note It has been established that one of the major functions of FKBP51 is to co-chaperone with HSP family members steroid receptors: glucocorticoid (GR) (Denny et al., 2000), progesterone (PR) (Barent et al., 1998), and androgen (AR) (Ni et al., 2010). In addition, FKBP5 intronic regions contain hormone response elements (HRE) that upon GR, PR, or AR activation bind their respective hormones.

Figure 6. Negative feedback loop on GR sensitivity. When HSP90-GR is bound to the FKBP51, it has a lower affinity for GR ligand (glucocorticoids). However, once glucocorticoids bind to the complex, FKBP51 dissociates from the complex and FKBP52 binds instead. That allows for the GR translocation into the nucleus and exertion of its action as a transcription factor. GR also acts on FKBP5 via its glucocorticoid response elements (GREs), increasing its transcription, which leads to an increase in amount of FKBP51 protein in the cell. That, in turn, decreases the GR affinity for its ligand, completing this negative feedback loop on GR sensitivity.



That, in turn, induces the FKBP5 gene transcription (Hubler et al., 2003; Hubler and Scammell, 2004; Makkonen et al., 2009; Paakinaho et al., 2010) leading to increases in the amount of FKBP51 protein in the cell. FKBP5 modulates steroid hormones binding affinity; therefore it affects their signaling pathways. For example FKBP51 plays an important role in regulating the activity of the glucocorticoid receptor (Davies et al., 2005). When FKBP51 is bound to the GR-complex, the receptor has lower affinity for glucocorticoids, which causes an increase of glucocorticoids in the intercellular environment. On the other hand, once glucocorticoid is bound, FKBP51 dissociate from the complex and is exchanged with FKBP52. That allows for the translocation of GR into the nucleus and interaction with DNA. Once, in the nucleus GR acts as a transcription factor and by binding to glucocorticoid receptor response elements (GRE) of FKBP5 increases its transcription. That leads to increased concentrations of FKBP51 that contribute to higher GR resistance, completing a negative feedback loop on GR sensitivity (Binder, 2009). Since GR plays a role in regulating a stress response, if FKBP5 expression is altered, it could potentially contribute to development of mood disorders, such as depression or post-traumatic stress disorder (Binder, 2009; Binder et al., 2008; Binder et al., 2004).

References Fischer G, Bang H, Mech C. [Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides]. Biomed Biochim Acta. 1984;43(10):1101-11

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Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Künzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Köhnlein O, Dabitz H, Brückl T, Müller N, Pfister H, Lieb R, Mueller JC, Lõhmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004 Dec;36(12):1319-25

Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004 Feb;6(2):97-105

Hubler TR, Scammell JG. Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Cell Stress Chaperones. 2004 Autumn;9(3):243-52

Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V, Venuta S, Romano MF. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood. 2005 Aug 15;106(4):1400-6

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Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18;307(5712):1098-101



Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006 Aug;7(8):606-19

Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007 Mar 23;25(6):917-31

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun 29;129(7):1261-74

Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008 Mar 19;299(11):1291-305

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Jiang W, Cazacu S, Xiang C, Zenklusen JC, Fine HA, Berens M, Armstrong B, Brodie C, Mikkelsen T. FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia. 2008 Mar;10(3):235-43

Li L, Fridley B, Kalari K, Jenkins G, Batzler A, Safgren S, Hildebrandt M, Ames M, Schaid D, Wang L. Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. Cancer Res. 2008 Sep 1;68(17):7050-8

Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S186-95

Makkonen H, Kauhanen M, Paakinaho V, Jääskeläinen T, Palvimo JJ. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res. 2009 Jul;37(12):4135-48

Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP, Tissenbaum HA. A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell. 2009 Mar 6;136(5):939-51

Pei H, Li L, Fridley BL, Jenkins GD, Kalari KR, Lingle W, Petersen G, Lou Z, Wang L. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009 Sep 8;16(3):259-66

Ni L, Yang CS, Gioeli D, Frierson H, Toft DO, Paschal BM. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010 Mar;30(5):1243-53

Paakinaho V, Makkonen H, Jääskeläinen T, Palvimo JJ. Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol Endocrinol. 2010 Mar;24(3):511-25

Pei H, Lou Z, Wang L. Emerging role of FKBP51 in AKT kinase/protein kinase B signaling. Cell Cycle. 2010 Jan 1;9(1):6-7

Romano S, D'Angelillo A, Pacelli R, Staibano S, De Luna E, Bisogni R, Eskelinen EL, Mascolo M, Calì G, Arra C, Romano MF. Role of FK506-binding protein 51 in the

control of apoptosis of irradiated melanoma cells. Cell Death Differ. 2010 Jan;17(1):145-57

. Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15

Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012 Nov 15;491(7424):399-405

Hou J, Wang L. FKBP5 as a selection biomarker for gemcitabine and Akt inhibitors in treatment of pancreatic cancer. PLoS One. 2012;7(5):e36252

Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM, Gnad F, Guan Y, Gilbert HN, Stinson J, Klijn C, Guillory J, Bhatt D, Vartanian S, Walter K, Chan J, Holcomb T, Dijkgraaf P, Johnson S, Koeman J, Minna JD, Gazdar AF, Stern HM, Hoeflich KP, Wu TD, Settleman J, de Sauvage FJ, Gentleman RC, Neve RM, Stokoe D, Modrusan Z, Seshagiri S, Shames DS, Zhang Z. Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 2012 Dec;22(12):2315-27

Ellsworth KA, Eckloff BW, Li L, Moon I, Fridley BL, Jenkins GD, Carlson E, Brisbin A, Abo R, Bamlet W, Petersen G, Wieben ED, Wang L. Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma. PLoS One. 2013a;8(8):e70216

Ellsworth KA, Moon I, Eckloff BW, Fridley BL, Jenkins GD, Batzler A, Biernacka JM, Abo R, Brisbin A, Ji Y, Hebbring S, Wieben ED, Mrazek DA, Weinshilboum RM, Wang L. FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. Pharmacogenet Genomics. 2013b Mar;23(3):156-66


Ellsworth KA, Wang L. FKBP5 (FK506 binding protein 5). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):314-320.




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ITGA9 (integrin, alpha 9) Carla Molist, Ana Almazán-Moga, Isaac Vidal, Aroa Soriano, Luz Jubierre, Miguel F Segura, Josep Sánchez de Toledo, Soledad Gallego, Josep Roma

Laboratory of Translational Research in Paediatric Cancer, Vall d'Hebron Research Institute, Barcelona, Spain (CM, AAM, IV, AS, LJ, MFS, JSdT, SG, JR), Paediatric Oncology and Haematology, Vall d'Hebron Hospital, Barcelona, Spain (JSdT, SG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ITGA9ID41010ch3p22.html DOI: 10.4267/2042/53642


Abstract Review on ITGA9, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: ALPHA-RLC, ITGA4L, RLC

HGNC (Hugo): ITGA9

Location: 3p22.2

DNA/RNA Description Chromosome 3: 37493606-37865005; forward strand. Segons omim: 3:37493812 - 37861280.

Transcription Exons: 28; Coding exons: 28; Transcript length: 7889 bps; Translation length: 1035 residues.

4 splice variants described (7889, 2282, 609 and 428 bp), three of which with protein translation (1035, 632 and 69 aa).

Protein Note Alpha9-Integrin.

Description Alpha-integrins, such as Alpha9-Integrin, are cell surface glycoproteins that contain a large N-terminal extracellular domain with 7 conserved repeats of putative metal-binding domains, a transmembrane segment, and a short C-terminal cytoplasmic tail. ITGA9, like ITGA4, lacks the domain I and the post-translational cleavage that usually occurs in the rest of alpha-integrins. Alpha9-Integrin forms a functional heterodimer with beta1-integrin.

ITGA9 (integrin, alpha 9) Molist C, et al.


Expression ITGA9 expression is widely distributed in normal human epithelia and muscle. For instance, it has been found in airway epithelium, basal layer of squamous epithelium, smooth muscle and skeletal muscle. Furthermore, its expression has been found in hepatocytes, breast tissue, neutrophils and polymorphonuclear leukocytes.

Localisation Cell membrane.

Function Adhesion with extracellular-matrix proteins, cell-cell interactions and signal transduction. ITGA9 has been shown to bind a plethora of ligands: tenascin, VCAM-1, osteopontin, uPAR, plasmin, angiostatin, several ADAMs (ADAM1, ADAM2, ADAM3, ADAM7, ADAM8, ADAM9, ADAM12, ADAM15, ADAM28 and ADAM33), EMILIN1, fibronectin, VEGF-A, VEGF-C and VEGF-D. Alpha9 knockout mice died from respiratory failure before day 12 after birth and showed chylothorax, defective lymphatic and venous valve morphogenesis, impaired development of neutrophils, improper re-epithelialisation during cutaneous wound-healing, impaired bone resorption and abnormal osteoclasts. In cancer, the heterodimer alpha9-beta1 has recently been shown to have an oncogenic role by inducing epithelial-mesenchymal transition and cell migration and metastatic ability in several cancers such as glioma, breast, colon and rhabdomyosarcoma. However, other authors have reported a tumour suppressor function for ITGA9 in a wide variety of tumours based on deletion or methylation states in varying percentages of patients. Furthermore, a very small percentage of patients (1%) with point mutations has also been reported.

Homology Alpha- and beta-integrins are completely distinct, with no detectable homology between them. Sequence identity among alpha-integrins is around 45%. All alpha-integrins are thought to have evolved from a common ancestor. Among all alpha-subunits, alpha-9 shows the greatest homology with alpha-4.

Mutations

Implicated in Small cell lung cancer (SCLC) Note Yamakawa et al. (1993) identified a region of homozygous deletions in chromosome 3p21.3 in lung cancer cell lines, where the ITGA9 gene is located. Furthermore, Hibi et al. (1994) reported an upregulation of the ITGA9 gene in SCLC cell lines and primary tumours, suggesting that an altered expression of the ITGA9 may contribute to the phenotype of this cancer. An activation of ITGA9 expression has been shown in different human tumours and cancer cells, for

ITGA9 (integrin, alpha 9) Molist C, et al.


example small cell lung cancer, medulloblastoma, astrocytoma and glioblastoma. On the other hand, several genetic and epigenetic aberrations (deletions and methylations) of ITGA9 have been described in several types of cancer such as kidney, lung, breast, ovarian, cervical, prostate and colorectal.

References Palmer EL, Rüegg C, Ferrando R, Pytela R, Sheppard D. Sequence and tissue distribution of the integrin alpha 9 subunit, a novel partner of beta 1 that is widely distributed in epithelia and muscle. J Cell Biol. 1993 Dec;123(5):1289-97

Yamakawa K, Takahashi T, Horio Y, Murata Y, Takahashi E, Hibi K, Yokoyama S, Ueda R, Takahashi T, Nakamura Y. Frequent homozygous deletions in lung cancer cell lines detected by a DNA marker located at 3p21.3-p22. Oncogene. 1993 Feb;8(2):327-30

Hibi K, Yamakawa K, Ueda R, Horio Y, Murata Y, Tamari M, Uchida K, Takahashi T, Nakamura Y, Takahashi T. Aberrant upregulation of a novel integrin alpha subunit gene at 3p21.3 in small cell lung cancer. Oncogene. 1994 Feb;9(2):611-9

Shang T, Yednock T, Issekutz AC. alpha9beta1 integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers. J Leukoc Biol. 1999 Nov;66(5):809-16

Taooka Y, Chen J, Yednock T, Sheppard D. The integrin alpha9beta1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1. J Cell Biol. 1999 Apr 19;145(2):413-20

Eto K, Huet C, Tarui T, Kupriyanov S, Liu HZ, Puzon-McLaughlin W, Zhang XP, Sheppard D, Engvall E, Takada Y. Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. J Biol Chem. 2002 May 17;277(20):17804-10

Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L. The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by

alternative splicing. J Biol Chem. 2002 Apr 26;277(17):14467-74

Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007;8(5):215

Mambole A, Bigot S, Baruch D, Lesavre P, Halbwachs-Mecarelli L. Human neutrophil integrin alpha9beta1: up-regulation by cell activation and synergy with beta2 integrins during adhesion to endothelium under flow. J Leukoc Biol. 2010 Aug;88(2):321-7

Mostovich LA, Prudnikova TY, Kondratov AG, Loginova D, Vavilov PV, Rykova VI, Sidorov SV, Pavlova TV, Kashuba VI, Zabarovsky ER, Grigorieva EV. Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors. Cell Adh Migr. 2011 Sep-Oct;5(5):395-401

Høye AM, Couchman JR, Wewer UM, Fukami K, Yoneda A. The newcomer in the integrin family: integrin α9 in biology and cancer. Adv Biol Regul. 2012 May;52(2):326-39

Majumder M, Tutunea-Fatan E, Xin X, Rodriguez-Torres M, Torres-Garcia J, Wiebe R, Timoshenko AV, Bhattacharjee RN, Chambers AF, Lala PK. Co-expression of α9β1 integrin and VEGF-D confers lymphatic metastatic ability to a human breast cancer cell line MDA-MB-468LN. PLoS One. 2012;7(4):e35094

Masià A, Almazán-Moga A, Velasco P, Reventós J, Torán N, Sánchez de Toledo J, Roma J, Gallego S. Notch-mediated induction of N-cadherin and α9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells. Br J Cancer. 2012 Oct 9;107(8):1374-83

Veeravalli KK, Ponnala S, Chetty C, Tsung AJ, Gujrati M, Rao JS. Integrin α9β1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway. Cell Signal. 2012 Jan;24(1):272-81

Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis NE. Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition. Oncogene. 2013 Jan 10;32(2):141-50


Molist C, Almazán-Moga A, Vidal I, Soriano A, Jubierre L, Segura MF, Sánchez de Toledo J, Gallego S, Roma J. ITGA9 (integrin, alpha 9). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):321-323.




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KIAA1199 (KIAA1199) Nikki Ann Evensen, Cem Kuscu, Jian Cao

Stony Brook University, Stony Brook, New York, USA (NAE, CK, JC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/KIAA1199ID51053ch15q25.html DOI: 10.4267/2042/53643


Abstract Review on KIAA1199, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: CCSP1, TMEM2L

HGNC (Hugo): KIAA1199

Location: 15q25.1

Note Reported in the Human Unidentified Gene-Encoded Large Proteins (HUGE) database as KIAA1199.

DNA/RNA Description The human KIAA1199 transcript spans 7080 base pairs on chromosome 15 in the region 15q25.1. It contains 29 exons, 28 of which are coding, and 28

introns. The transcriptional start site is within the second exon. There is a canonical TATA-box present in the KIAA1199 promoter region at -31 to -27 base pairs, as well as a GC-box at -248 to -243 base pairs. However, this GC-box was not found to be required for transcriptional activation of KIAA1199, nor was there any methylation of the cytosines found within this region, which is often an important feature of GC-boxes. KIAA1199 also contains a CpG island within the first intron (+525 50 +1025). The methylation status of this CpG island was found to effect the expression level of KIAA1199, with high levels of DNA methylation found in non-aggressive, low expressing, cancer cell lines (Kuscu et al., 2012).

Transcription An AP-1 binding site, located between -48 and -45 within the KIAA1199 promoter, was found to be important for KIAA1199 promoter activity. AP-1 was found to directly bind to this region in order to activate transcription of KIAA1199.

KIAA1199 (KIAA1199) Evensen NA, et al.


AP-1 transcription factors have been associated with increased promoter activity of genes associated with cancer. Additionally, among four potential NF-κB binding sites, the site furthest from the transcriptional start site (-1345 to -1333) was found to play a role in KIAA1199 promoter activation. NF-κB was found to directly bind to this site to increase transcription of KIAA1199 (Kuscu et al., 2012).

Protein Description The KIAA1199 open reading frame consists of 4083 base pairs, which encodes a protein 1361 amino acids in length. It has a predicted molecular weight of approximately 163 kDa. The KIAA1199 protein has a G8 domain between a.a. 44-166, which is a novel domain that contains eight conserved glycines and consists of five β-strand pairs (He et al., 2006). Several disease related proteins contain this domain, including polyductin protein (PKHD1) and transmembrane protein 2 (TMEM2), although the exact function of the G8 motif remains unclear (He et al., 2006). A GG domain, characterized by seven β-strands and two α-helices, can also be found within the KIAA1199 protein (Guo et al., 2006). This novel domain also has no known function. KIAA1199 is also predicted to have a cleavable signal peptide at its NH2-terminus (Sabates-Bellver et al., 2007). KIAA1199 has been demonstrated to be N-linked glycosylated (Tiwari et al., 2013).

Expression Northern blot analysis of normal human tissues revealed expression of KIAA1199 mRNA in various tissues, with the highest levels found in the brain, placenta, lung, and testis (Michishita et al., 2006). KIAA1199 is also expressed in various cell types found in the inner ear (Abe et al., 2003; Usami et al., 2008), and in dermal fibroblasts of the skin (Yoshida et al., 2013). Increased levels of KIAA1199 have also been demonstrated in numerous cancer tissues compared to normal tissues, including colorectal adenomas (Sabates-Bellver et al., 2007).

Localisation Cytoplasmic and nuclear staining for KIAA1199 has been observed in gastric and colon cancer tissue samples (Sabates-Bellver et al., 2007; Matsuzaki et al., 2009; Birkenkamp-Demtroder et al., 2011). More detailed subcellular localization revealed expression of exogenous and endogenous KIAA1199 within the endoplasmic reticulum (ER) of various cell types (Evensen et al., 2013; Tiwari et al., 2013). KIAA1199 was found to interact with the ER chaperone binding immunoglobulin protein

(BiP)/glucose-regulated protein (GRP-78), which further supports the ER localization of KIAA1199 (Evensen et al., 2013). Secretion of KIAA1199 has also been demonstrated for certain cell types (Tiwari et al., 2013).

Function KIAA1199 plays a key role in cancer progression via increasing cancer cell migration and invasion, which are necessary steps for cancer metastasis. Expression of KIAA1199 in non-aggressive cancer cell lines leads to an epithelial-to-mesenchymal transition along with increased migratory capabilites. Furthermore, knockdown of KIAA1199 leads to a loss of mesenchymal characteristics with decreased invasive and migratory abilities, as well as reduced metastastic potential (Evensen et al., 2013). A role for KIAA1199 in maintaining ion homeostasis, and more specifically calcium signaling, has also been suggested (Abe et al., 2003; Tiwari et al., 2013). KIAA1199-mediated migration was found to involve elevated cytosolic calcium levels followed by protein kinase C alpha (PKCα) translocation/activation. This change in cytosolic calcium is due to increased release of calcium from the ER via an unknown mechanism induced by KIAA1199 (Evensen et al., 2013). Additional studies revealed an interaction with KIAA1199 and inositol 1,4,5-triphosphate receptor 3 (ITPR3) which is a ligand-gated ion channel located on the ER membrane that is known to mediate the release of calcium from the ER (Tiwari et al., 2013). KIAA1199 is thought to be a target of the Wnt signaling pathway and a potential player in the progression of colorectal adenomatous (Sabates-Bellver et al., 2007; Tiwari et al., 2013). Additionally, silencing of KIAA1199 was shown to alter the expression of genes known to be involved in the Wnt/β-catenin pathway and decrease cell proliferation (Birkenkamp-Demtroder et al., 2011). In human skin fibroblasts, KIAA1199 expression was found to cause increased degradation of hyaluronan (HA), which is a glycosaminoglycan found in the extracellular matrix surrounding tissues. It acts as a structural component and can affect cell signaling and cellular behavior, including angiogenesis and cell migration (Yoshida et al., 2013).

Homology The KIAA1199 gene product shares 38% identity (63% similarity) with transmembrane protein 2 (TMEM2). A small region within the KIAA1199 gene product (aa 55-155) also shares 38% identity (57% similarity) with polyductin protein (PKHD1) (Abe et al., 2003). However, none of these homologies revealed any functional information.

KIAA1199 (KIAA1199) Evensen NA, et al.


Mutations Somatic Nine DNA variants of the KIAA1199 gene were identified, six of which were missense (R187C, R187H, H783R, H783Y, V1109I, and P1169A) and three of which were synonymous substitutions (L532L, P619P, D800D). R187C, R187H, H783Y, and V1109I were found only in families with nonsyndromic hearing loss, suggesting a potential role for these specific mutations in this disease state (Abe et al., 2003).

Implicated in Gastric and colorectal cancers Prognosis Numerous studies have implicated KIAA1199 expression with cancer progression. Gastric cancer patients with low expression of KIAA1199 were found to have significantly better overall 5-year survival rates as compared to those expressing higher levels. Furthermore, lymph node metastasis, distant metastasis, and peritoneal dissemination were more often observed in the patients with higher levels of KIAA1199 (Matsuzaki et al., 2009). Additionally, there is evidence to suggest that KIAA1199 could potentially be used as a biomarker for cancer. Higher levels of KIAA1199 transcripts were found in the serum of patients with adenoma and colorectal cancer as compared to neoplasia free controls (LaPointe et al., 2012). KIAA1199 was also found to be upregulated in cancerous tissues from gastric adenocarcinoma patients, further supporting the idea of using KIAA1199 for diagnostics, early detection, or as a predictor of cancer progression (Chivu Economescu et al., 2010).

Nonsyndromic hearing loss Prognosis Several mutations within KIAA1199 were found in patients with nonsyndromic hearing loss but not in control subjects. Based on the expression pattern of KIAA1199 in the cells of the inner ear, it is thought that it could play a role in normal auditory development with these particular mutations having a negative impact (Abe et al., 2003).

References Abe S, Usami S, Nakamura Y. Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss. J Hum Genet. 2003;48(11):564-70

Guo J, Cheng H, Zhao S, Yu L. GG: a domain involved in phage LTF apparatus and implicated in human MEB and

non-syndromic hearing loss diseases. FEBS Lett. 2006 Jan 23;580(2):581-4

He QY, Liu XH, Li Q, Studholme DJ, Li XW, Liang SP. G8: a novel domain associated with polycystic kidney disease and non-syndromic hearing loss. Bioinformatics. 2006 Sep 15;22(18):2189-91

Michishita E, Garcés G, Barrett JC, Horikawa I. Upregulation of the KIAA1199 gene is associated with cellular mortality. Cancer Lett. 2006 Jul 28;239(1):71-7

Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A, Faggiani R, Anti M, Jiricny J, Clevers H, Marra G. Transcriptome profile of human colorectal adenomas. Mol Cancer Res. 2007 Dec;5(12):1263-75

Usami S, Takumi Y, Suzuki N, Oguchi T, Oshima A, Suzuki H, Kitoh R, Abe S, Sasaki A, Matsubara A. The localization of proteins encoded by CRYM, KIAA1199, UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea. Neuroscience. 2008 Jun 12;154(1):22-8

Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M. Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann Surg Oncol. 2009 Jul;16(7):2042-51

Chivu Economescu M, Necula LG, Dragu D, Badea L, Dima SO, Tudor S, Nastase A, Popescu I, Diaconu CC. Identification of potential biomarkers for early and advanced gastric adenocarcinoma detection. Hepatogastroenterology. 2010 Nov-Dec;57(104):1453-64

Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, Thorsen K, Andersen CL, Øster B, Hahn S, Ørntoft TF. Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells. Br J Cancer. 2011 Aug 9;105(4):552-61

Kuscu C, Evensen N, Kim D, Hu YJ, Zucker S, Cao J. Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer. PLoS One. 2012;7(9):e44661

LaPointe LC, Pedersen SK, Dunne R, Brown GS, Pimlott L, Gaur S, McEvoy A, Thomas M, Wattchow D, Molloy PL, Young GP. Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing. PLoS One. 2012;7(1):e29059

Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Kadam P, Hu YJ, Pulkoski-Gross A, Bahou WF, Zucker S, Cao J. Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst. 2013 Sep 18;105(18):1402-16

Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski MJ, Roschitzki B, Uzozie A, Menigatti M, Jiricny J, Marra G. Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS One. 2013;8(7):e69473

Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T, Sakai S, Sugiyama Y, Enomoto H, Okada Y, Inoue S. KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5612-7


Evensen NA, Kuscu C, Cao J. KIAA1199 (KIAA1199). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):324-326.




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MMP19 (matrix metallopeptidase 19) King Chi Chan, Maria Li Lung

Department of Clinical Oncology and Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, P.R. China (KCC, MLL)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MMP19ID41395ch12q13.html DOI: 10.4267/2042/53644


Abstract Review on MMP19, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: MMP18, RASI-1

HGNC (Hugo): MMP19

Location: 12q13.2

DNA/RNA Description MMP-19 can be found at chromosome 12q13.2 at location 56229214-56236767. The DNA sequence contains nine exons and eight introns, spanning 7,55 kb.

Transcription The MMP-19 promoter contains a TATA-box at position -29 and AP-1 binding site at position -73. Potential binding sites for other transcription factors such as NFκB, AP-2, and SP-1 also exist (Mueller et al., 2000).

Protein Description MMP-19 is a secreted protein. It contains a signal peptide for targeting to secretory vesicles. Like most secreted MMPs, MMP-19 is translated and secreted as catalytic inactive proproteins (zymogens), which needed to be activated by proteolytic cleavage of the propeptide region by other extracellular matrix (EMC) proteinases (Ra and Parks, 2007).

Alternative splicing results in multiple transcript variants for this gene (provided by RefSeq, Jan 2013). With reference to UniProtKB database, variant 1 represents the longest transcript and encodes isoform 1 (508 aa, 57 kDa, also known as RASI-1). Variant 2 encoded protein isoform 2 (222 aa, 25 kDa, also known as RASI-9). Variant 3 encoded protein isoform 3 (63 aa, 6 kDa, also known as RASI-6). Isoform 1 has been described as the canonical sequence and all the information described here, unless stated, refers to isoform 1.

MMP19 (matrix metallopeptidase 19) Chan KC, Lung ML


MMP-19 shares a typical MMP structural domain, containing the signal peptide, propeptide, catalytic domain, hinge region, and four hemopexin repeats (Pendás et al., 1997). MMP-19 is a zinc-dependent endopeptidase. The catalytic domain contains the active site for zinc ion binding and functions in catalytic activity such as substrate degradation. The hemopexin domain is responsible for substrate recognition (Ra and Parks, 2007). The catalytic activities of MMPs were reported to be regulated by tissue inhibitor of metalloproteinases (TIMPs). MMP-19 is reported to be strongly inhibited by TIMP-2, TIMP-3, and TIMP-4, and less efficiently by TIMP-1 (Clark et al., 2008).

Expression MMP-19 was found to be expressed in a wide range of normal tissue types, such as nasopharyngeal epithelial cells, lung, breast, skin, intestine, pancreas, spleen, and ovary. MMP-19 was down-regulated or lost during neoplastic progression in nasopharyngeal carcinoma (NPC), mammary gland tumor, skin neoplasm, intestine, and colon cancers (Pendás et al., 1997; Djonov et al., 2001; Impola et al., 2003; Bister et al., 2004; Chan et al., 2011).

Localisation MMP-19 is located in the cytoplasm and secreted into the extracellular matrix.

Function MMP-19 is a member of the MMP family of zinc-dependent endopeptidases. The catalytic domain responsible for degradation of various components of the ECM includes collagen type IV, nidogen-1, fibronectin, tenascin-C isoform, aggrecan, and laminin-5-gamma-2-chain (Stracke et al., 2000; Shiomi et al., 2010). MMP-19 is involved in many physiological activities such as cell proliferation, migration, and anti-angiogenesis.

Implicated in Various cancers Note Due to the ability of MMPs to degrade a variety of substrates, which may be involved in both cancer

progression and repression, the role of MMP-19 in cancer development is as controversial as for all other MMPs. MMP-19 is reported to cleave insulin-like growth factor binding protein-3 (IGFBP-3), thereby causing the release of IGF-1 and enhanced human keratinocyte cell proliferation, migration, and adhesion on type I collagen (Sadowski et al., 2003). Also, MMP-19 was reported to process the laminin-5-gamma-2-chain in keratinocyte cells, which leads to the integrin switch favoring epithelial cell migration (Sadowski et al., 2005). On the other hand, a MMP-19 deficiency mouse model increased the onset of skin tumor invasion and vascularization, implicating the role of MMP-19 in inhibition of tumor invasion and anti-angiogenesis (Jost et al., 2006). The anti-angiogenic role of MMP-19 was demonstrated in the tube formation assay in human microvascular endothelial cells (HMEC-1). MMP-19 inhibited tube formation by degradation of nidogen-1, which is a scaffolding protein required for stabilizing new capillary formation (Titz et al., 2004). Further studies of MMP-19 on endothelial cells suggested other mechanisms of MMP-19 in inhibition of angiogenesis. MMP-19 digests plasminogen to generate angiostatin-like fragments, which are antagonists of angiogenesis and inhibit migration and proliferation of endothelial cells (Brauer et al., 2011). Functional studies of MMP-19 demonstrated its tumor suppressive and anti-angiogenesis functions in nasopharyngeal carcinoma (NPC). MMP-19 reduces colony-forming ability of NPC cells and suppresses tumor formation in nude mice. Also, MMP-19 reduces tube-forming ability in human umbilical vein endothelial cells (HuVEC) and human microvascular endothelial cells (HMEC-1). The anti-angiogenic activity of MMP-19 in NPC is associated with reduction of secreted vascular endothelial growth factor (VEGF) in the conditioned media (Chan et al., 2011). Recent study in NPC cells demonstrated MMP-19 increased cisplatin sensitivity through production of γ-H2AX

MMP19 (matrix metallopeptidase 19) Chan KC, Lung ML


and attenuation of NER activity to repair cisplatin-induced DNA damage, therefore increasing the cisplatin-induced apoptosis in NPC (Liu et al., 2013).

Rheumatoid arthritis (RA) Note MMP-19 was first isolated as an autoantigen from the synovium of a rheumatoid arthritis patient suggesting its role in RA-associated joint tissue destruction (Sedlacek et al., 1998).

References Pendás AM, Knäuper V, Puente XS, Llano E, Mattei MG, Apte S, Murphy G, López-Otín C. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem. 1997 Feb 14;272(7):4281-6

Sedlacek R, Mauch S, Kolb B, Schätzlein C, Eibel H, Peter HH, Schmitt J, Krawinkel U. Matrix metalloproteinase MMP-19 (RASI-1) is expressed on the surface of activated peripheral blood mononuclear cells and is detected as an autoantigen in rheumatoid arthritis. Immunobiology. 1998 Feb;198(4):408-23

Mueller MS, Mauch S, Sedlacek R. Structure of the human MMP-19 gene. Gene. 2000 Jul 11;252(1-2):27-37

Stracke JO, Fosang AJ, Last K, Mercuri FA, Pendás AM, Llano E, Perris R, Di Cesare PE, Murphy G, Knäuper V. Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP). FEBS Lett. 2000 Jul 28;478(1-2):52-6

Djonov V, Högger K, Sedlacek R, Laissue J, Draeger A. MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours. J Pathol. 2001 Sep;195(2):147-55

Impola U, Toriseva M, Suomela S, Jeskanen L, Hieta N, Jahkola T, Grenman R, Kähäri VM, Saarialho-Kere U. Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation. Int J Cancer. 2003 Mar 1;103(6):709-16

Sadowski T, Dietrich S, Koschinsky F, Sedlacek R. Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3. Mol Biol Cell. 2003 Nov;14(11):4569-80

Bister VO, Salmela MT, Karjalainen-Lindsberg ML, Uria J,

Lohi J, Puolakkainen P, Lopez-Otin C, Saarialho-Kere U. Differential expression of three matrix metalloproteinases, MMP-19, MMP-26, and MMP-28, in normal and inflamed intestine and colon cancer. Dig Dis Sci. 2004 Apr;49(4):653-61

Titz B, Dietrich S, Sadowski T, Beck C, Petersen A, Sedlacek R. Activity of MMP-19 inhibits capillary-like formation due to processing of nidogen-1. Cell Mol Life Sci. 2004 Jul;61(14):1826-33

Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch E, Titz B, Sedlacek R. Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration. Cell Mol Life Sci. 2005 Apr;62(7-8):870-80

Jost M, Folgueras AR, Frérart F, Pendas AM, Blacher S, Houard X, Berndt S, Munaut C, Cataldo D, Alvarez J, Melen-Lamalle L, Foidart JM, López-Otín C, Noël A. Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. Cancer Res. 2006 May 15;66(10):5234-41

Ra HJ, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007 Oct;26(8):587-96

Clark IM, Swingler TE, Sampieri CL, Edwards DR. The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008;40(6-7):1362-78

Shiomi T, Lemaître V, D'Armiento J, Okada Y. Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol Int. 2010 Jul;60(7):477-96

Brauer R, Beck IM, Roderfeld M, Roeb E, Sedlacek R. Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen. BMC Biochem. 2011 Jul 25;12:38

Chan KC, Ko JM, Lung HL, Sedlacek R, Zhang ZF, Luo DZ, Feng ZB, Chen S, Chen H, Chan KW, Tsao SW, Chua DT, Zabarovsky ER, Stanbridge EJ, Lung ML. Catalytic activity of Matrix metalloproteinase-19 is essential for tumor suppressor and anti-angiogenic activities in nasopharyngeal carcinoma. Int J Cancer. 2011 Oct 15;129(8):1826-37

Liu RY, Dong Z, Liu J, Zhou L, Huang W, Khoo SK, Zhang Z, Petillo D, Teh BT, Qian CN, Zhang JT. Overexpression of asparagine synthetase and matrix metalloproteinase 19 confers cisplatin sensitivity in nasopharyngeal carcinoma cells. Mol Cancer Ther. 2013 Oct;12(10):2157-66


Chan KC, Lung ML. MMP19 (matrix metallopeptidase 19). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):327-329.

Gene Section Review



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RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6) Tuoen Liu, Shousong Cao

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri, United States (TL), Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, United States (SC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/RPS6KA6ID43481chXq21.html DOI: 10.4267/2042/53645


Abstract Review on RPS6KA6, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: PP90RSK4, RSK4

HGNC (Hugo): RPS6KA6

Location: Xq21.1

DNA/RNA Description The human RPS6KA6 gene is located at Xq21, and

contains 22 exons that span approximately 75 kb of genomic DNA and are located on cosmids E1, H22 and G9 in a telomeric to centromeric orientation (Yntema et al, 1999; Dümmler et al., 2005; Kantojärvi et al., 2011).

Protein Note Human RPS6KA6 gene codes for the protein RSK4, a serine- threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al., 1999; Dümmler et al., 2005; Anjum and Blenis, 2008; Serra et al., 2013).

The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and carboxyl-terminal kinase domain (CTKD), a linker region and amino- and carboxyl-terminal tails. The NTKD is responsible for substrate phosphorylation and CTKD regulates sutophosphorylation of the RSK4. The two kinase domains are connected by a linker region which is about 100 amino acids containing essential regulatory domains including hydrophobic and turn motifs, involved in the activation of NTKD. An ERK-docking motif, known also as the D domain, is located in the carboxyl-terminal tail (Dümmler et al., 2005; Anjum and Blenis, 2008; Romeo et al., 2012).

RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6)

Liu T, Cao S


The activation of the RSK4 family protein. All RSK family membranes including RSK4 are involved in MAPK pathways and can be activated by various molecules including growth factors, neurotransmitters, hormones, phorbol esters. First, activation of cell surface receptors creates docking site for adaptor molecules like growth factor receptor-bound protein-2 (GRB2). GRB2 links the receptor to the guanine nucleotide-exchange factor son of sevenless (SOS). SOS catalyses GDP release and GTP binding to the small G-protein Ras. The GTP-bound Ras then binds to the Raf protein kinases. Upon the activation of Raf, it activates MAPK kinase (MEK), then downstream extracellular signal-regulated kinase (ERK). All four RSK family members are directly phosphorylated and activated by ERK1/2. RSKs are also phosphorylated by 3'-phosphoinositide-dependent kinase-1 (PDK1) which is a serine-threonine kinase. Activated RSKs can then phosphorylate their substrates via serine and threonine sites (Anjum and Blenis, 2008).

Description RSK4 is a serine- threonine kinase and there are six phosphorylation sites in RSK4: Ser232, Thr368, Ser372, Ser389, Thr581, and Ser742. Upon activation of the cell surface receptors, ERK first bound to the ERK-docking motif in the carboxyl-terminal and phosphorylates Ser372 in the linker region and Thr581 in the CTKD. Phosphorylation of Thr581 activates CTK which autophosphorylates RSK4 at Ser389 in the linker region. Phosphorylation of Ser389 recruites and activiates PDK1 which phosphorylates Ser232 in NTKD. After dissociation of PDK1 from RSK, the Ser386 phosphorylated motif interacts with NTKD and activates the NTK in synergy with phosphor-Ser232. The phosphorylation of Ser372 increases the activity of NTK. Thr368 is phosphorylated by ERK and Ser742 can be phosphorylated by activated NTK, which leads to the association of RSK and ERK, serving as an inhibitory feedback mechanism to "shut off" the process (Dümmler et al., 2005). The CTKD activity of RSK1, RSK2 and RSK4 can be regulated by the irreversible inhibitor, pyrrolopyrimidine FMK (Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone) (Romeo et al., 2012).

Expression RSK4 expression is low in both mouse and human embryonic and adult tissues compared with other three RSK family members. RSK4 mRNA was detected in the brain, cerebellum, heart, kidney and skeletal muscle, but not in other tissues such as lung, liver, pancreas and adipose. Specifically, RSK4 was found to be ubiquitously expressed at a low level through mouse development, and it is more highly expressed in specific phases of embryogenesis such as egg cylinder, gastrula and organ genesis (Kohn et al., 2003; Lleonart et al., 2006; Romeo et al., 2012).

Localisation RSK is predominantly located in cytosol, and contrary to other RSKs, its expression is relatively low and does not significantly accumulate in the nucleus after mitogenic stimulation (Dümmler et al., 2005; Romeo et al., 2012).

Function Recent studies showed RSK4 can be either oncogenic or tumor suppressive depending on many factors, and Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition.


Liu T, Cao S


RSK4 can induce cellular senescence which is mediated by p21. Also, inhibition of RSK4 causes bypass of cellular senescence induced by stress or oncogene, suggesting RSK4 inhibition may be an important factor in facilitating cell transformation. (López-Vicente et al., 2011). shRNA against RPS6KA6 bypassed p53-dependent G1 cell cycle arrest and suppressed mRNA expression of cyclin-dependent kinase inhibitor p21cip1, suggesting RSK4 is needed for growth arrest induced by p53 (Berns et al., 2004). In addition, RSK4 is identified to be an inhibitor of fibroblast growth factor (FGF)-Ras-ERK signal transduction. RSK4 plays an inhibitory role during embryogenesis by suppressing receptor tyrosine kinase signaling (López-Vicente et al., 2009).

Homology The RSK family members share 73-80% amino acids similarity to each other and are mostly different in their amino- and carboxyl-terminal sequences (Romeo et al., 2012). Difference from other RSK members whose activation needs the stimulation by growth factors, RSK4 can be constitutively activated under serum-starved condition without growth factor. The constitutive activation is due to constitutive phosphorylation of Ser232, Ser372 and Ser389 (Dümmler et al., 2005). PDK1 is required for mitogenic stimulation of RSK1-3, however, RSK4 does not appear to require PDK1 to maintain its high basal activity (Romeo et al., 2012). Unlike other three family members, RSK4 expression can disrupt mouse mesoderm formation induced by the FGF-Ras-ERK signaling pathway (Myers et al., 2004).

Implicated in Breast cancer Note RSK4 is highly expressed and has anti-invasive and anti-metastatic activities in breast cancer. Exogenous expression of RSK4 resulted in decreased breast cancer cell proliferation and increased accumulation of cells in G0-G1 phase of the cell cycle, also with enhanced expression several tumor suppressor genes: retinoblastoma protein, retinoblastoma-associated 46 kDa protein (RbAp46), and p21 protein (Thakur et al., 2007; Thakur et al., 2008). In addition, RSK4 expression enhances breast cancer cell survival upon PI3K/mTOR inhibitors treatment through inhibition of apoptosis and up-regulation of protein translation. Adding MEK- or RSK-specific inhibitors can overcome the RSK4 mediated resistance, thus, combination of RSK and PI3K

pathway inhibitors may overcome the resistance mediated by RSK4 in breast cancer (Serra et al., 2013).

Colon, kidney cancer and melanoma Note RSK4 is down-regulated in colon carcinomas, renal cell carcinomas and colon adenomas. Overexpression of RSK4 induced cell arrest and senescence features in normal fibroblasts and malignant colon carcinoma cell lines. In addition, RSK4 is up-regulated in both replicative and stress-induced senescence and RSK4 inhibition induces senescence resistance in colon carcinoma cells, suggesting RSK4 may be a tumor suppressor gene by regulating senescence induction and inviting cell proliferation in colon carcinogenesis and renal cell carcinomas (Myers et al., 2004). RSK4 expression causes Sunitinib resistance in kidney carcinoma and melanoma cells, thus, RSK4 may be a potential resistance marker in Sunitinib therapy and a potential target for new drug development to overcome Sunitinib resistance (Llenaont et al., 2006; Bender and Ullrich, 2012).

Endometrial cancer Note RSK4 is frequently hypermethylated in endometrial cancer and RSK4 methylation is significantly associated with tumor grade, with higher grade tumors having lower levels of methylation. Thus, RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation (Dewdney et al., 2011).

X-linked mental retardation Note RPS6KA6 gene is commonly deleted in complex X-linked mental retardation patients (Yntema et al., 1999).

Autism spectrum disorder Note RPS6KA6 plays a role in brain development and could be associated with mental retardation. RSP6KA6 is located in the chromosomal region, which is commonly deleted in males with mental retardation. Its mutation may be associated with autism spectrum disorders (Kantojärvi et al., 2011).

AIDS Note SNP rs5968255, located at human Xq21.1 in a conserved sequence element near the RPS6KA6 and CYLC1 genes, was identified as a significant genetic determinant of AIDS progression in HIV infected women.


Liu T, Cao S


However, whether RPS6KA6 gene is functionally involved in the observed phenotype is not clear (Siddiqui et al., 2009).

References Yntema HG, van den Helm B, Kissing J, van Duijnhoven G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel BC, Heilbronner H, Pander HJ, Brunner HG, Ropers HH, Cremers FP, van Bokhoven H. A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics. 1999 Dec 15;62(3):332-43

Kohn M, Hameister H, Vogel M, Kehrer-Sawatzki H. Expression pattern of the Rsk2, Rsk4 and Pdk1 genes during murine embryogenesis. Gene Expr Patterns. 2003 May;3(2):173-7

Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley PS, Beijersbergen RL, Bernards R. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature. 2004 Mar 25;428(6981):431-7

Myers AP, Corson LB, Rossant J, Baker JC. Characterization of mouse Rsk4 as an inhibitor of fibroblast growth factor-RAS-extracellular signal-regulated kinase signaling. Mol Cell Biol. 2004 May;24(10):4255-66

Dümmler BA, Hauge C, Silber J, Yntema HG, Kruse LS, Kofoed B, Hemmings BA, Alessi DR, Frödin M. Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. J Biol Chem. 2005 Apr 8;280(14):13304-14

LLeonart ME, Vidal F, Gallardo D, Diaz-Fuertes M, Rojo F, Cuatrecasas M, López-Vicente L, Kondoh H, Blanco C, Carnero A, Ramón y Cajal S. New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas. Oncol Rep. 2006 Sep;16(3):603-8

Thakur A, Rahman KW, Wu J, Bollig A, Biliran H, Lin X, Nassar H, Grignon DJ, Sarkar FH, Liao JD. Aberrant expression of X-linked genes RbAp46, Rsk4, and Cldn2 in breast cancer. Mol Cancer Res. 2007 Feb;5(2):171-81

Anjum R, Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58

Thakur A, Sun Y, Bollig A, Wu J, Biliran H, Banerjee S, Sarkar FH, Liao DJ. Anti-invasive and antimetastatic

activities of ribosomal protein S6 kinase 4 in breast cancer cells. Clin Cancer Res. 2008 Jul 15;14(14):4427-36

López-Vicente L, Armengol G, Pons B, Coch L, Argelaguet E, Lleonart M, Hernández-Losa J, de Torres I, Ramon y Cajal S. Regulation of replicative and stress-induced senescence by RSK4, which is down-regulated in human tumors. Clin Cancer Res. 2009 Jul 15;15(14):4546-53

Siddiqui RA, Sauermann U, Altmüller J, Fritzer E, Nothnagel M, Dalibor N, Fellay J, Kaup FJ, Stahl-Hennig C, Nürnberg P, Krawczak M, Platzer M. X chromosomal variation is associated with slow progression to AIDS in HIV-1-infected women. Am J Hum Genet. 2009 Aug;85(2):228-39

Dewdney SB, Rimel BJ, Thaker PH, Thompson DM Jr, Schmidt A, Huettner P, Mutch DG, Gao F, Goodfellow PJ. Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers. Clin Cancer Res. 2011 Apr 15;17(8):2120-9

Kantojärvi K, Kotala I, Rehnström K, Ylisaukko-Oja T, Vanhala R, von Wendt TN, von Wendt L, Järvelä I. Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD). Autism Res. 2011 Jun;4(3):228-33

López-Vicente L, Pons B, Coch L, Teixidó C, Hernández-Losa J, Armengol G, Ramon Y Cajal S. RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence. Carcinogenesis. 2011 Apr;32(4):470-6

Bender C, Ullrich A. PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines. Int J Cancer. 2012 Jul 15;131(2):E45-55

Romeo Y, Zhang X, Roux PP. Regulation and function of the RSK family of protein kinases. Biochem J. 2012 Jan 15;441(2):553-69

Serra V, Eichhorn PJ, García-García C, Ibrahim YH, Prudkin L, Sánchez G, Rodríguez O, Antón P, Parra JL, Marlow S, Scaltriti M, Pérez-Garcia J, Prat A, Arribas J, Hahn WC, Kim SY, Baselga J. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest. 2013 Jun 3;123(6):2551-63


Liu T, Cao S. RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):330-333.

Gene Section Review



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SIVA1 (SIVA1, Apoptosis-Inducing Factor) João Agostinho Machado-Neto, Fabiola Traina

Hematology and Hemotherapy Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciencia e Tecnologia do Sangue, Campinas, Sao Paulo, Brazil (JAMN, FT), Hematology/Oncology Division, Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (FT)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SIVA1ID42301ch14q32.html DOI: 10.4267/2042/53646


Abstract Review on SIVA1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: CD27BP, SIVA, Siva-1, Siva-2

HGNC (Hugo): SIVA1

Location: 14q32.33

DNA/RNA Description The entire SIVA1 gene is about 15.3 Kb and contains 4 exons (Start: 105219437 bp and End: 105234831; Orientation: plus strand).

Two alternatively-spliced transcript variants encoding distinct proteins have been described, SIVA1 transcript variant 1, which is the predominant transcript variant with a cDNA containing 790 bp (codifying the SIVA1 protein), and the SIVA1 transcript variant 2 lacking the exon 2 with a cDNA containing 595 bp (codifying the SIVA2 protein).

Protein Description SIVA1 contains a unique amphipathic helical region (SAH) in the N-terminal region, a death domain homology region (DDHR) in the central part of the protein, and a Zinc finger-like structure at its C-terminal region. The SIVA2 isoform lacks the DDHR domain (Figure 1).

Figure 1. Schematic structure of SIVA1 and SIVA2 proteins. The amphipathic helical region (SAH) at the N-terminal region, a death domain homology region (DDHR) in the central section, and a Zinc finger-like (ZF) structure at its C-terminal region are illustrated. The amino acids (aa) positions are indicated.

SIVA1 (SIVA1, Apoptosis-Inducing Factor) Machado-Neto JA, Traina F


Figure 2. Intracellular localization of SIVA1 protein in a prostate cancer cell line. Confocal analysis of LNCaP cells displaying SIVA (green), DAPI (blue) and Actin (red) staining; MERGE shows the overlapped images. Scale bar, 10 µm. Note the cytoplasmatic and nuclear localization of SIVA1. Anti-SIVA1 (sc-7436) was from Santa Cruz Biotechnology, (Santa Cruz, CA, USA), Phalloidin (A12379) and DAPI (P-36931) were from Invitrogen (Carlsbad, CA, USA). Personal data.

Expression Ubiquitous.

Localisation SIVA1 is found in the nucleus and cytoplasm (Figure 2).

Function The proapoptotic function of SIVA1 is well elucidated and characterized. SIVA1 binds to death receptors, including CD27 and TNFRSF18, and plays a role in the transduction of the proapoptotic signal by the extrinsic pathway (Prasad et al., 1997; Spinicelli et al., 2002). SIVA1 interacts with BCL2 and BCL-XL, abrogates their antiapoptotic functions and modulates the intrinsic apoptosis pathway (Chu et al., 2004; Chu et al., 2005). In addition, SIVA1 associates with XIAP and regulates the apoptosis mediated by NFkB and JNK signaling (Resch et al., 2009). The SIVA gene is a transcription target of p53, p73 and E2F1 and is

upregulated under stress or following DNA damage (Ray et al., 2011; Fortin et al., 2004). Recently, novel partners and functions have been attributed to SIVA1. SIVA1 binds to and regulates p53 stability by acting as an adapter protein between p53 and MDM2, and participates in an auto-regulatory feedback loop between p53 and SIVA1 (Du et al., 2009; Mei and Wu, 2012). SIVA1 associates with ARF, enabling its ubiquitination and degradation; this mechanisms also regulates the p53/MDM2 signaling pathway (Wang et al., 2013). Finally, SIVA1 is a novel adaptor protein that promotes Stathmin 1/CaMKII interaction. SIVA1 inhibits Stathmin 1 activity through Stathmin 1 phosphorylation at serine 16, which results in reduced cell migration and metastasis by stabilizing microtubules of tumor cells (Li et al., 2011). The main functions and signaling pathways of SIVA1 are illustrated in Figure 3.



Figure 3. SIVA1 signaling pathway. (1) SIVA1 binds to death receptors and modulates the extrinsic apoptosis pathway. (2) SIVA 1 binds to BCL2 proteins family, inhibits the antiapoptotic proteins, BCL2 and BCL-XL, and leads to proapoptotic BAD protein oligomerization, and modulates the intrinsic apoptosis pathway. (3) SIVA1 binds to the XIAP protein and balances the proapoptotic and antiapoptotic signaling through the JNK and NFkB pathway, respectively, and modulates the extrinsic apoptosis pathway. (4) SIVA1 promotes Stathmin 1/CaMKII interaction, Stathmin 1 phosphorylation and inhibition, and modulates microtubule dynamics. (5) The SIVA1 gene is a transcription target of p53, p73 and E2F1. (6) SIVA1 protein acts as an adapter protein between p53 and MDM2, and promotes p53 ubiquitination. (7) SIVA1 acts as an ARF E3 ubiquitin ligase and regulates cell proliferation by the ARF/p53/MDM2 pathway. Abbreviations: P, phosphorylation; Ac, acetylation; Ub, ubiquitination. Figure was produced using Servier Medical Art. The binding partners of SIVA1 are: CD27: SIVA1 was initially identified by two-hybrid (Y2H) screening using CD27 as a bait, and its interaction was confirmed by immunoprecipitation (IP) of 293 cells co-expressing both proteins (Prasad et al., 1997). In agreement, Yoon et al. found that murine Siva1 and Siva2 also bind to CD27 (Yoon et al., 1999). c-abl oncogene 2, non-receptor tyrosine kinase (ABL2): Y2H screening using ABL2 (previously known as ARG) as the bait identified SIVA1 as a binding partner. This protein association was confirmed by IP of MCF7 cells co-expressing FLAG-ABL2 and GFP-SIVA1 (Cao et al., 2001). Tumor necrosis factor receptor superfamily, member 18 (TNFRSF18): TNFRSF18 (previously known as GITR) presents high homology with CD27. The interaction between TNFRSF18 and SIVA1 was identified using GST pull down and IP assays (Spinicelli et al., 2002). BCL2-like 1 (BCL-XL): The association of BCL-XL and SIVA1 was first identified using purified GST-SIVA and BCL-XL proteins and confirmed by GST pull down assays using GST-SIVA1 in 293

cells expressing the GFP-BCL-XL protein (Xue et al., 2002). Later on, Chu et al. reported that the SAH region of SIVA1 was sufficient to specifically interact with BCL-XL (Chu et al., 2004). B-cell CLL/lymphoma 2 (BCL2): The association of BCL2 and SIVA1 was verified using GST pull down assays with GST-SIVA in Cos-7 cells overexpressing full-length BCL2 protein, and this interaction occurred at the SAH region of SIVA1 (Chu et al., 2004). CD4: Y2H screen using cytoplasmic domain of CD4 as the bait identified SIVA1. This protein interaction was confirmed by in vitro binding assays with GST-SIVA1. The interaction was mapped through GST pull-down assay using GST tagged deletion mutants of SIVA1; the C-terminal region of SIVA1 binds to the cytoplasmic domain of CD4 (Py et al., 2007). Lysophosphatidic acid receptor 2 (LPAR2): Y2H screening using the C-terminal region of LPAR2 as the bait identified SIVA1. GST pull-down assays confirmed this protein association and the SIVA1 C-terminal region (aa 139-175) is required for this interaction (Lin et al., 2007).



Table 1. Comparative identity of human SIVA1 with other species. Source: homologene.

Pyrin (MEFV): Y2H screening using Pyrin as the bait identified SIVA1 binding, and this association was confirmed by IP. Using deletion mutants of Pyrin and of SIVA1 or SIVA2, the C-terminal, rfp and SRPY domain of pyrin were found to interact with the N-terminal region of SIVA (Balci-Peynircioglu et al., 2008). X-linked inhibitor of apoptosis (XIAP): Y2H screening using XIAP as the bait identified SIVA1 binding, and this protein association was confirmed by IP of 293 cells co-expressing both proteins (Resch et al., 2009). FHL1 four and a half LIM domains 1 (FHL1): Y2H screening using the SLIMMER isoform of FHL1 as the bait identified SIVA; and this protein association was confirmed by IP. Three different isoforms of FHL1 were used in a Y2H assay for protein interaction mapping, SIVA1 binds only with the SLIMMER and not with FHL1 and KyoT2 isoforms (Cottle et al., 2009). p53: The interaction between p53 and SIVA1 was tested by IP using H1229 cells co-expressing FLAG-p53 and GFP-SIVA1 and confirmed by IP using endogenous proteins from A549 cells. GST pull-down assays indicate that SIVA1 binds to p53 using its N-terminal region and DDHR, while p53 binds to SIVA1 via its DBD domain (Du et al., 2009). Tyrosine kinase 2 (TYK2): Y2H screening using TYK2 as the bait identified SIVA1 binding, and this association was confirmed by IP of 293 cells co-expressing FLAG-SIVA1 and full-length TYK2. The SIVA1 N-terminal region binds to TYK2, as demonstrated by IP of 293T cells overexpressing GFP tagged deletion mutants of SIVA1 and FLAG-TYK2 (Shimoda et al., 2010). Stathmin 1: Y2H screening using SIVA1 as bait identified Stathmin 1, and this association was confirmed by IP of U2OS cells co-expressing

exogenous or endogenous SIVA1 and Stathmin 1 proteins (Li et al., 2011). Cyclin-dependent kinase inhibitor 2A (CDKN2A) , also known as ARF: The ARF and SIVA interaction was tested by IP assays of H1229 cells containing FLAG-SIVA1 and GFP-ARF, and purified recombinant proteins were used for confirmation. The protein interaction mapping was performed by GST pull down assays using deletion mutants of SIVA1 and ARF overexpressed in 293 cells. SIVA1 binds to ARF by its N-terminal region and DDHR, while the residue aa 21-64 of ARF is required (Wang et al., 2013).

Homology SIVA1 shares high homology (around 40%) in its DDHR domain with the FADD and RIP proteins. SIVA1 also shares a high homology with different species (Table 1).

Mutations Mutations in the SIVA1 gene are rare, only six missense and one nonsense mutations are reported at COSMIC (Catalogue of somatic mutations in cancer).

Implicated in Breast cancer Note In breast cancer cells, SIVA1 acts synergistically with cisplatin in inducing apoptosis (Chu et al., 2005). Recently, SIVA1 protein has been reported to be downregulated in primary and metastatic breast cancer tumors and SIVA 1 negatively correlates with Stathmin 1 activity (Li et al., 2011). SIVA1 silencing augments metastasis in a xenograft breast cancer model (Li et al., 2011).



Acute lymphoid leukemia Note In acute lymphoid leukemia cell lines, SIVA1 overexpression induces apoptosis (Py et al., 2004), while SIVA1 inhibition reduces apoptosis (Resch et al., 2009).

Colorectal cancer Note In colorectal cancer samples, using a DNA array approach, SIVA1 has been shown to be downregulated when compared to normal tissue (Okuno et al., 2001). In colon cancer cell lines, SIVA1 was found to be a transcriptional target of p53 and E2F1 and to participate in the apoptosis induced by MDM2 inhibition (Ray et al., 2011). In addition, SIVA1 silencing reduces apoptosis in a p53-dependent manner in colon cancer cells treated with cisplatin (Barkinge et al., 2009).

Osteosarcoma Note In a xenograft osteosarcoma model, SIVA1 silencing increases p53 stability and augments the tumor growth (Du et al., 2009). In osteosarcoma cell lines, SIVA1 silencing increases cell migration and metastasis, while SIVA1 overexpression has an opposite effect (Li et al., 2011).

Prostate cancer Note In a study focused on the identification of genes modulated in prostate cancer cells under apoptosis, SIVA1 transcripts were found to be upregulated. This finding indicates a possible role of SIVA1 in the apoptotic pathway of prostate cancer cells (Lin and Ying, 1999).

To be noted Note SIVA1 was initially identified as a potent protein in the induction of apoptosis, which led it to be given a similar name to the Hindu god of destruction, Shiva (Prasad et al., 1997). In 2009, the paradigm that SIVA1 has a function strictly related to apoptosis was broken when its role in p53 stability was reported. More recently, among the new roles proposed for SIVA1 are cell proliferation, migration and metastasis (Du et al., 2009; Mei and Wu, 2012).

References Prasad KV, Ao Z, Yoon Y, Wu MX, Rizk M, Jacquot S, Schlossman SF. CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6346-51

Lin S, Ying SY. Differentially expressed genes in activin-induced apoptotic LNCaP cells. Biochem Biophys Res Commun. 1999 Apr 2;257(1):187-92

Yoon Y, Ao Z, Cheng Y, Schlossman SF, Prasad KV. Murine Siva-1 and Siva-2, alternate splice forms of the mouse Siva gene, both bind to CD27 but differentially transduce apoptosis. Oncogene. 1999 Nov 25;18(50):7174-9

Cao C, Ren X, Kharbanda S, Koleske AJ, Prasad KV, Kufe D. The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress. J Biol Chem. 2001 Apr 13;276(15):11465-8

Okuno K, Yasutomi M, Nishimura N, Arakawa T, Shiomi M, Hida J, Ueda K, Minami K. Gene expression analysis in colorectal cancer using practical DNA array filter. Dis Colon Rectum. 2001 Feb;44(2):295-9

Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini R, Riccardi C. GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. Cell Death Differ. 2002 Dec;9(12):1382-4

Xue L, Chu F, Cheng Y, Sun X, Borthakur A, Ramarao M, Pandey P, Wu M, Schlossman SF, Prasad KV. Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6925-30

Chu F, Borthakur A, Sun X, Barkinge J, Gudi R, Hawkins S, Prasad KV. The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis. Apoptosis. 2004 Jan;9(1):83-95

Fortin A, MacLaurin JG, Arbour N, Cregan SP, Kushwaha N, Callaghan SM, Park DS, Albert PR, Slack RS. The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. J Biol Chem. 2004 Jul 2;279(27):28706-14

Py B, Slomianny C, Auberger P, Petit PX, Benichou S. Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway. J Immunol. 2004 Apr 1;172(7):4008-17

Chu F, Barkinge J, Hawkins S, Gudi R, Salgia R, Kanteti PV. Expression of Siva-1 protein or its putative amphipathic helical region enhances cisplatin-induced apoptosis in breast cancer cells: effect of elevated levels of BCL-2. Cancer Res. 2005 Jun 15;65(12):5301-9

Py B, Bouchet J, Jacquot G, Sol-Foulon N, Basmaciogullari S, Schwartz O, Biard-Piechaczyk M, Benichou S. The Siva protein is a novel intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Apoptosis. 2007 Oct;12(10):1879-92

Lin FT, Lai YJ, Makarova N, Tigyi G, Lin WC. The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival. J Biol Chem. 2007 Dec 28;282(52):37759-69

Balci-Peynircioglu B, Waite AL, Hu C, Richards N, Staubach-Grosse A, Yilmaz E, Gumucio DL. Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva. J Cell Physiol. 2008 Sep;216(3):595-602

Barkinge JL, Gudi R, Sarah H, Chu F, Borthakur A, Prabhakar BS, Prasad KV. The p53-induced Siva-1 plays a significant role in cisplatin-mediated apoptosis. J Carcinog. 2009;8:2



Cottle DL, McGrath MJ, Wilding BR, Cowling BS, Kane JM, D'Arcy CE, Holdsworth M, Hatzinisiriou I, Prescott M, Brown S, Mitchell CA. SLIMMER (FHL1B/KyoT3) interacts with the proapoptotic protein Siva-1 (CD27BP) and delays skeletal myoblast apoptosis. J Biol Chem. 2009 Sep 25;284(39):26964-77

Du W, Jiang P, Li N, Mei Y, Wang X, Wen L, Yang X, Wu M. Suppression of p53 activity by Siva1. Cell Death Differ. 2009 Nov;16(11):1493-504

Resch U, Schichl YM, Winsauer G, Gudi R, Prasad K, de Martin R. Siva1 is a XIAP-interacting protein that balances NFkappaB and JNK signalling to promote apoptosis. J Cell Sci. 2009 Aug 1;122(Pt 15):2651-61

Shimoda HK, Shide K, Kameda T, Matsunaga T, Shimoda K. Tyrosine kinase 2 interacts with the proapoptotic protein Siva-1 and augments its apoptotic functions. Biochem Biophys Res Commun. 2010 Sep 17;400(2):252-7

Li N, Jiang P, Du W, Wu Z, Li C, Qiao M, Yang X, Wu M. Siva1 suppresses epithelial-mesenchymal transition and

metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules. Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12851-6

Ray RM, Bhattacharya S, Johnson LR. Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. Apoptosis. 2011 Jan;16(1):35-44

Mei Y, Wu M. Multifaceted functions of Siva-1: more than an Indian God of Destruction. Protein Cell. 2012 Feb;3(2):117-22

Wang X, Zha M, Zhao X, Jiang P, Du W, Tam AY, Mei Y, Wu M. Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nat Commun. 2013;4:1551


Machado-Neto JA, Traina F. SIVA1 (SIVA1, Apoptosis-Inducing Factor). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):334-339.

Gene Section Review



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OPEN ACCESS JOURNAL

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila)) Behnam Nabet, Jonathan D Licht

Feinberg School of Medicine, Northwestern University, Hematology/Oncology Division, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA (BN, JDL)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SPRY1ID51064ch4q28.html DOI: 10.4267/2042/53647


Abstract Review on SPRY1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: hSPRY1

HGNC (Hugo): SPRY1

Location: 4q28.1

DNA/RNA Description SPROUTY1 (SPRY1) is located on the plus strand of chromosome 4 (124319541-124324915) and contains three exons (Figure 1A). The third exon is the coding exon.

Transcription Four transcript variants exist for SPRY1, all of which encode the same protein (according to UCSC genome browser (hg19)). Transcript variant 1 contains three exons, the last of which is the coding exon. Transcript variant 2 lacks exon 2 but retains the same coding exon as transcript variant 1. Transcript variants 3 and 4 also lack exon 2, have alternative promoters, and retain the same third coding exon (Figure 1B).

Protein Description SPRY1 is a member of the SPRY gene family, which is composed of four genes (SPRY1, SPRY2, SPRY3, and SPRY4). SPRY1 protein is composed of 319 amino acids, which include a conserved serine-rich motif and a conserved cysteine-rich domain (Figure 1C). The C-terminal cysteine-rich domain of SPRY1 contains 23 cysteine residues, 19 of which are shared among the four family members (reviewed in Guy et al., 2009). This cysteine-rich domain facilitates homo- and heterodimer formation between SPRY proteins (Ozaki et al., 2005). SPRY1 functions as a regulator of fundamental signaling pathways and its activity is regulated by post-translational modifications. Spry1 is phosphorylated in response to the growth factors, fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) (Mason et al., 2004). Xenopus xSpry1 is phosphorylated on the tyrosine 53 (Tyr53) residue in response to FGF treatment (Hanafusa et al., 2002). The xSpry1 Y53F mutant, which prevents this phosphorylation event, functions as a dominant-negative suggesting that phosphorylation is required for xSpry1 inhibitory activity toward growth signaling pathways (Hanafusa et al., 2002).

SPRY1 (Sprouty Homolog 1, Antagonist Of FGF Signaling (Drosophila))

Nabet B, Licht JD


Figure 1. SPROUTY1 (SPRY1) genomic context, transcript variants, and protein structure. (A) UCSC genome browser (hg19) snapshot of SPRY1 genomic context on chromosome 4q28.1. Image modified from: UCSC genome Bioinformatics. (B) UCSC genome browser (hg19) snapshot of the four SPRY1 transcripts. All transcripts retain the same coding exon. Image modified from: UCSC genome Bioinformatics. (C) Schematic of SPRY1 protein. Highlighted is the conserved N-terminal tyrosine 53 (Y53) that is phosphorylated in response to growth factor treatment, the serine-rich motif (SRM) that is phosphorylated upon growth factor treatment, and the conserved C-terminal cysteine-rich domain (CRD).

Serine residues of Spry1 are also phosphorylated in response to FGF (Impagnatiello et al., 2001). Finally, Spry1 can be palmitoylated, and serves as a possible mechanism of membrane localization (Impagnatiello et al., 2001).

Expression Spry1 is expressed in localized domains throughout organogenesis in the developing mouse embryo and in adult tissues (Minowada et al., 1999). Spry1 is expressed during the development of the brain, salivary gland, lung, digestive tract, lens, and kidney (Minowada et al., 1999, Zhang et al., 2001, Boros et al., 2006). Notably, Spry1 is expressed in the developing mouse kidney at the condensing mesenchyme and the ureteric tree (Gross et al., 2003). During mouse embryonic development Spry1 expression patterns strongly correlate with regions of FGF expression, which may directly promote Spry1 gene activation (Minowada et al., 1999). For example, Spry1 expression is induced in response to FGF8 in explant cultures of the mouse mandibular arch (Minowada et al., 1999). Spry1 expression is dynamically regulated in response to environmental stimuli, although the kinetics of activation vary depending on the specific

cell line or stimulus used. Serum starved NIH-3T3 cells treated with FGF, PDGF, epidermal growth factor (EGF) or phorbol 12-myristate-13-acetate (PMA), upregulate Spry1 mRNA expression 30-60 minutes after stimulation (Ozaki et al., 2001). However, at time-points beyond 2 hours, Spry1 mRNA expression is downregulated in serum-starved NIH-3T3 cells treated with FGF (Gross et al., 2001). Taken together these results may reflect a transient burst of Spry1 mRNA induction in response to growth factor signaling. In mouse microvascular endothelial cells (1G11), Spry1 mRNA expression is modulated as cells are serum deprived and stimulated with FGF. Spry1 expression increases upon serum starvation, decreases after 2 hours of FGF treatment, and then increases after 6-18 hours of FGF treatment (Impagnatiello et al., 2001). Spry1 mRNA expression is increased in Th1 cells upon activation of T-cell receptor (TCR) signaling pathways (Choi et al., 2006). SPRY1 protein expression increases in U937 cells upon interferon α or β treatment (Sharma et al., 2012). Finally, SPRY1 mRNA expression increases when human umbilical vein endothelial cells


Nabet B, Licht JD


(HUVECs) are subject to hypoxic conditions (Lee et al., 2010). Spry1 activity is also regulated by transcription factors such as Wilms Tumor 1 (WT1), which binds directly to the Spry1 promoter to activate its expression (Gross et al., 2003). Furthermore, Spry1 expression is directly repressed by microRNA-21 (miR-21) (Thum et al., 2008). Importantly, miR-21 mediated repression of Spry1 leads to increased Ras-extracellular signal regulated kinase (Erk) signaling pathway activation causing cardiac fibrosis and dysfunction (Thum et al., 2008).

Localisation SPRY1 is primarily expressed in the cytoplasm and its localization to the plasma membrane is modulated upon serum deprivation and growth factor treatment. Impagnatiellio et al. demonstrated that in freely growing HUVECs, SPRY1 is localized to perinuclear and vesicular structures as well as the plasma membrane. Upon serum deprivation, SPRY1 remains cytoplasmic but is no longer detected at the plasma membrane. In response to FGF treatment, SPRY1 is again localized to the plasma membrane (Impagnatiello et al., 2001). Similarly, ectopic Spry1 in COS-1 cells translocates to membrane ruffles upon EGF treatment (Lim et al., 2002).

Function Elegant studies in Drosophila identified dSpry as a novel inhibitor of FGF and EGF signaling pathway activation during tracheal branching, oogenesis, and eye development, with specificity towards regulating the Ras-Erk cascade (Hacohen et al., 1998; Casci et al., 1999; Kramer et al., 1999; Reich et al., 1999). Similarly, subsequent studies using mammalian cell lines and mouse models revealed that SPRY1 negatively regulates receptor tyrosine kinase (RTK) signaling pathway activation in various cellular contexts. As a result, SPRY1 controls organ development and fundamental biologic processes including cell proliferation, differentiation, survival, and angiogenesis (reviewed in Mason et al., 2006; Edwin et al., 2009). In vivo loss-of-function experiments in mice demonstrated that Spry1 is a key regulator of proper organ and tissue development. Spry1 knockout (Spry1-/-) mice have striking defects in branching morphogenesis of the kidney, develop kidney epithelial cysts, and a disease resembling the human condition known as congenital anomalies of the kidney and urinary track (Basson et al., 2005; Basson et al., 2006). Conditional deletion of Spry1 in satellite cells demonstrated that Spry1 is required for the muscle stem cell quiescence during muscle cell regeneration as well as the maintenance of muscle stem cell quiescence during ageing (Shea et

al., 2010; Chakkalakal et al., 2012). Studies conditionally deleting both Spry1 and Spry2 revealed that Spry1 and Spry2 are also critical regulators of proper lens and cornea, as well as brain development. The conditional deletion of the combination of Spry1 and Spry2 results in lens and cornea defects, and cataract formation (Kuracha et al., 2011; Shin et al., 2012). Spry1 and Spry2 conditional double knockout mutants lack proper patterning of the murine brain, and altered gene expression downstream of Fgf signaling pathway activation (Faedo et al., 2010). SPRY family members including SPRY1 function as inhibitors of Ras-Erk signaling, although the point at which SPRY inhibits pathway activation remains controversial (reviewed in Mason et al., 2006). In the developing mouse kidney, Spry1 antagonizes the glial cell line-derived neurotrophic factor (GDNF)/Ret signaling pathway to control Erk activation (Basson et al., 2005). Similarly, conditional deletion of the combination of Spry1 and Spry2 in the murine lens leads to elevated Erk activation, as well as activation of downstream FGF target genes (Kuracha et al., 2011; Shin et al., 2012). In cell lines, Spry1 regulates signaling pathway activation in response to various defined stimuli. Spry1 inhibits Ras-Erk pathway activation in response to growth factors including FGF, PDGF, and VEGF, correlating with the ability of Spry1 to control cell proliferation and differentiation (Gross et al., 2001; Impagnatiello et al., 2001). By contrast, overexpression of SPRY1 in HeLa cells leads to increased Ras-Erk pathway activation in response to EGF (Egan et al., 2002). Recent evidence demonstrates that SPRY1 is involved in inhibiting ERK and p38 MAPK activation in response to interferons, limiting expression of interferon-stimulated genes and decreasing interferon-mediated biologic responses (Sharma et al., 2012). Growing evidence also links the SPRY family as critical regulators of phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB, also known as AKT) and phospholipase C gamma (PLCγ)- protein kinase C (PKC) pathway activation. In an inner medullary collecting duct cell line, Spry1 knockdown results in enhanced and prolonged phosphorylated, activated Akt in response to GDNF treatment (Basson et al., 2006). Spry1 binds to PLCγ and inhibits PLCγ pathway activation, resulting in decreased inositol triphosphate (IP3), calcium, and diacylglycerol (DAG) production (Akbulut et al., 2010). SPRY1 regulates TCR signaling pathway activation in a cell-type specific manner. In Th1 cells (Choi et al., 2006) and CD4+ cells (Collins et al., 2012), Spry1 inhibits signaling pathway activation, while in naïve T-cells Spry1 potentiates signaling pathway activation (Choi et al., 2006).


Nabet B, Licht JD


Spry1 binds to numerous signaling intermediates including linker of activated T-cells (LAT), PLCγ1, and c-Cbl to suppress Ras-Erk, nuclear factor of activated T-cells (NFAT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway activation (Lee et al., 2009).

Implicated in Breast cancer Note SPRY1 is significantly downregulated in the majority of breast cancer cases. This down-regulation was observed by comparing the expression of SPRY1 in breast cancer tumors and matched normal tissues using cDNA arrays (39/50 (78%) of paired samples) and quantitative real-time PCR (qRT-PCR) (18/19 (94%) of paired samples) (Lo et al., 2006). This data suggests that SPRY1 has tumor suppressive activity in breast cancer.

Clear cell renal cell carcinoma (ccRCC) Note Gene expression profiling of 29 ccRCC patient tumors revealed that SPRY1 expression serves as a prognostic biomarker associated with good outcome (Takahashi et al., 2001).

Embryonal rhabdomyosarcoma subtype (ERMS) Note cDNA microarray and Affymetrix microarray experiments revealed that SPRY1 mRNA expression is elevated in ERMS tumors compared to alveolar rhabdomyosarcoma subtype (RMS) tumors. Oncogenic Ras mutations leading to elevated Ras-Erk pathway activation in ERMS cell lines, result in increased SPRY1 protein expression. Inhibition of SPRY1 in ERMS cell lines decreases cell growth, survival and xenograft formation (Schaaf et al., 2010). This data suggests that in ERMS tumors driven by oncogenic Ras with elevated SPRY1 expression, targeting SPRY1 may prove to be efficacious.

Glioma Note Analysis of a glioma dataset containing expression data from 276 tumor samples revealed that SPROUTY (SPRY1, SPRY2, and SPRY4) genes are coordinately upregulated in EGFR amplified gliomas (Ivliev et al., 2010). The role and significance of SPRY1 in glioma has not been functionally addressed.

Hepatocellular carcinoma Note An initial study comparing hepatocellular carcinoma tumors with non-tumor livers, found that SPRY2 was significantly downregulated, while SPRY1 was not significantly downregulated in tumor tissue (Fong et al., 2006). qRT-PCR analysis of tissues from hepatocellular carcinoma patients revealed that SPRY1 expression levels are upregulated in 68% of patients, while SPRY2 and SPRY4 are commonly downregulated (79% and 75%, respectively). The upregulated SPRY1 levels were found in patients that did not display cirrhosis in their non-tumor tissue (Sirivatanauksorn et al., 2012). Recent evidence suggests that downregulation of SPRY1 in liver cancers occurs through miR-21 mediated repression (Jin et al., 2013).

Medullary thyroid carcinoma (MTC) Note SPRY1 has been proposed to have tumor suppressive activity in MTC. Spry1-/- mice display evidence of thyroid cell hyperplasia. Overexpression of Spry1 in an MTC cell line with low Spry1 expression reduces cell proliferation and tumor formation in xenografts through activation of the CDKN2A locus. The majority of human MTC samples tested display promoter methylation and downregulation of SPRY1 expression, in line with the proposed tumor suppressive role of SPRY1 in MTC (Macia et al., 2012).

Non-small cell lung cancer (NSCLC) Note SPRY1 mRNA expression is upregulated in NSCLC tumors compared to matched normal lung tissues, while SPRY2 mRNA expression is commonly downregulated (Sutterluty et al., 2007).

Ovarian cancer Note SPRY1 mRNA and protein expression varies in ovarian cancer cell lines. 4/7 cell lines (SKOV-3, CAOV-3, OV-90, and IGROV-1) display significantly lower SPRY1 protein expression, 1/7 cell lines (OVCAR-3) display significantly higher SPRY1 protein expression, and 2/7 cell lines (1A9 and A2780) display equivalent SPRY1 expression, as compared to normal primary human ovarian cells (Moghaddam et al., 2012).

Prostate cancer Note SPRY1 expression is downregulated in prostate cancer.


Nabet B, Licht JD


This downregulation was observed by comparing prostate cancer tissue to normal tissues using immunohistochemistry (40% of 407 of paired samples) and qRT-PCR (16/20 of samples assessed) (Kwabi-Addo et al., 2004). Moderate down-regulation of SPRY1 mRNA expression was also detected in an independent study (Fritzsche et al., 2006). In addition, SPRY1 protein levels are significantly decreased in prostate cancer cell lines (LNCaP, Du145, and PC-3) compared to prostatic epithelial cell lines. Overexpression of SPRY1 in LNCaP and PC-3 cells significantly inhibits cell growth (Kwabi-Addo et al., 2004). Increased methylation of the SPRY1 promoter and miR-21 mediated repression are in part responsible for abnormal SPRY1 silencing that occurs in prostate cancer (Kwabi-Addo et al., 2009; Darimipourain et al., 2011). More recently, it was confirmed in vivo that Spry1 and Spry2 function together to inhibit prostate cancer progression (Schutzman and Martin, 2012). The conditional deletion of both Spry1 and Spry2 in mouse prostate epithelium results in ductal hyperplasia and low-grade prostatic intraepithelial neoplasia. Notably, the deletion of Spry1 and Spry2 synergizes with reduction of Pten to increase the grade and invasiveness of prostate tumorigenesis through increased PI3K-Akt and Ras-Erk signaling pathway activation (Schutzman and Martin, 2012).

To be noted Note Acknowledgements: This work was supported by the National Institutes of Health grant CA59998 (J.D.L.) and the Lynn Sage and Northwestern Memorial Foundations (J.D.L.). B.N. is supported by a National Institutes of Health Cellular and Molecular Basis of Disease Training Grant (GM08061) and a Malkin Scholars Award from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

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Egan JE, Hall AB, Yatsula BA, Bar-Sagi D. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6041-6

Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol. 2002 Nov;4(11):850-8

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Gross I, Morrison DJ, Hyink DP, Georgas K, English MA, Mericskay M, Hosono S, Sassoon D, Wilson PD, Little M, Licht JD. The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development. J Biol Chem. 2003 Oct 17;278(42):41420-30

Kwabi-Addo B, Wang J, Erdem H, Vaid A, Castro P, Ayala G, Ittmann M. The expression of Sprouty1, an inhibitor of fibroblast growth factor signal transduction, is decreased in human prostate cancer. Cancer Res. 2004 Jul 15;64(14):4728-35

Mason JM, Morrison DJ, Bassit B, Dimri M, Band H, Licht JD, Gross I. Tyrosine phosphorylation of Sprouty proteins regulates their ability to inhibit growth factor signaling: a dual feedback loop. Mol Biol Cell. 2004 May;15(5):2176-88

Basson MA, Akbulut S, Watson-Johnson J, Simon R, Carroll TJ, Shakya R, Gross I, Martin GR, Lufkin T, McMahon AP, Wilson PD, Costantini FD, Mason IJ, Licht JD. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell. 2005 Feb;8(2):229-39

Ozaki K, Miyazaki S, Tanimura S, Kohno M. Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms. J Cell Sci. 2005 Dec 15;118(Pt 24):5861-71

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Collins S, Waickman A, Basson A, Kupfer A, Licht JD, Horton MR, Powell JD. Regulation of CD4⁺ ⁺ and CD8 effector responses by Sprouty-1. PLoS One. 2012;7(11):e49801

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Gene Section Review



INIST-CNRS

OPEN ACCESS JOURNAL

TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)) Maria V Bogachek, Ronald J Weigel

Department of Surgery, Carver College of Medicine, University of Iowa, 5269 CBRB, 500 Newton Road, Iowa City, Iowa 52242, USA (MVB), Department of Surgery, Carver College of Medicine, University of Iowa, 200 Hawkins Drive Room 1509 JCP, Iowa City, Iowa 52242, USA (RJW)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TFAP2CID42528ch20q13.html DOI: 10.4267/2042/53648


Abstract Review on TFAP2C, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: AP2-GAMMA, ERF1, TFAP2G, hAP-2g

HGNC (Hugo): TFAP2C

Location: 20q13.31

Note: TFAP2C is a member of the retinoic acid-inducible, developmentally regulated family of AP-2 factors. TFAP2C regulates cell growth and differentiation during ectodermal development (Qiao et al., 2012; Hoffman et al., 2007).

It plays a critical role in establishing the luminal phenotype of normal mammary cells during their differentiation process.

TFAP2C was shown to be involved in regulation of ESR1 and luminal - associated genes in breast cancer (Woodfield et al., 2010).

TFAP2C maintains breast cancer luminal phenotype through the induction of luminal-

associated genes and repression of genes characteristic of the basal subtype.

DNA/RNA Description TFAP2C consists of 7 encoding exons. The open reading frame of the coding region is 1353 bp. TFAP2C cDNA was isolated in 1996 (Williamson et al., 1996) and predicted protein was conserved with TFAP2A DNA-binding and dimerization domains, and differs in the N-terminal activation domain. The promoter lacks canonical binding sites for basal transcription factors such as TATA and CCAAT boxes, but contains a cluster of CpG islands and may rely on an initiator element for transcription (Li et al., 2002). A potential trophoblast cell-specific regulatory element located approximately 6 kb upstream of the murine Tfap2c gene transcription start site (Li and Kellems, 2003).

Transcription 3 splice variants are described (Ensembl).

Pseudogene No pseudogenes are reported.

TFAP2C human gene including promoter, 7 exons (blue rectangles) and 6 introns. Modified from Entrez Gene (Genomic DNA).

TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma))

Bogachek MV, Weigel RJ


Assignment of TFAP2C functional domains. AA: aminoacids, K10: SUMOylation site, AD: activation domain, Di/DBD: dimerization domain/DNA binding domain (adapted from Williams and Tjian, 1991).

Protein Note Active TFAP2C forms consist of homo - and heterodimers and play an important role in activation of retinoic acid-mediated differentiation including development of the eyes, face, body wall, limbs, neural tube (Hoffman et al., 2007; Li and Cornell, 2007). Placental defect and embryonic death were reported as results of TFAP2C total knockdown. TFAP2C protein was purified in 1997 (McPherson et al., 1997) from ESR1 - positive cell line, was designed as ERF1. TFAP2C, 450-aa protein, has 48 kDa molecular mass. TFAP2C has 65% sequence homology to TFAP2A overall and 76% identity in C-terminal part. The consensus site from the ChIP-seq data, SCCTSRGGS (S=G/C, r=A/G), is consistent with the optimal binding site, GCCTGAGGG, which was determined by in vitro PCR-assisted binding site selection (Woodfield et al., 2010). Estrogen receptor-alpha (ESR1) and HER2/c-erbB2 genes are regulated by TFAP2C (Bosher et al., 1995; McPherson et al., 1997; Delacroix et al., 2005; Woodfield et al., 2007) along with genes associated with luminal phenotype of breast cancer (Woodfield et al., 2010). Activity of TFAP2C at specific target genes depends upon epigenetic chromatin structure. The combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ESR1 gene in ESR1-negative breast cancer cells (Woodfield et al., 2009). TFAP2C repressed CD44 expression in basal-derived breast cancer (Spanheimer et al., 2013a). TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides (Kulak et al., 2013). Wwox tumor suppressor protein inhibits TFAP2C oncogenic activity by sequestering it in the cytoplasm (Aqeilan et al., 2004). Reporter and chromatin immunoprecipitation assays demonstrated a direct, functional interaction by TFAP2C at the CDKN1A proximal promoter.

TFAP2C silencing coincided with acquisition of an active chromatin conformation at the CDKN1A locus and increased gene expression (Gee et al., 2009). TFAP2C SUMOylation modification was described in mammalian cells and SUMO site was mapped to conserved lysine 10 (Eloranta and Hurst, 2002). Epithelial hyperplasia and impaired differentiation were reported in Tfap2c overexpressing transgenic mice (Jäger et al., 2003).

Description A helixloop-helix motif in the DNA binding domain binds to GC-rich consensus site, SCCTSRGGS (S=G/C, R=A/G) (Woodfield et al., 2010), in the promoters of target genes and mediates TFAP2C specific transcriptional activity.

Expression TFAP2C is widely expressed within secondary outgrowths in the human mammary gland by 19 weeks gestation. In the adult mammary gland TFAP2C expression can be found in epithelial and myoepithelial compartments. TFAP2C expression was reported in 16-40 weeks placenta, 5-10 weeks decidu and chorion (Li et al., 2002). TFAP2C is expressed in gonocytes at weeks 12-37 of gestation, indicating a role of this transcription factor in fetal germ cell development. TFAP2C and c-KIT, a known target of AP-2 transcription factors, were coexpressed in gonocytes, making a direct regulation possible. With increasing differentiation of fetal testis, gradual downregulation of TFAP2C from the 12th to 37th week of gestation was observed. Furthermore, TFAP2C was expressed abundantly in 25/25 IGCNUs, 52/53 testicular seminomas, 10/10 metastatic seminomas, 9/9 extragonadal seminomas and 5/5 dysgerminomas (Pauls et al., 2005). Normal tissues with TFAP2C expression: colon, lymph node, brain, heart, kidney, liver, lung, thyroid, adrenal gland, ovary, prostate, testis.

Localisation Nuclear.




Function It plays a role in the development of the eyes, face, body wall, limbs, and neural tube (Hoffman et al., 2007; Li and Cornell, 2007). Deletion of Tcfap2c during development resulted in a specific reduction of upper layer neurons in the occipital cortex (Pinto et al., 2009). Conditional ablation of Tcfap2c results in a delay in skin development and abnormal expression of p63, K14, K1, filaggrin, repetin and secreted Ly6/Plaur domain containing 1, key genes required for epidermal development and differentiation (Guttormsen et al., 2008). Heterozygous Tfap2c-knockout mice were detected to have decreased body size while homozygous mice died at 7-9 days of embryonic development due to failure of proliferation of extraembryonic trophectodermal cells (Werling and Schorle, 2002). TFAP2C is also implicated in the regulation of the adenosine deaminase (ADA) gene, a gene involved in purine metabolism found expressed at the maternal-fetal interface (Werling and Schorle, 2002).

Homology Mouse, Tfap2c (Mus musculus: NP_033361.2) (NCBI). Predicted homology: chicken (Gallus gallus: XM_417497.4), zebrafish (Danio rerio: NM_001008576.1) (NCBI).

Mutations Germinal 2 patients with deletions of chromosome 20q13.2-q13.3 were reported to have feeding difficulties, microcephaly, facial dysmorphism with high forehead, broad nasal bridge, small chin and malformed ears, mild psychomotor retardation, and hypotonia (Geneviève et al., 2005).

Somatic 39 mutations were detected after analysis of 8164 samples (COSMIC: gene overview for TFAP2C) without direct links to certain diseases pathogenesis. Deletion analyses of the promoter and chloramphenicol acetyl transferase reporter gene assays indicate that the sequence between -746 and -575 is important for its expression in mammary carcinoma cell lines (Li et al., 2002). Combined mutation of the three putative Sp sites reduced promoter activity by 80% in trophoblast and nontrophoblast cells, demonstrating the functional importance of these sites in regulating

TFAP2C gene expression (Li and Kellems, 2003).

Implicated in Breast cancer Note TFAP2C plays a critical role in maintaining the luminal subtype of breast cancer. TFAP2C directly binds to promoters and activates ESR1 along with luminal-associated genes (Woodfield et al., 2010). TFAP2C repressed CD44 expression in basal-derived breast cancer (Spanheimer et al., 2013a). Regulation of Ret by TFAP2C occurs independently of ESR1 expression in breast carcinoma (Spanheimer et al., 2013b). TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides (Kulak et al., 2013).

Prognosis Resistance to Tamoxifen treatment and reduction of survival rate had correlation with TFAP2C overexpression (Guler et al., 2007). ERBB2-negative/AP-2-positive expression patients had a better prognosis than patients with ERBB2-positive/AP-2-positive tumors (Gee et al., 2009). In primary breast cancer specimens, high TFAP2C and low CD44 expression were associated with pCR after neoadjuvant chemotherapy and could be predictive of tumors that have improved response to neoadjuvant chemotherapy (Spanheimer et al., 2013a). Elevated expression levels of TFAP2C in breast tumors were reported as predictors of poor prognosis (Zhao et al., 2003) and advancing clinical grade (Sotiriou et al., 2006).

Seminomatous germ cell tumors Note Immunohistochemistry marker to the detection of germ cell tumors (Pauls et al., 2005).

Melanoma Note AP-2γ expression is lower in thick melanomas, it is associated with unfavourable histo-pathological parameters (increased vascularity, vascular invasion and mitoses) (Osella-Abate et al., 2012).

Pre-eclampsia Note Elevated TFAP2C concentrations are associated with human placental defects such as pre-eclampsia and intrauterine growth restriction (Kuckenberg et al., 2012).




TFAP2C target genes. Analysis was done by Ingenuity Systems. Red tone indicates genes repressed by TFAP2C and green indicates genes induced by TFAP2C. Insert: TFAP2C target genes RXR, RAR, and CRABP2 are involved in the retinoic acid signaling pathway (Woodfield et al., 2010).

Breakpoints See figure above.

References Williams T, Tjian R. Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins. Science. 1991a Mar 1;251(4997):1067-71

Williams T, Tjian R. Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991b Apr;5(4):670-82

Bosher JM, Williams T, Hurst HC. The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl

Acad Sci U S A. 1995 Jan 31;92(3):744-7

Williamson JA, Bosher JM, Skinner A, Sheer D, Williams T, Hurst HC. Chromosomal mapping of the human and mouse homologues of two new members of the AP-2 family of transcription factors. Genomics. 1996 Jul 1;35(1):262-4

McPherson LA, Baichwal VR, Weigel RJ. Identification of ERF-1 as a member of the AP2 transcription factor family. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4342-7

Eloranta JJ, Hurst HC. Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo. J Biol Chem. 2002 Aug 23;277(34):30798-804

Li M, Wang Y, Yu Y, Nishizawa M, Nakajima T, Ito S, Kannan P. The human transcription factor activation




protein-2 gamma (AP-2gamma): gene structure, promoter, and expression in mammary carcinoma cell lines. Gene. 2002 Nov 13;301(1-2):43-51

Werling U, Schorle H. Transcription factor gene AP-2 gamma essential for early murine development. Mol Cell Biol. 2002 May;22(9):3149-56

Jäger R, Werling U, Rimpf S, Jacob A, Schorle H. Transcription factor AP-2gamma stimulates proliferation and apoptosis and impairs differentiation in a transgenic model. Mol Cancer Res. 2003 Oct;1(12):921-9

Li M, Kellems RE. Sp1 and Sp3 Are important regulators of AP-2gamma gene transcription. Biol Reprod. 2003 Oct;69(4):1220-30

Zhao C, Yasui K, Lee CJ, Kurioka H, Hosokawa Y, Oka T, Inazawa J. Elevated expression levels of NCOA3, TOP1, and TFAP2C in breast tumors as predictors of poor prognosis. Cancer. 2003 Jul 1;98(1):18-23

Aqeilan RI, Palamarchuk A, Weigel RJ, Herrero JJ, Pekarsky Y, Croce CM. Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor. Cancer Res. 2004 Nov 15;64(22):8256-61

Delacroix L, Begon D, Chatel G, Jackers P, Winkler R. Distal ERBB2 promoter fragment displays specific transcriptional and nuclear binding activities in ERBB2 overexpressing breast cancer cells. DNA Cell Biol. 2005 Sep;24(9):582-94

Geneviève D, Sanlaville D, Faivre L, Kottler ML et al.. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet. 2005 Sep;13(9):1033-9

Pauls K, Jäger R, Weber S, Wardelmann E, Koch A, Büttner R, Schorle H. Transcription factor AP-2gamma, a novel marker of gonocytes and seminomatous germ cell tumors. Int J Cancer. 2005 Jun 20;115(3):470-7

Sotiriou C, Wirapati P, Loi S, Harris A, Fox S et al.. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006 Feb 15;98(4):262-72

Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M, Huebner K. Wwox and Ap2gamma expression levels predict tamoxifen response. Clin Cancer Res. 2007 Oct 15;13(20):6115-21

Hoffman TL, Javier AL, Campeau SA, Knight RD, Schilling TF. Tfap2 transcription factors in zebrafish neural crest development and ectodermal evolution. J Exp Zool B Mol Dev Evol. 2007 Sep 15;308(5):679-91

Li W, Cornell RA. Redundant activities of Tfap2a and Tfap2c are required for neural crest induction and development of other non-neural ectoderm derivatives in zebrafish embryos. Dev Biol. 2007 Apr 1;304(1):338-54

Woodfield GW, Horan AD, Chen Y, Weigel RJ. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling. Cancer Res. 2007 Sep 15;67(18):8439-43

Guttormsen J, Koster MI, Stevens JR, Roop DR, Williams T, Winger QA. Disruption of epidermal specific gene expression and delayed skin development in AP-2 gamma mutant mice. Dev Biol. 2008 May 1;317(1):187-95

Ailan H, Xiangwen X, Daolong R, Lu G, Xiaofeng D, Xi Q,

Xingwang H, Rushi L, Jian Z, Shuanglin X. Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells. BMC Cancer. 2009 Aug 11;9:279

Gee JM, Eloranta JJ, Ibbitt JC, Robertson JF, Ellis IO, Williams T, Nicholson RI, Hurst HC. Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti-hormone therapy and reduced patient survival. J Pathol. 2009 Jan;217(1):32-41

Pinto L, Drechsel D, Schmid MT, Ninkovic J et al.. AP2gamma regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex. Nat Neurosci. 2009 Oct;12(10):1229-37

Williams CM, Scibetta AG, Friedrich JK, Canosa M, Berlato C, Moss CH, Hurst HC. AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene. EMBO J. 2009 Nov 18;28(22):3591-601

Woodfield GW, Hitchler MJ, Chen Y, Domann FE, Weigel RJ. Interaction of TFAP2C with the estrogen receptor-alpha promoter is controlled by chromatin structure. Clin Cancer Res. 2009 Jun 1;15(11):3672-9

Woodfield GW, Chen Y, Bair TB, Domann FE, Weigel RJ. Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells. Genes Chromosomes Cancer. 2010 Oct;49(10):948-62

Kuckenberg P, Kubaczka C, Schorle H. The role of transcription factor Tcfap2c/TFAP2C in trophectoderm development. Reprod Biomed Online. 2012 Jul;25(1):12-20

Osella-Abate S, Novelli M, Quaglino P, Orso F, Ubezio B, Tomasini C, Berardengo E, Bernengo MG, Taverna D. Expression of AP-2α, AP-2γ and ESDN in primary melanomas: correlation with histopathological features and potential prognostic value. J Dermatol Sci. 2012 Dec;68(3):202-4

Qiao Y, Zhu Y, Sheng N, Chen J, Tao R, Zhu Q, Zhang T, Qian C, Jing N. AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning. Cell Res. 2012 Nov;22(11):1546-61

Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Spanheimer PM, Li T, Price DH, Domann FE, Weigel RJ. Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene. 2013 Aug 22;32(34):4043-51

Spanheimer PM, Askeland RW, Kulak MV, Wu T, Weigel RJ. High TFAP2C/low CD44 expression is associated with an increased rate of pathologic complete response following neoadjuvant chemotherapy in breast cancer. J Surg Res. 2013a Sep;184(1):519-25

Spanheimer PM, Woodfield GW, Cyr AR, Kulak MV, White-Baer LS, Bair TB, Weigel RJ. Expression of the RET proto-oncogene is regulated by TFAP2C in breast cancer independent of the estrogen receptor. Ann Surg Oncol. 2013b Jul;20(7):2204-12


Bogachek MV, Weigel RJ. TFAP2C (transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma)). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):346-350.

Gene Section Review



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USP1 (ubiquitin specific peptidase 1) Iraia García-Santisteban, Godefridus J Peters, Jose A Rodriguez, Elisa Giovannetti

Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Leioa, Spain (IGS, JAR), Department of Medical Oncology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands (GJP, EG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/USP1ID43072ch1p31.html DOI: 10.4267/2042/53649


Abstract Review on USP1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

Identity Other names: UBP

HGNC (Hugo): USP1

Location: 1p31.3

Local order: Based on Mapviewer, genes flanking USP1 are: - L1TD1 (LINE-1 type transposase domain containing 1); 1p31.3 - ANKRD38 (ankyrin repeat domain 38); 1p31.3 - USP1 (ubiquitin specific peptidase 1); 1p31.3 - DOCK7 (dedicator of cytokinesis 7); 1p31.3 - ANGPTL3 (angiopoietin-like 3); 1p31.1-p22.3.

DNA/RNA Note Structural organization of USP1 gene: USP1 gene is located on chromosome 1. 3 transcripts of this gene, encoding the same protein product, have been identified. The gene contains 14 distinct gt-ag introns.

Description Ubiquitin specific peptidase 1 is located at chromosome 1 in the region p31.3. USP1 was first cloned in 1998 as part of the Human Genome Project (Fujiwara et al., 1998).

Transcription USP1 transcription is controlled by different mechanisms. On one hand, USP1 mRNA levels fluctuate during the cell cycle, reaching a peak in S phase, and remaining low before and after it (Nijman et al., 2005). On the other hand, DNA damaging agents can repress USP1 transcription by a mechanism that involves p21 cyclin dependent kinase inhibitor (Rego et al., 2012). Transcription produces 10 different mRNAs, 6 alternatively spliced variants and 4 unspliced forms. There are 5 probable alternative promotors, 2 non overlapping alternative last exons and 9 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 5' end, overlapping exons with different boundaries. Efficacy of translation may be reduced by the presence of a shorter translated product (uORF) initiating at an AUG upstream of the main open reading frame.

Structural organization of USP1 protein. Cys and His boxes containing the catalytic residues (C90, H593, D751) are represented in green. The "degradation signal" (Degron) that mediates APC/CCdh1-mediated degradation of USP1 is shown in orange, also the location of the Serine 313 CDK phosphorylation site is highlighted. The diglycine motif (Gly-Gly) represented in purple constitutes the USP1 autocleavage site. Nuclear localization signals (NLSs) are illustrated in blue.

USP1 (ubiquitin specific peptidase 1) García-Santisteban I, et al.


Pseudogene No reported pseudogenes. Paralogs for USP1 gene include USP12, USP35, USP38, and USP46.

Protein Description USP1 gene encodes a 785 amino acid protein with a predicted molecular weight of 88,2 kDa (Fujiwara et al., 1998). USP1 belongs to the ubiquitin specific protease (USP) family of human deubiquitinases (DUBs). Like other members of its family, it harbours a highly conserved USP domain organization comprising a N-terminal Cys box and a C-terminal His box, which contain the catalytic residues (C90, H593 and D751) (Fujiwara et al., 1998; Villamil et al., 2012a; Békés et al., 2013). The enzymatic activity of USP1 alone is relatively low, but is enhanced upon binding to USP1 associated factor 1 (UAF1) (Cohn et al., 2007; Villamil et al., 2012a). The UAF1 binding region in USP1 is somewhat controversial, since two binding motifs have been proposed based on different experimental approaches. Villamil and co-workers proposed that the UAF1 binding region comprised residues 235-408 (Villamil et al., 2012b), but García-Santisteban et al. described that the binding motif was between amino acid residues 420-520 (García-Santisteban et al., 2012a). Further experimental evidence should clarify this controversy.

Expression USP1 protein levels can be regulated through different mechanisms that involve proteasome mediated degradation. On one hand, anaphase promoting complex/cyclosomeCdh1 (APC/CCdh1) recognizes the 295-342 amino acid region (Degron) in USP1, mediating its degradation by the proteasome (Cotto-Rios et al., 2011a). The serine 313 residue located in this region is phosphorylated by cyclin dependent kinases (CDKs), which might prevent USP1 degradation in mitosis (Cotto-Rios et al., 2011b). On the other hand, UV damage causes USP1 autocleavage at an internal diglycine motif (Gly-Gly) located in the C-terminal end of the protein. The resulting USP1 fragments are

subjected to proteasomal degradation (Huang et al., 2006; Piatkov et al., 2012).

Localisation The localization of USP1 is nuclear. USP1 bears two nuclear localization signals (NLSs) which mediate the import of the USP1/UAF1 complex to the cell nucleus, where it exerts its function (García-Santisteban et al., 2012b). USP1 also contains a nuclear export signal (NES, not indicated in the figure) that was shown to be functional in an export assay, but whose function in the context of the full length protein needs to be evaluated (García-Santisteban et al., 2012a).

Function USP1, together with UAF1, plays an important role in the DNA damage response, mainly in the Fanconi anemia (FA) pathway and in the process of translesion synthesis (TLS). Deubiquitination of FANCD2 and FANCI by the USP1/UAF1 complex is an essential step for the correct function of the FA pathway (Nijman et al., 2005; Sims et al., 2007). In addition, the USP1/UAF1 complex mediates the deubiqutination of Proliferating Cell Nuclear Antigen (PCNA), preventing the recruitment of low fidelity DNA polymerases in the absence of DNA damage (Huang et al., 2006). In addition to its DNA damage-related functions, USP1 has also been reported to deubiquitinate and stabilize three members of the family of inhibitors of DNA binding (ID) proteins (ID1, ID2 and ID3), and thus contributing to preserve the undifferentiated state of osteosarcoma cells (Williams et al., 2011).

Homology The USP1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.

Mutations Note A survey in the COSMIC mutation database (accession date: 16 September 2013) revealed a total of 40 mutations that lead to different modifications in different human tumors.



Cancer-associated mutations in USP1. Schematic representation of USP1 protein showing the position of cancer-associated USP1 mutations reported to date (September 2013) in the COSMIC mutation database. Missense amino acid substitutions are indicated in black, nonsense amino acid substitutions in red and frameshift insertion/deletions in blue. Synonymous amino acid substitutions have been omitted. The Table shows the detailed list of mutations, including the DNA modification (CDS Mutation), protein modification (AA Mutation), type of mutation and tissue.



Most of the modifications are missense mutations whose functional consequences need to be addressed.

Implicated in Osteosarcoma Note A recent study showed that USP1 mRNA and protein levels were elevated in a subset of primary osteosarcoma tumors, and that increased USP1 levels correlated with increased levels of its substrate ID2. This observation is consistent with the finding that USP1 deubiquitinates and stabilizes ID proteins, contributing to preserve the undifferentiated state of osteosarcoma cells.

Cytogenetics Comparative genomic hybridization (CGH) analyses found that the USP1 locus 1p31.3 was amplified in 26%-57% of osteosarcoma tumors (Ozaki et al., 2003; Stock et al., 2000).

Lung cancer Note One study reported lower USP1 mRNA and protein levels in lung cancer cells and tissues (Zhiqiang et al., 2012). However, most data support the view that USP1 is overexpressed in lung cancer. Thus, a survey in the Oncomine research edition database revealed that USP1 was overexpressed in 25% of the lung cancer microarray datasets available, while none of these studies reported significant downregulation of USP1 (García-Santisteban et al., 2013). In line with these data, immunohistochemical analysis on a NSCLC tissue microarray revealed USP1 overexpression (Liu et al., 2012). An association between USP1 overexpression with lung cancer was already demonstrated in a recent study on USP1 mRNA expression in NSCLC tissue and cell lines indicating that USP1 expression was higher in tumors and tumor-derived cells than in normal lung tissue (García-Santisteban et al., 2013).

Fanconi anemia (FA) Note Fanconi anemia (FA) is a rare hereditary disorder that results in congenital abnormalities, progressive bone marrow failure, DNA crosslinker hypersensitivity, genomic instability and increased susceptibility to cancer (Kee and D'Andrea, 2012). The disorder is the result of mutations in any of at least 15 genes that regulate the DNA repair pathway that corrects interstrand crosslinks (ICLs). USP1 cannot be considered a bona fide FA gene, since mutations in USP1 have not been identified in FA patients yet. However, recent evicence supports the view that USP1 is crucial for the correct regulation of the FA pathway.

Disruption of the USP1 gene in mice results in genomic instability and FA phenotype, and also leads to defects in hematopoietic stem cell maintenance (Kim et al., 2009; Parmar et al., 2010).

To be noted Note This work was supported by the Basque Country Government Department of Industry (grant number ETORTEK BioGUNE2010 to JAR), the Spanish Government MICINN (Ministerio de Ciencia e Innovacion) (grant number BFU2009-13245 to JAR), the University of the Basque Country (UFI11/20), Department of Education of the Basque Country Government Fellowship (to IG-S), the Netherlands Organization for Scientific Research, Veni grant (to EG) and CCA Foundation (grant number 2012-5-07 to EG and GJP).

References Fujiwara T, Saito A, Suzuki M, Shinomiya H, Suzuki T, Takahashi E, Tanigami A, Ichiyama A, Chung CH, Nakamura Y, Tanaka K. Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease. Genomics. 1998 Nov 15;54(1):155-8

Stock C, Kager L, Fink FM, Gadner H, Ambros PF. Chromosomal regions involved in the pathogenesis of osteosarcomas. Genes Chromosomes Cancer. 2000 Jul;28(3):329-36

Ozaki T, Neumann T, Wai D, Schäfer KL, van Valen F, Lindner N, Scheel C, Böcker W, Winkelmann W, Dockhorn-Dworniczak B, Horst J, Poremba C. Chromosomal alterations in osteosarcoma cell lines revealed by comparative genomic hybridization and multicolor karyotyping. Cancer Genet Cytogenet. 2003 Jan 15;140(2):145-52

Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D'Andrea AD, Bernards R. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005 Feb 4;17(3):331-9

Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 2006 Apr;8(4):339-47

Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007 Dec 14;28(5):786-97

Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7

Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA, Kutok JL, D'Andrea AD. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell. 2009 Feb;16(2):314-20

Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, Gilliland DG, D'andrea A. Hematopoietic stem cell defects



in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010 Jul;28(7):1186-95

Cotto-Rios XM, Jones MJ, Busino L, Pagano M, Huang TT. APC/CCdh1-dependent proteolysis of USP1 regulates the response to UV-mediated DNA damage. J Cell Biol. 2011a Jul 25;194(2):177-86

Cotto-Rios XM, Jones MJ, Huang TT. Insights into phosphorylation-dependent mechanisms regulating USP1 protein stability during the cell cycle. Cell Cycle. 2011b Dec 1;10(23):4009-16

Williams SA, Maecker HL, French DM, Liu J, Gregg A, Silverstein LB, Cao TC, Carano RA, Dixit VM. USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell. 2011 Sep 16;146(6):918-30

García-Santisteban I, Bañuelos S, Rodríguez JA. A global survey of CRM1-dependent nuclear export sequences in the human deubiquitinase family. Biochem J. 2012a Jan 1;441(1):209-17

Garcia-Santisteban I, Zorroza K, Rodriguez JA. Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex. PLoS One. 2012b;7(6):e38570

Kee Y, D'Andrea AD. Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest. 2012 Nov 1;122(11):3799-806

Liu Y, Luo X, Hu H, Wang R, Sun Y, Zeng R, Chen H. Integrative proteomics and tissue microarray profiling indicate the association between overexpressed serum proteins and non-small cell lung cancer. PLoS One. 2012;7(12):e51748

Piatkov KI, Colnaghi L, Békés M, Varshavsky A, Huang

TT. The auto-generated fragment of the Usp1 deubiquitylase is a physiological substrate of the N-end rule pathway. Mol Cell. 2012 Dec 28;48(6):926-33

Rego MA, Harney JA, Mauro M, Shen M, Howlett NG. Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor. Oncogene. 2012 Jan 19;31(3):366-75

Villamil MA, Chen J, Liang Q, Zhuang Z. A noncanonical cysteine protease USP1 is activated through active site modulation by USP1-associated factor 1. Biochemistry. 2012a Apr 3;51(13):2829-39

Villamil MA, Liang Q, Chen J, Choi YS, Hou S, Lee KH, Zhuang Z. Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1. Biochemistry. 2012b Nov 13;51(45):9112-23

Zhiqiang Z, Qinghui Y, Yongqiang Z, Jian Z, Xin Z, Haiying M, Yuepeng G. USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells. J Cancer Res Clin Oncol. 2012 Jul;138(7):1231-8

Bekes M, Huang T.. Ubiquitin-specific peptidase 1. Handbook of proteolytic enzymes. Volume 1. 3rd edition. Edited by Rawlings ND, Salvesen G.; 2013: 2079-2085.

Garcia-Santisteban I, Peters GJ, Giovannetti E, Rodriguez JA.. USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy. Mol Cancer. 2013 Aug 10;12:91. doi: 10.1186/1476-4598-12-91. (REVIEW)


García-Santisteban I, Peters GJ, Rodriguez JA, Giovannetti E. USP1 (ubiquitin specific peptidase 1). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):351-355.

Leukaemia Section Short Communication



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t(3;11)(q12;p15) NUP98/LNP1 Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0311q12p15ID1518.html DOI: 10.4267/2042/53650


Abstract Review on t(3;11)(q12;p15) NUP98/LNP1, with data on clinics, and the genes implicated.

Clinics and pathology Disease Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and T-cell acute lymphoblastic leukemia (T-ALL)

Phenotype/cell stem origin Six cases are available: one case of MDS, two cases of AML not otherwise specified, one M2-AML, and two T-ALL cases, one being a case of early T-cell precursor leukaemia (Romana et al., 2006; Chen et al., 2007; Gorello et al., 2008; Coustan-Smith et al., 2009; Lugthart et al., 2010).

Epidemiology There was 4 male and 2 female patients. Ages were: 3, 28, and 30 years in myeloid cases, and 16 and 36 years in T-ALLs.

Prognosis Data on prognosis is very scarce: two AML cases died 11 and 23 months after diagnosis, and the early T-cell precursor leukaemia phenotype, in this study of 17 cases with various karyotypes, was said to bear a poor prognosis, but no individual data is available (Coustan-Smith et al., 2009).

Cytogenetics Cytogenetics morphological The t(3;11)(q12;p15) was the sole anomaly in four

of six cases. +19 was found in one T-ALL.

Genes involved and proteins Note NUP98 was found fused to LNP1 in cases with molecular studies (Romana et al., 2006; Gorello et al., 2008).

LNP1 Location 3q12.2

Note Also named NP3 or LOC348801.

DNA/RNA Four exons, the first exon is non-coding.

Protein Protein of unknown function. 178 amino acids, 21 kDa.

NUP98 Location 11p15.4

Protein Component of nuclear pore complex. NUP98 is found in the nucleoplasmic and cytoplasmic sides of the nuclear pore complex, and functions as nuclear import and nuclear export mRNA factor. NUP98 has a role in the regulation of gene expression via EP300. NUP98 appears to be involved in mitotic spindle formation and cell cycle progression (review in Iwamoto et al., 2010).

t(3;11)(q12;p15) NUP98/LNP1 Huret JL


Result of the chromosomal anomaly Hybrid gene Description Nucleotide 1718 (exon 13) of NUP98 was fused in-frame with nucleotide 1248 (exon 2) of LNP1. The reciprocal LNP1-NUP98 fusion transcript was also present (Gorello et al., 2008).

Fusion protein Description The protein fuses the NUP98 FG repeat motifs and GLEBS-like motif to the entire LNP1, at the start of LNP1 exon 2 (Gorello et al., 2008).

References Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N, Talmant P, Bilhou-Nabera C, Mugneret F, Lafage-Pochitaloff M, Mozziconacci MJ, Andrieu J, Lai JL, Terre C, Rack K, Cornillet-Lefebvre P, Luquet I, Nadal N, Nguyen-Khac F, Perot C, Van den Akker J, Fert-Ferrer S, Cabrol C, Charrin C, Tigaud I, Poirel H, Vekemans M, Bernard OA, Berger R. NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique. Leukemia. 2006 Apr;20(4):696-706

Chen CC, Yang CF, Lee KD, You JY, Yu YB, Ho CH, Tzeng CH, Chau WK, Hsu HC, Gau JP. Complex

karyotypes confer a poor survival in adult acute myeloid leukemia with unfavorable cytogenetic abnormalities. Cancer Genet Cytogenet. 2007 Apr 15;174(2):138-46

Gorello P, Brandimarte L, La Starza R, Pierini V, Bury L, Rosati R, Martelli MF, Vandenberghe P, Wlodarska I, Mecucci C. t(3;11)(q12;p15)/NUP98-LOC348801 fusion transcript in acute myeloid leukemia. Haematologica. 2008 Sep;93(9):1398-401

Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009 Feb;10(2):147-56

Iwamoto M, Asakawa H, Hiraoka Y, Haraguchi T. Nucleoporin Nup98: a gatekeeper in the eukaryotic kingdoms. Genes Cells. 2010 Jun;15(7):661-9

Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Köhne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg B, Döhner H. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol. 2010 Aug 20;28(24):3890-8


Huret JL. t(3;11)(q12;p15) NUP98/LNP1. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):356-357.




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t(7;8)(p12;q24) /MYC Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0708p12q24ID2140.html DOI: 10.4267/2042/53651


Abstract Review on t(7;8)(p12;q24) /MYC, with data on clinics, and the genes implicated.

Clinics and pathology Disease Diffuse large B-cell lymphoma (DLBCL)

Epidemiology One case to date, a female patient aged 80 years (Bertrand et al., 2007).

Prognosis The patient died 6 months after diagnosis.

Cytogenetics Cytogenetics morphological A complex karyotype was found, with an i(6)(p10), a +20, and other abnormalities.

Genes involved and proteins Note Breakpoints occurred close to MYC in 8q24 and 100 kb from COBL and 1Mb from IKZF1 in 7p12. - COBL is an actin nucleator which uses its WH2 domains for binding actin, to promote actin filament formation. Role in neuromorphogenesis (dendrite formation and dendritic arborisation) (Schwintzer et al., 2011). - IKZF1 is a zinc finger transcription factor involved in both activation and repression of target

genes. IKZF1 is expressed during early embryonic hematopoiesis, including hematopoietic stem cells, lymphoid precursors, erythroid precursors, and myeloid precursors. It is also expressed in developing striatal neurons. In the adult, IKZF1 expression is mainly restricted to lymphopoietic tissues and peripheral blood leukocytes (review in John and Ward, 2011).

MYC Location 8q24.2

Protein DNA binding protein. Binds DNA as a heterodimer with MAX. Involved in various cellular processes including cell growth, proliferation, cell adhesion, apoptosis, angiogenesis, and stem cell behaviour modulation.

References Bertrand P, Bastard C, Maingonnat C, Jardin F, Maisonneuve C, Courel MN, Ruminy P, Picquenot JM, Tilly H. Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. Leukemia. 2007 Mar;21(3):515-23

John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011 May;48(9-10):1272-8

Schwintzer L, Koch N, Ahuja R, Grimm J, Kessels MM, Qualmann B. The functions of the actin nucleator Cobl in cellular morphogenesis critically depend on syndapin I. EMBO J. 2011 Jul 1;30(15):3147-59


Huret JL. t(7;8)(p12;q24) /MYC. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):358.




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t(2;3)(p21;q26) THADA/MECOM Jean-Loup Huret


Published in Atlas Database: November 2013

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0203p21q26ID1665.html DOI: 10.4267/2042/53652


Abstract Review on t(2;3)(p21;q26) THADA/MECOM, with data on clinics, and the genes implicated.

Identity Note This translocation is found in a subset of cases described in the card t(2;3)(p15-23;q26-27). Other subsets involve other genes, such as BCL11A in the t(2;3)(p16;q26) BCL11A/MECOM.

Clinics and pathology Disease Acute myeloid leukemia (AML)

Epidemiology One case to date, a 59-year old male patient with a M4-AML (Trubia et al., 2006).

Prognosis Clinical outcome in cases with the t(2;3)(p16;q26) BCL11A/MECOM and the case with the t(2;3)(p21;q26) THADA/MECOM (plotted together) was severe: "One patient is alive with active disease at 12 months, five patients died after 4-14 months" (Trubia et al., 2006).

Genetics Note MECOM was overexpressed.

Cytogenetics Cytogenetics morphological The t(2;3)(p21;q26) was the sole anomaly.

Genes involved and proteins THADA Location 2p21

Protein THADA is assumed to be involved it in the TRAIL-induced apoptosis. Truncated THADA have been found in thyroid adenomas; it would compete with normal THADA, thereby disturbing normal apoptosis of follicular cells (Rippe et al., 2003; Kloth et al., 2011).

MECOM Location 3q26

Note MECOM is also known as EVI1 or PRDM3; MECOM symbol means: "MDS1 and EVI1 complex locus".

Protein "EVI1" contains two domains of seven and three zinc finger motifs, respectively, a repression domain between the two sets of zinc fingers, and an acidic domain at its C-term.

t(2;3)(p21;q26) THADA/MECOM Huret JL


Sequence specific DNA binding protein. Interacts with transcriptional coactivators, corepressors, and other sequence specific transcription factors. MECOM ("MDS1-EVI1") also contains a PR domain from "MDS1" in N-term (Wieser, 2008).

Result of the chromosomal anomaly Hybrid gene Description Regulatory sequences were transferred telomerically to MECOM.

Fusion protein Description The t(2;3) brings about the juxtaposition at 3q26 of the MECOM locus with regulatory elements normally located in proximity of the 2p breakpoints, with consequent EVI1 overexpression, without the formation of a fusion protein.

References Rippe V, Drieschner N, Meiboom M, Murua Escobar H, Bonk U, Belge G, Bullerdiek J. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene. 2003 Sep 4;22(38):6111-4

Trubia M, Albano F, Cavazzini F, Cambrin GR et al.. Characterization of a recurrent translocation t(2;3)(p15-22;q26) occurring in acute myeloid leukaemia. Leukemia. 2006 Jan;20(1):48-54

Wieser R.. MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1). Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):306-310. http://documents.irevues.inist.fr/bitstream/handle/2042/38551/12-2007-EVI103q26ID19.pdf?sequence=2

Kloth L, Belge G, Burchardt K, Loeschke S, Wosniok W, Fu X, Nimzyk R, Mohamed SA, Drieschner N, Rippe V, Bullerdiek J.. Decrease in thyroid adenoma associated (THADA) expression is a marker of dedifferentiation of thyroid tissue. BMC Clin Pathol. 2011 Nov 4;11:13. doi: 10.1186/1472-6890-11-13.


Huret JL. t(2;3)(p21;q26) THADA/MECOM. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):359-360.



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Deep Insight Section

Adiponectin and cancer Maria Dalamaga, Vassiliki Koumaki

Department of Clinical Biochemistry, University of Athens, School of Medicine, Attikon General University Hospital, Rimini 1, 12462 Athens, Chaidari, Greece (MD), Department of Microbiology, University of Athens, School of Medicine, University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece (VK)

Published in Atlas Database: November 2013

Online updated version : http://AtlasGeneticsOncology.org/Deep/AdiponectinandCancerID20128.html DOI: 10.4267/2042/53653


Abstract Deep insight on adiponectin and cancer.

Obesity and cancer Obesity has increased worldwide, becoming a major global health issue with epidemic proportions. Obesity is implicated in many diseases such as cardiovascular disease, type 2 diabetes mellitus and various cancers (Hubert et al., 1983; Mokdad et al., 2003; Ogden et al., 2007; Renehan et al., 2008; Dalamaga et al., 2012; Dalamaga et al., 2013b) such as colon cancer, postmenopausal breast cancer, endometrial cancer, renal cell cancer, esophageal adenocarcinoma, non-Hodgkin's lymphoma, leukemia, multiple myeloma (Pischon et al., 2008; Lichtman, 2010; Dalamaga et al., 2009a; Dalamaga et al., 2010), thyroid cancer, pancreatic cancer (Dalamaga et al., 2009b), gallbladder cancer, high-grade prostate cancer and ovarian cancer (Renehan et al., 2008; Larsson et al., 2007; Wiseman, 2008; Hsing et al., 2007; Dalamaga et al., 2012). The main mechanisms associating obesity to cancers are: i) abnormalities of the insulin-like growth factor-I (IGF-I) system; ii) hyperinsulinemia and insulin resistance; iii) obesity-driven chronic low-grade systemic inflammation; iv) the influence of obesity in sex hormones biosynthesis; and v) variations in the levels of adipokines (Park et al., 2011; van Kruijsdijk et al., 2009).

Adiponectin biology, physiology and pathophysiology Adiponectin is mainly produced by white adipose tissue (Ziemke and Mantzoros, 2010; Maeda et al., 2012), although other tissues express lower quantities of adiponectin. Adiponectin is alternatively called AdipoQ (Hu et al., 1996), Acrp30 (adipocyte complement-related protein of 30 kDa) (Scherer et al., 1995), apM1 (gene product of the adipose most abundant gene transcript-1) (Maeda et al., 2012), and GBP28 (gelatin-binding protein-28) (Nakano et al., 1996), and was first described in the mid-1990s. The adiponectin gene is located on chromosome 3q27 and consists of three exons and two introns (Takahashi et al., 2000). Some polymorphisms of the adiponectin gene have been shown to present functional consequences of the adiponectin protein and have been associated with clinical manifestations (Dalamaga et al., 2012). Adiponectin is a 244-amino acid protein encompassing four structural domains: an amino-terminal signal peptide followed by a variable domain, a collagen-like region of 22 Gly-X-Y repeats, and a carboxyl-terminal globular domain that binds to the adiponectin receptors and resembles tumor necrosis factor-α (TNF-α) (Dalamaga et al., 2012).

Adiponectin and cancer Dalamaga M, Koumaki V


Adiponectin is firstly synthesized as a single subunit that forms trimers, hexamers, and multimers before secretion. The monomeric form of adiponectin is thought to be present only in the adipocyte (Chandran et al., 2003), whereas adiponectin is mainly circulating as a trimer. Adiponectin can be found into five different configurations with different biological effects: the globular adiponectin (gAPN), full-length adiponectin (fAPN), low-molecular-weight adiponectin, medium molecular-weight adiponectin, and high-molecular-weight adiponectin (HMW) (Dalamaga et al., 2012). Adiponectin binds to two main receptors, adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2) encoded by genes located on chromosomes 1p36.13-q41 and 12p13.31, respectively (Yamauchi et al., 2003). AdipoR1 is expressed ubiquitously but most abundantly in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. Although both receptors are expressed in almost every tissue, including pancreatic β-cells, one or the other receptor usually prevails (Dalamaga et al., 2012). A plethora of cancer cell lines express adiponectin receptors, suggesting that adiponectin may exhibit direct effects on these cells and limit their proliferation at least in vitro (Kim et al., 2010). The two main receptors are integral membrane proteins with seven transmembrane domains with an internal N-terminal collagenous domain and an external C-terminal globular structure. AdipoR1 has high affinity for gAPN whereas AdipoR2 mainly recognizes fAPN (Kadowaki and Yamauchi, 2005). T-cadherin has also been proposed as an adiponectin receptor, acting as a co-receptor by competing with AdipoR1/R2 and binding to the hexameric and HMW forms of adiponectin; though its pathophysiological importance is not yet elucidated in humans (Hug et al., 2004). The two classical adiponectin receptors, AdipoR1 and AdipoR2, are structurally very related and share 67% identity in their protein sequence. They are also highly conserved sharing 95% homology between humans and mice (Dalamaga et al., 2012). Adiposity is considered to downregulate the expression of AdipoR1/R2, which results to a decrease in adiponectin sensitivity, leading to insulin resistance (Ouchi et al., 2000). On the other hand, physical exercise upregulates adiponectin receptors in muscles and adipose tissue, and increases the levels of circulating adiponectin (Blüher et al., 2006). Adiponectin exerts diverse effects on different tissues and organs, and the various isoforms present various biological effects on different target tissues (Ziemke and Mantzoros, 2010). Adiponectin is considered to be a protective hormone, exhibiting insulin-sensitizing, anti-inflammatory, anti-atherogenic and cardioprotective properties.

Adiponectin plays also an important role in lipid metabolism (Barb et al., 2007; Ziemke and Mantzoros, 2010) by redirecting fatty acids to the muscles to undergo oxidation, decreasing the liver uptake of fatty acids and the total triglyceride content resulting in increased insulin sensitivity in liver and skeletal muscle. Particularly in the liver, these actions are considered to be achieved by HMW adiponectin (Hada et al., 2007). Adiponectin presents anti-atherogenic actions by direct inhibition of atherosclerosis and plaque formation. Adiponectin presents also central actions by modulating food intake and energy expenditure (Dalamaga et al., 2012). Circulating adiponectin levels are generally measured in the range of 2 to 20 µg/mL. Depending on the assay methodology, race and gender, median adiponectin levels in healthy individuals with a body mass index (BMI) between 20 and 25 kg/m2 are approximately 8 µg/mL for men and 12.5 µg/mL for women (Dalamaga et al., 2012; Fabian, 2012). Circulating adiponectin levels are regulated by factors like genetic background, anthropometric characteristics, hormonal profile, inflammation, nutritional habits, and pharmacologic parameters. In obesity, serum adiponectin is decreased, in contrast to other hormones secreted by the adipose tissue, and presents, generally, a negative correlation with BMI, waist and hip circumference, waist-to-hip ratio, and visceral fat (Barb et al., 2007; Ziemke and Mantzoros, 2010). Hypoadiponectinemia related to genetic and environmental factors, such as diet and obesity, may be implicated in the pathogenesis of insulin resistance (Weyer et al., 2001), metabolic syndrome, type 2 diabetes (Weyer et al., 2001), gestational diabetes (Mazaki-Tovi et al., 2009), hypertension and cardiovascular disease (Trujillo and Scherer, 2005). Low adiponectin levels are the common pathodenominator of the constellation of risk factors that synthesize the metabolic syndrome such as hypertension, dyslipidemia, obesity, hyperglycemia, hyperinsulinemia and insulin resistance (Dalamaga et al., 2012).

Adiponectin and carcinogenesis mechanisms A growing body of evidence suggests that adiponectin presents anti-neoplastic effects via two mechanisms. First, adiponectin can act directly on tumor cells by enhancing receptor-mediated signaling pathways. Secondly, adiponectin may act indirectly by regulating inflammatory responses, influencing cancer angiogenesis and regulating insulin sensitivity at the target tissue site (Dalamaga et al., 2012). In vitro and in vivo studies have shown the expression of AdipoR1 and AdipoR2 in various cancer cell types, suggesting that adiponectin can exhibit direct receptor-mediated effect. Adiponectin



has shown to restrain proliferation of most obesity-related cancer types with some conflicting published data. For example, in the case of liver carcinoma, esophageal adenocarcinoma, gastric, endometrial and prostate carcinoma, adiponectin presented clear anti-carcinogenic effects, whereas it had no effect on melanoma cell proliferation (Dalamaga et al., 2012). However, inhibition of proliferation or no effect on proliferation of colorectal cancer cell lines was noted after treatment with adiponectin (Williams et al., 2008). Also, in vitro studies on breast cancer cell lines have been conflicting pointing towards cell line dependent effects (Dalamaga et al., 2012). Potential reasons for these discrepancies may be biological variations between the several lines of the respective cells used in various laboratories, differences in culture conditions, glucose availability medium, incubation time or adiponectin dosage, the specific isoform of adiponectin used, etc. The signaling pathways linking adiponectin to inhibition of tumorigenesis involve several intracellular signaling pathways, including 5' AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K)/v-Akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT 3), nuclear factor-κB (NFκB) and the sphingolipid metabolic pathway. Furthermore, inhibition of β-catenin, activation of c-AMP/protein kinase A and reduction of reactive oxygen species (ROS) may also contribute to the response of tumor cells to adiponectin (Dalamaga et al., 2012). Nevertheless, most of the effects of adiponectin on cancer cells are mediated through AMPK. Collectively, the adiponectin anti-neoplastic effects result in decreased protein and fatty acid synthesis, reduced cellular growth, proliferation and DNA-mutagenesis as well as enhanced cell cycle arrest and apoptosis (Dalamaga et al., 2012). The interplay between the mentioned pathways adds further complexity to the adiponectin signaling network. Interestingly, recent evidence has indicated that adiponectin can stimulate ceramidase activity independently of AMPK via the classical adiponectin receptors (Holland et al., 2011), contributing to increased amounts of prosurvival sphingosine 1 phosphate (S1P). Elevated S1P is associated with enhanced cell survival and higher local pro-angiogenic activity as observed in mammary tumor mouse models (Landskroner-Eiger et al., 2009). Adiponectin can also present receptor-independent, anti-proliferative actions through controlling the bioavailability of certain growth and inflammatory factors related to carcinogenesis. Finally, in vitro studies have shown interactions between adiponectin and other hormonal signaling pathways

such as sex steroids and leptin, underscoring the complex mechanisms that regulate carcinogenesis in vivo (Dalamaga et al., 2012). Animal experiments have been conducted in order to further evaluate the in vitro adiponectin findings. Animal models testing the role of adiponectin in carcinogenesis have elucidated the anti-tumorigenic action of adiponectin, particularly in obesity-associated cancer types. The diet-mediated influences have also been tested in animal models and have contributed to the knowledge of the role of adiponectin in vivo. Importantly, adiponectin presents the strongest effect under the high-fat diet condition, which is characterized by insulin resistance and a pro-inflammatory state. Generally, inhibition of tumor growth has been shown for colon, gastric, liver, breast and lung cancer as well as melanoma (Dalamaga et al., 2012). Finally, the role of adiponectin in tumor angiogenesis remains to be defined as both pro-angiogenic (Ouchi et al., 2004) and anti-angiogenic activities (Bråkenhielm et al., 2004) have been described with a prevailing pro-angiogenic function (Dalamaga et al., 2012).

Adiponectin and cancer: epidemiologic evidence Epidemiological evidence has linked adiponectin to the risk of obesity-associated cancers, including but not limited to breast, endometrial, prostate, gastric, colon, pancreatic, and hematologic malignancies. Moreover, many studies have reported adiponectin receptors and their expression in specific cancer tissues. Few epidemiologic studies have related specific gene polymorphisms of adiponectin and adiponectin receptors with cancer risk presenting variable associations (Dalamaga et al., 2012). Hypoadiponectinemia has been proposed as a biological link between obesity, insulin resistance and colorectal cancer as well as colorectal adenoma. Two meta-analyses and a large, prospective study in the context of the Health Professionals Study examining the association between circulating adiponectin and the risk of CC and adenoma have found significantly lower adiponectin levels than healthy controls and an elevated risk for colorectal cancer associated with hypoadiponectinemia (Wei et al., 2005; Xu et al., 2011; An et al., 2012). Determining serum adiponectin levels and assessing the expression of adiponectin receptors in colorectal cancer tissue could be useful in predicting the risk of colorectal cancer, establishing the prognosis and recurrence of colorectal cancer. Hypoadiponectinemia has also been found in patients with gastric cancer, especially upper gastric cancer, esophageal adenocarcinoma and esophageal squamous cell carcinoma in comparison to healthy controls (Ishikawa et al., 2005; Yildirim et al., 2009). In particular, lower plasma adiponectin levels were inversely correlated with tumor size,



depth of invasion and tumor TNM stage, underscoring a potential role for adiponectin in gastric cancer progression (Ishikawa et al., 2005). Evidence for the relationship between pancreatic adenocarcinoma and adiponectin levels is conflicting and depends mainly on the study design (retrospective versus prospective). In general, circulating adiponectin levels have been reported decreased in prospective studies (Bao et al., 2013) and increased in retrospective case-control studies (Dalamaga et al., 2009a; Dalamaga et al., 2009b). Elevated adiponectin levels seen in retrospective studies for pancreatic cancer may be a compensatory response to inflammation, insulin resistance and the disease-induced weight loss due to cancer cachexia, a metabolic state characterized by adipose and muscle tissue loss (Dalamaga et al., 2009b). Moreover, cachectic patients may exhibit glucose intolerance and insulin resistance due to alterations in fat metabolism, hypoleptinemia, a pro-inflammatory state and an increased activity of the Cori cycle (Dalamaga, 2013). The majority of epidemiologic evidence has linked lower total or HMW adiponectin levels to an increased risk for breast cancer independently of classical risk factors, including leptin and the IGF-I system in both premenopausal and postmenopausal women (Mantzoros et al., 2004; Dalamaga et al., 2011; Dalamaga et al., 2012). Macis et al. identified hypoadiponectinemia in premenopausal women as a risk biomarker for progression from intraepithelial neoplasia to invasive breast cancer independently of age, BMI, and treatment group (Macis et al., 2012). Because adipocytes constitute the predominant breast stromal element, adiponectin may exert a major paracrine and autocrine influence in mammary epithelium. Since AdipoR1/R2 are expressed in breast cancer tissue samples and cell lines, adiponectin could act not only through altering the hormonal milieu but directly through suppression of breast cancer cell proliferation. In addition, some studies have pointed out that breast tumors arising in women with low adiponectin levels may present a more aggressive phenotype characterized by a higher histologic grade, a large size of tumor and estrogen-receptor negativity (Dalamaga et al., 2012). Hypoadiponectinemia was also associated with lymph node metastases and increased mortality in breast cancer survivors after adjustment for parameters, including obesity and insulin resistance (Duggan et al., 2011). Finally, some studies focusing on adiponectin genetic variants (ADIPOQ) and adiponectin receptor genes (ADIPOR1) and breast cancer risk have reported associations of ADIPOQ single nucleotide polymorphisms (SNPs) and ADIPOR1 SNP with breast cancer risk. However, other studies did not find such associations (Dalamaga et al., 2012). Hypoadiponectinemia was associated with an elevated risk of endometrial cancer, particularly in

women younger than 65 years, independently from BMI, leptin, the IGF system and other known risk factors (Petridou et al., 2003). Interestingly, a combination of obesity and hypoadiponectinemia constitutes a greater risk for endometrial cancer occurrence. In particular, among obese and peri-/ postmenopausal women, lower pre-diagnostic circulating adiponectin levels may predispose to a higher risk of endometrial cancer independently from BMI, measures of central obesity and other obesity-related biological risk factors such as circulating levels of C-peptide, a biomarker reflecting pancreatic insulin production, endogenous sex steroid hormones, and IGF binding proteins (Cust et al., 2007). Although the relationship between adiponectin concentrations and prostate cancer has not been consistently shown, there is growing evidence that hypoadiponectinemia is not only associated with prostate cancer risk (Dalamaga et al., 2012) but also with the histologic grade and disease stage (Michalakis et al., 2007). Indeed, in a 25-year prospective study, men with elevated pre-diagnostic adiponectin levels presented lower risk for developing high-grade or metastatic prostate cancer (Li et al., 2010). Finally, circulating adiponectin levels have been related mainly to the risk of hematologic malignancies of the "myeloid" cell line (Dalamaga et al., 2012) such as childhood acute myeloblastic leukemia, myelodysplastic syndromes (Dalamaga et al., 2007; Dalamaga et al., 2008; Dalamaga et al., 2013a), and myeloproliferative disorders including chronic myelogenous leukemia (Avcu et al., 2006). Interestingly, lower serum adiponectin and free leptin, and elevated fetuin-A levels, may mediate effects of excess body weight on insulin resistance and risk for myelodysplastic syndromes (Dalamaga et al., 2013a). These findings are in accordance with a previous hypothesis showing that adiponectin induces apoptosis and inhibits the proliferation of myeloid cell lineage predominanltly (Yokota et al., 2000). Controversial data exist in the literature in relation to circulating adiponectin levels as a biomarker of hematologic malignancies from "lymphoid" origin. A decrease, no change and even an elevation in adiponectinemia have been reported (Dalamaga et al., 2012). In addition, no prospective epidemiologic studies have been performed examining the association of pre-diagnostic adiponectin levels and non-Hodgkin lymphomas due to the rarity of these malignancies in the general population. Lower levels of adiponectin were associated with a greater risk for multiple myeloma adjusting for age, gender, BMI, serum leptin and resistin (Dalamaga et al., 2009a) in accordance with a recent research by Fowler et al., which reported a significant percent decrease in circulating HMW adiponectin concentrations in patients with monoclonal gammopathy of



undetermined significance that either progress or do not progress to multiple myeloma from age-, gender-, and BMI-matched controls (Fowler et al., 2011). This is in accordance with the finding that adiponectin can induce apoptosis of myeloma cells through an activation of AMPK, and that myeloma cell apoptosis is reduced in myeloma-bearing adiponectin-deficient mice (Fowler et al., 2011). Augmenting adiponectin via an apolipoprotein peptide mimetic, L-4F, increased apoptosis of myeloma cells in vivo and prevented myeloma bone disease (Fowler et al., 2011). Therefore, adiponectin could not only represent a biomarker for cancer development in obesity, but could also act as a molecular mediator relating adipose tissue with carcinogenesis. The mechanisms underlying the actions of adiponectin and its potential diagnostic, prognostic and/or therapeutic utility need further investigation (Dalamaga et al., 2012).

Future perspectives The action of adiponectin in ameliorating insulin sensitivity synergistically with its anti-proliferative and pro-apoptotic properties has rendered this adipokine a promising potential diagnostic and prognostic biomarker, and a novel therapeutic tool in the pharmacologic armamentarium for cancer treatment. In the future, based on circulating adiponectin determinations and specific combinations of adiponectin pathway SNPs, a high-risk population for developing cancer could be identified and benefit from adiponectin replacement therapy. Research efforts could be directed towards identifying ways to augment endogenous adiponectin levels in order to moderate the obesity-cancer relationship. Adiponectin-mimetics, agonists of AdipoR1/R2 and strategies to increase adiponectin receptors and to modulate their sensitivity to adiponectin could provide novel therapeutic approaches for insulin resistance, diabetes type 2 and obesity-associated cancers. Pharmacologic agents such as full and selective PPAR-γ agonists increasing circulating adiponectin levels or stimulating adiponectin signaling are at the forefront of future therapeutic modalities for obesity-linked cancers. Nonetheless, further basic research, in vivo animal studies, observational human studies, and prospective and longitudinal studies are required in order to clearly determine the mechanisms underlying the actions of adiponectin in cancer. At present, lifestyle amelioration remains the most important component in preventing obesity-related cancer. Physical exercise, reduction of body-weight, a Mediterranean-based diet with consumption of fruits, nuts, coffee and/or moderate amounts of alcohol present a well-established association with

increased adiponectin levels, and a lower risk of developing insulin resistance, diabetes type 2, cardiovascular disease and malignancies.

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Dalamaga M, Koumaki V. Adiponectin and cancer. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5):361-367.


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