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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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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, clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.

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

Staff Mohammad Ahmad, Mélanie Arsaban, Mikael Cordon, Isabelle Dabin, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Database Director: Philippe Dessen, and the Chairman of the on-line version: Alain Bernheim (Gustave Roussy Institute, Villejuif, France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 6 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)

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)



Editor-in-Chief

Jean-Loup Huret (Poitiers, France)

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




Volume 12, Number 4, July-August 2008

Table of contents

Gene Section AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)) 267 Hsueh Kung Lin

CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)) 269 Yatender Kumar, Vegesna Radha, Ghanshyam Swarup

GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) 276 Prakash Radhakrishnan, Pi-Wan Cheng

HYAL2 (hyaluronoglucosaminidase 2) 279 Lillian SN Chow, Kwok-Wai Lo

PEBP1 (phosphatidylethanolamine binding protein 1) 282 Sandy Beach, Kam C Yeung

LMO2 (LIM domain only 2 (rhombotin-like 1)) 286 Pieter Van Vlierberghe, Jean-Loup Huret

RNF7 (RING finger protein-7) 289 Yi Sun

STARD13 (star-related lipid transfer (START) domain containing 13) 292 Thomas Ho-Yin Leung, Judy Wai Ping Yam, Irene Oi-lin Ng

TTL (twelve-thirteen translocation leukemia) 295 Jean-Loup Huret

ZFP36L1 (zinc finger protein 36, C3H type-like 1) 296 Deborah J Stumpo, Perry J Blackshear

ZNF384 (zinc finger protein 384) 299 Paolo Gorello, Roberta La Starza, Cristina Mecucci

CD53 (CD53 molecule) 303 Pedro A Lazo

EVI1 (ecotropic viral integration site 1 (EVI1) and myelodysplastic syndrome 1 (MDS1)-EVI1) 306 Rotraud Wieser

KIF14 (kinesin family member 14) 311 Brigitte L Thériault, Timothy W Corson

NTRK2 (neurotrophic tyrosine kinase, receptor, type 2) 314 Nadia Gabellini

PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)) 318 Dina Stepanova, Jonathan Chernoff

POU4F1 (POU class 4 homeobox 1) 320 Vishwanie Budhram-Mahadeo, David S Latchman




PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)) 325 Wael El-Rifai, Abbes Belkhiri

RMRP (RNA component of mitochondrial RNA processing endoribonuclease) 328 Pia Hermanns, Kerstin Reicherter, Brendan Lee

TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) 334 Jiangping Wu, Bing Han

TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) 339 Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani

Leukaemia Section dic(1;15)(p11;p11) 344 Jean-Loup Huret

t(2;19)(p11;p13) 346 Jean-Loup Huret

t(3;4)(p21;q34) 347 Adriana Zamecnikova

t(3;18)(q26;q11) 349 Jean-Loup Huret

t(4;21)(q31;q22) 350 Jean-Loup Huret

Case Report Section A case of chronic lymphocytic leukemia (CLL) with a rare chromosome abnormality: t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32) 351 Alka Dwivedi, Thomas Casey, Siddharth G Adhvaryu

Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage 355 Marta Susana Gallego, Mariela Coccé, Andrea Bernasconi, Maria Felice, Cristina Alonso, Myriam Guitter

Gene Section Mini Review

Atlas Genet Cytogenet Oncol Haematol. 2008;12(4) 267



AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)) Hsueh Kung Lin

Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, Oklahoma 73104, USA

Published in Atlas Database: November 2007

Online updated version: http://AtlasGeneticsOncology.org/Genes/AKR1C3ID612ch10p15.html DOI: 10.4267/2042/38539

This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: AKR1C3 Other names: DD3; HA1753; HAKRB; HAKRe; HSD17B5; KIAA0119; hluPGFS Location: 10p15.1

DNA/RNA Transcription 1170 bp mRNA; transcript has been detected in brain, lung, liver, small intestine, mammary gland, uterus, prostate, testis.

Protein Description 323 amino acids, molecular weight 37 kDa.

Expression Activated macrophage, malignant prostate epithelium, normal mammary epithelium, mature blood vessel.

Localisation Mainly in cytoplasm.

Function AKR1C3 metabolizes various androgen metabolites including 5a-dihydrotestosterone to 5a-androstane-3a,17b-diol, Delta4-androstene-3,17-dione to testosterone, androstanedione to 5a-dihydrotestosterone, androsterone to 5a-androstane-3a,17b-diol. AKR1C3 is also involved in estrogen metabolism converting estrone to 17b-estradiol as well as progesterone metabolism converting prostaglandin D2 to 9a,11b-prostaglandin F2a.

AKR1C3 has the capability of regulating the trans-activation of various nuclear receptors including androgen receptor, estrogen receptor, and peroxisome proliferator activated receptor (PPARG) by regulating the ligand availability for the nuclear receptors.

Homology A member of the of AKR1C family proteins; AKR1C1, AKR1C2, AKR1C3, AKR1C4 in human, and AKR1C9 in rat.

Mutations Note: Mutation of AKR1C3 has not been identified.

Implicated in Various cancers Note: Elevated levels of AKR1C3 expression are implicated in leukemia cell differentiation, prostate cancer (in both androgen-dependent and androgen-independent prostate cancer), and endometrial cancer. Expression of AKR1C3 was detected in a patient with myelodysplastic syndrome (MDS, refractory anemia) with progression to acute myelogenous leukemia. Overexpression of AKR1C3 in a human promyelocytic leukemia cell line, HL-60, rendered cells more resistant to all-trans retinoic acid (ATRA) and 1a,25-dihydroxyvitamin D3 induced cell differentiation.

Prostate cancer Disease Immunohistochemical staining of human prostate tissues detected negative or low levels of AKR1C3 expression in normal prostate epithelial cells. Strong positive AKR1C3 immunoreactivity was demonstrated in primary and androgen-independent prostate cancers.

AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)) Lin HK


Variable increases in AKR1C3 expression were also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy, and urothelial cell metaplasia.

Endometrial cancer Disease Quantitative transcriptosome analysis using real-time polymerase chain reaction, AKR1C3 mRNA expression was shown to be elevated in endometrial cancer versus adjacent normal endometrium.

Breast tumor Disease Expression of AKR1C3 mRNA was reduced in breast tumor as compared to adjacent normal breast tissue. Immunohistochemstry revealed that the ductal epithelial cells and stromal cells of the breast express AKR1C3. In myoepithelial cells of the breast, immunoreactive AKR1C3 was absent in normal tissues, whereas strong AKR1C3 staining was apparent in cells surrounding the neoplastic epithelium of ductal carcinoma in situ.

References Lin H-K, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM. Expression and characterization of recombinant type 2 3a-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3a/17b-HSD activity and cellular distribution. Mol Endocrinol 1997;11:1971-1984.

El-Alfy M, Luu-The V, Huang XF, Berger L, Labrie F, Pelletier G. Localization of type 5 17b-hydroxysteroid dehydrogenase, 3a-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinol 1999;140:1481-1491.

Pelletier G, Luu-The V, El-Alfy M, Li S, Labrie F. Immunoelectron microscopic localization of 3a-hydroxysteroid dehydrogenase and type 5 17b-hydroxysteroid dehydrogenase in the human prostate and mammary gland. J Mol Endocrinol 2001;26:11-19.

Desmond JC, Mountford JC, Drayson MT, Walker EA, Hewison M, Ride JP, Luong QT, Hayden RE, Vanin EF, Bunce CM. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of

nonsteroidal anti-inflammatory drugs. Cancer Res 2003;63:505-512.

Ji Q, Aoyama C, Nien YD, Liu PI, Chen PK, Chang L, Stanczyk FZ, Stolz A. Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Cancer Res 2004;64:7610-7617.

Lewis MJ, Wiebe JP, Heathcote JG. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. BMC Cancer 2004;4:27.

Nakamura Y, Suzuki T, Nakabayashi M, Endoh M, Sakamoto K, Mikami Y, Moriya T, Ito A, Takahashi S, Yamada S, Arai Y, Sasano H. In situ androgen producing enzymes in human prostate cancer. Endocr Relat Cancer 2005;12(1):101-107.

Amin SA, Huang CC, Reierstad S, Lin Z, Arbieva Z, Wiley E, Saborian H, Haynes B, Cotterill H, Dowsett M, Bulun SE. Paracrine-stimulated gene expression profile favors estradiol production in breast tumors. Mol Cell Endocrinol 2006;253:44-55.

Fung KM, Samara S, Wong C, Jones AN, Bane B, Pitha JA, Culkin DJ, Kropp BP, Penning TM, Lin HK. Detection of type 2 3a-hydroxysteroid dehydrogenase/type 5 17b-hydroxysteroid dehydrogenase (AKR1C3) distribution and its relationship with androgen receptor expression in normal and diseased human prostate. Endocr Relat Cancer 2006;13:169-180.

Mahadevan D, DiMento J, Croce KD, Riley C, George B, Fuchs D, Mathews T, Wilson C, Lobell M. Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia. Am J Hematol 2006;81:779-786.

Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, Fung KM, Lin HK. Aldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol 2006;248:182-191.

Rizner TL, Smuc T, Rupreht R, Sinkovec J, Penning TM. AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Mol Cell Endocrinol 2006;248:126-135.

Stanbrough M, Bubley G, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006;66:2815-2825.

This article should be referenced as such:

Lin HK. AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):267-268.

Gene Section Review




CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)) Yatender Kumar, Vegesna Radha, Ghanshyam Swarup

Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad - 500 007, India


Online updated version: http://AtlasGeneticsOncology.org/Genes/CASP1ID145ch11q22.html DOI: 10.4267/2042/38540


Identity Hugo: CASP1 Other names: ICE; IL1BC; P45 Location: 11q22.3 Local order: ICEBERG, INCA1, INCA2, COP, Caspase-1, Caspase-5, Caspase-4:

The human caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspases are absent in the mouse genome, suggesting their occurrence recently by duplication of caspase-1 during evolution. Note: 11q22.2-q22.3: a site frequently involved in rearrangement in human cancers.

CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)) Kumar Y, et al.


DNA/RNA Description The human caspase-1 gene is comprised of 10 exons, spanning 10.6 kb on chromosome 11q22.2-q22.3.

Transcription Six alternatively spliced forms of caspase-1 have been identified in Homo sapiens. The longest termed CASP1alpha is 1364 bp with an ORF encoding 404 amino acids (aa) and is the most predominant isoform. CASP1beta is 1185 bp, lacks entire exon3 (275-338 bp; 92-112 aa), ORF encoding 383 aa. CASP1gamma is 969 bp, lacks most of exon2

and entire exon3 (59-338 bp; 20-112 aa), ORF encoding 291 aa. CASP1delta is 825 bp, lacks entire exon7 (863-1006 bp; 288-335 aa), ORF encoding 356 aa. CASP1epsilon is 300 bp, lacks most of exon2 and exon3-exon7 (59-1006 bp; 20-335 aa), ORF encoding 98 aa. CASP1zeta is 1131 bp, missing 79 bp in prodomain of caspase-1, ORF encoding 365 aa. Among these alpha, beta, gamma and zeta forms are proteolytically active and can induce apoptosis. As delta and epsilon lack part of the catalytic domain, they do not induce apoptosis and serve as inhibitors of caspase-1 when overexpressed.

Pseudogene COP (Card Only Protein).



Protein Description Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspases-4, caspases-5, and caspases-12. It is also involved in some

forms of apoptosis. Caspase-1 protein consists of an N-terminal CARD (caspase activation and recruitment domain), a large P20 subunit and a small P10 subunit. Due to its long N-terminal prodomain, caspase-1 belongs to the initiator group of caspases and is therefore suspected to act proximally in a caspase activation cascade leading to apoptosis.



Caspase-1 is synthesized as a proenzyme of 45 kDa, which undergoes proteolytic cleavage at Asp residues to produce the active enzyme. The active caspase-1 enzyme is a hetrotetramer comprised of two P20 and two P10 subunits. The catalytic site is formed by amino acids from both P20 and P10 subunits, with the active cysteine located within the P20 subunit. Caspase-1 is activated through interactions with other CARD containing proteins such as ASC, RIP2 and NLRC4 via homotypic CARD-CARD interactions. Bacterial and viral proteins like SipB, IpaB, CrmA, and Serp2 which do not contain the CARD domain, also regulate caspase-1. Caspase-1 is activated by phosphorylation at serine 376 residue by PAK1 upon Helicobacter pylori infection.

Expression Caspase-1 is highly expressed in leukocytes, monocytes and epithelial cells. Caspase-1 gene expression is induced in response to various stimuli such as microbial infections (Mycobacterium avium, Salmonella typhimurium, Legionella pneumophila, Bacillus anthracis, Francisella tularenis and bacterial LPS), cytokines (IFN-gamma and TNF-alpha ), growth factors (TGF-beta), and DNA damaging agents (Doxorubicin, UV radiation and Paclitaxel). Levels of caspase-1 mRNA are high in ischemic tissues. Tumor suppressor p53, p73, SP1, ETS-1, IFT57/HIPPI and IRF-1 activate transcription of full length caspase-1 mRNA by binding to respective sites in the promoter, within a region 550 bp upstream of the transcription start site.

Localisation Predominantly cytoplasmic. See Table-1 and Table-2.

Function The adaptor molecules ASC, NLRC4 and Cryopyrin/Nalp3 regulate caspase-1 within a multiprotein complex known as the 'Inflammasome'. Caspase-1 activation results in cleavage and activation of proinflammatory cytokines such as IL-1beta and IL-18. Caspase-1 deficient mice have a defect in the maturation of proIL-1beta and are resistant to the lethal effect of endotoxins. Various pathogens such as S. typhimurium (TypeIII secretion), L. pneumophila (Type IV secretion), B. anthracis (Lethal Toxin), F. tularenis activate caspase-1 through 'inflammasomes'. Caspase-1 activation also occurs upon exposure to bacterial RNA, imidazoquilone compounds, LPS, extracellular ATP, muramyl dipeptide (MDP), monosodium urate, calcium pyrophosphate dehydrate and other TLR ligands via 'inflammasomes'. In addition to bacterial pathogens, viral infection also induces caspase-1 activation. Caspase-1 acts apically in neuronal cell death pathways induced by hypoxia and ischaemia. Caspase-1 is also involved in p53-mediated

apoptosis in a cell type specific manner. Caspase-1 sensitizes cells to death induced by agents like Fas ligand, radiation and cisplatin. Caspase-1 stimulates membrane biogenesis to repair damage caused by pore-forming toxins, thereby promoting host cell survival.

Homology CARD of caspase-1 bears significant homology with the CARDs of Caspase-4, Caspase-5, SFRS2IP/Caspase-11, Caspase-12, ICEBERG, Nod1, NLRC4, NEDD2, cIAP2, cIAP3 and ced3.

Mutations Germinal Not known.

Somatic Not known.

Implicated in Various diseases Disease In diseases such as ischemic and hypoxia induced brain injury, acute bacterial meningitis, ischemia of the heart and kidney. A role for caspase-1 has been implicated in Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinsons disease, Crohns disease, Age-related cognitive dysfunctions, spinalcord inflammation and gout. Caspase1- activation is enhanced in patients with CINCA syndrome.

Cancers Disease In ovarian cancer and stomach cancer: there is a decreased expression of caspase-1.

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Kumar Y, Radha V, Swarup G. CASP1 (caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):269-275.





GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) Prakash Radhakrishnan, Pi-Wan Cheng

Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/GCNT3ID44105ch15q21.html DOI: 10.4267/2042/38541


Identity Hugo: GCNT3 Other names: C2GnT-M; hC2GnT-M; C2GnT2; C2/C4gnT; GnT-M; mucus type C2GnT Location: 15q21.3 Note: GCNT3/C2GnT-M is a single pass type II membrane protein belonging to glycosyltransferase 14 family.

DNA/RNA Note: Human GCNT3/C2GnT-M is located on chromosome 15 in the region of q21.3, oriented from centromere to telomere. Description Human GCNT3/C2GnT-M gene is approximatively 8.26 kb in size and located in chromosome 15q21.3 at the position of 57,691,415 - 57,699,501.

Schematic representation of Human GCNT3/C2GnT-M gene and transcripts. There are three different sized transcripts. (TIS, Transcription Initiation Site designated as +1; E, Exon; I, Intron; UTR, Untranslated region; ATG, start codon; ORF, Open reading frame).

GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) Radhakrishnan P, Cheng PW


Recently, the GCNT3/C2GnT-M promoter (-417/+187) containing two basal cis-regulatory region (-291/-182 and -62/-43) was identified. The Th2 cytokine and retinoic acid responsive cis-regulatory elements reside in -417/+187 region.

Transcription Human GCNT3/C2GnT-M contains three different sized transcripts: 2.3-2.5, 3.6-3.8 and 6.8-7.0 kb. The transcript 1 (approximatively 2.3-2.5kb) is made of 3 exons, exon 1 (69-198 bp), exon 2 (333-401 bp), and exon 3 (1864 bp). Exon 3 contains 59 bp of 5' UTR, 1314 bp of ORF and 491 bp of 3'UTR. It does not contain any introns. Whereas, the intermediate sized transcript (3.6-3.8kb) contains 1.3kb of intron 2 and the large sized transcript (6.8-7.0 kb) contains 4.5kb of intron 1 in addition to all three exons. Exon 1 is heterogeneous in size, which ranges from 69 to 198 bp depending on tissues and cells. Exon 1 is present in all transcripts and has same 3' end but different 5' ends. A 333 bp Exon 2 is identified in most of the mucus secreting tissues and airway epithelial cells while a 401 bp of exon 2 is only detected in A549 cells.

Protein Note: Human GCNT3/C2GnT-M (EC 2.4.1.102) has 438 amino acids and molecular weight of 50,863 Da.

The predicted GCNT3/C2GnT-M structure shows a short N-terminal cytoplasmic tail (CT), a transmembrane domain (TM), a stem region and a long catalytic domain at the C-terminal region.

Description GCNT3/C2GnT-M is a type II membrane protein located in the Golgi apparatus. It contains a nine-amino acid peptide tail at the N-terminus located in the cytoplasm, which is followed by a transmembrane domain consisted of 18 amino acids, a stem region, and a catalytic domain located in the Golgi lumen. The protein contains 13 cysteines, including 4 at the N-terminal region, which are conserved among GCNT3/C2GnT-M across species, and 9 at the C-terminal region, which are conserved among all mucin glycan b6GlcNAc branching enzymes. Structural information obtained from bovine GCNT3/C2GnT-M shows that among the 9 conserved cysteines, the second cysteine is unconjugated and the other 8 cysteines form 4 cystine bonds between first and ninth, third and seventh, fourth and fifth, and sixth and eighth. The disulfide bonds formed from the nine conserved cysteines are different between GCNT3/C2GnT-M and C2GnT-L. GCNT3/C2GnT-M contains two potential N-glycosyltaion sites at N-69 and N-289.

Expression Human GCNT3/C2GnT-M gene is expressed in mucus-secretory tissues in the following decreasing order of expression: Colon; testis; stomach; small intestine; adrenal gland; kidney; trachea; thyroid gland; Uterus; Ovary; Pancreas; fetal liver; Prostate. Unlike bovine GCNT3/C2GnT-M gene, the type of transcript expressed by hC2GnT-M gene is not tissue specific among the mucus secretory tissues. Expression of GCNT3/C2GnT-M gene is down regulated in colon and colorectal tumors and various colorectal cancer cells. GCNT3/C2GnT-M expression is regulated by various external agent(s). It is inhibited by EGF and enhanced by Th2 cytokines, retinoic acids and sodium butyrate.

Localisation Golgi membrane.

Function GCNT3/C2GnT-M is responsible for the synthesis of all three branch structures, including core 2, core 4, and I antigen found in the glycans of secreted mucins. These three branch structures are generated by the transfer of GlcNAc from UDP-GlcNAc to core 1, core 3, and I antigen, respectively as shown below. 1. UDP-GlcNAc + Galbeta1-3GalNAca1-S/T gives Galbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP. 2. UDP-GlcNAc + GlcNAcbeta1-3GalNAc1a-S/T gives GlcNAcbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP. 3. UDP-GlcNAc + GlcNAcbeta1-3Galbeta1-R gives GlcNAcbeta1-3(GlcNAcbeta1-6)Galbeta1-R + UDP(R: sugars). The primary function of secreted mucins is to protect mucus secretory epithelium by retention of water and maintenance of the rheological properties of the mucus, and adherence to airborne and ingested pathogens to facilitate their removal from these tissues. The first two properties depend primarily on the carbohydrate content and this property depends on the heterogeneity of carbohydrate structure. Secreted mucins contain very high carbohydrate content, i.e. 70-90% by weight, and very heterogeneous carbohydrate structure, e.g. up to 100 different oligosaccharides in mucins isolated from a single donor. The three b6GlcNAc branch structures found in the secreted mucins are responsible for the increase of carbohydrate content and structural complexity. Decrease of GCNT3/C2GnT-M in the secretory epithelium can result in dehydration of the mucus and compromise of bacterial clearance.

Homology Human GCNT3/C2GnT-M shows a very high level of similarity to other non-human GCNT3/C2GnT-M: bovine (83%), rat (78%) and mouse (77%). Further, it shows moderate level of (48% and 38%) similarity to human C2GnT-L and C2GnT-T, respectively.

GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type) Radhakrishnan P, Cheng PW


Implicated in Colorectal cancer Note: GCNT3/C2GnT-M enzyme is down regulated in colon and colorectal tumors and most cancerous cells derived from mucus-secretory tissues. Re-expression of GCNT3/C2GnT-M suppresses tumor growth in the xenografts of nude mice.

Disease Colorectal cancer is the 3rd most common form of cancer and the 2nd leading cause of cancer-related death among men and women in the Western world. It causes 655,000 deaths worldwide per year. The survival rate of colorectal cancer is not much higher than 50% even if the disease is diagnosed at an early stage. Colorectal cancer is mostly formed from adenomatous polyps. These polyps can be detected and removed during colonoscopy, which would decrease cancer death by greater than 80%. Metastasis of cancer cells through bowel wall of the colon to lymph nodes is very common. If metastasis is detected, 5 year survival rate is less than 10%.

Prognosis Recent reports suggest that deficiency or down regulation of human GCNT3/C2GnT-M expression is associated with development of colitis and colorectal cancer. This enzyme may be used as a prognostic marker for colorectal cancer.

Oncogenesis GCNT3/C2GnT-M expression is down regulated in colorectal cancers. Down regulation of GCNT3/C2GnT-M would lead to the production of secreted mucins with lower carbohydrate content and less heterogeneous carbohydrate, which would compromise the protective function of these mucins. As a result, bacteria can not be cleared effectively, which causes irritation of the epithelium and chronic inflammation, and eventually cancer. Its re-expression suppresses tumor cell spreading, adhesion, motility, and invasion. It also inhibits cell growth and colony-forming ability, and induces apoptotic cell death. In addition, expression of C2GnT-M suppresses tumor growth in the xenografts of nude mice. The results suggest that GCNT3/C2GnT-M is important in protecting the normal functional architecture of colon epithelial cells.

References Schwientek T, Nomoto M, Levery SB, Merkx G, van Kessel AG, Bennett EP,Hollingsworth MA, Clausen H. Control of O-glycan branch formation. Molecular cloning of human cDNA encoding a novel beta1,6-N-acetylGlucosaminyl transferase forming core 2 and core 4. J Biol Chem 1999;274(8):4504-4512.

Yeh JC, Ong E, Fukuda M. Molecular cloning and expression of a novel beta-1,6-N-acetyl glucosaminyltransferase that forms core 2, core 4, and I branches. J Biol Chem 1999;274(5):3215-3221.

Beum PV, Cheng PW. Biosynthesis and function of beta 1,6 branched mucin-type glycans. Adv Exp Med Biol 2001;491:279-312. (Review).

Beum PV, Bastola DR, Cheng PW. Mucin biosynthesis: epidermal growth factor downregulates core 2 enzymes in a human airway adenocarcinoma cell line. Am J Respir Cell Mol Biol 2003;29(1):48-56.

Singh J, Khan GA, Kinarsky L, Cheng H, Wilken J, Choi KH, Bedows E, Sherman S,Cheng PW. Identification of disulfide bonds among the nine core 2 N-acetylglucosaminyltransferase-M cysteines conserved in the mucin beta6-N-acetylglucosaminyltransferase family. J Biol Chem 2004;279(37):38969-38977.

Beum PV, Basma H, Bastola DR, Cheng PW. Mucin biosynthesis: upregulation of core 2 beta 1,6 N-acetyl glucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2005;288(1):L116-L124.

Ishibashi Y, Inouye Y, Okano T, Taniguchi A. Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line. Glycoconj J 2005;22(1-2):53-62.

Huang MC, Chen HY, Huang HC, Huang J, Liang JT, Shen TL, Lin NY, Ho CC, Cho IM, Hsu SM. C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells. Oncogene 2006;25(23):3267-3276.

Hashimoto M, Tan S, Mori N, Cheng H, Cheng PW. Mucin biosynthesis: molecular cloning and expression of mouse mucus-type core 2 beta1,6 N-acetylglucosaminyl transferase. Glycobiology 2007;17(9):994-1006.

Radhakrishnan P, Beum PV, Tan S, Cheng PW. Butyrate induces sLex synthesis by stimulation of selective glycosyltransferases genes. Biochem Biophys Res Commun 2007;359(3):457-462.

Tan S, Cheng PW. Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene. Am J Respir Cell Mol Biol 2007;36(6):737-745.


Radhakrishnan P, Cheng PW. GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):276-278.





HYAL2 (hyaluronoglucosaminidase 2) Lillian SN Chow, Kwok-Wai Lo

Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology, and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China


Online updated version: http://AtlasGeneticsOncology.org/Genes/HYAL2ID40904ch3p21.html DOI: 10.4267/2042/38542


Identity Hugo: HYAL2 Other names: LuCa-2; LUCA2 Location: 3p21.3 Local order: Telomeric to TUSC2 and centromeric to HAYL1. Note: HYAL2 was identified in an EST database search of PH-20 hyaluronidase related sequences. HYAL2 appears to be an inactive hyaluronidase. Characterization of HYAL2 mostly focuses on its role as the cell entry receptor of Jaagsiekte sheep retrovirus (JSRV), and the putative function as a tumor suppressor gene, based on its specific chromosomal location.

DNA/RNA Description The HYAL2 gene contains 4 exons, spanning 4.99 kb.

Transcription The gene encodes two alternatively spliced transcripts (NM_033158 and NM_003773) which differ only in the 5' UTR. Distinct noncoding exon 1 was found in these two transcripts. Both variants encode the same protein. The ORF size is 1422 bp.

Pseudogene No known pseudogenes.

Two alternatively spliced variants (NM_033158.2 and NM_003773.2) of HYAL2 are shown. Both of them contain four exons. Black boxes represent the coding exons of HYAL2. White boxes represent untranslated regions.

HYAL2 (hyaluronoglucosaminidase 2) Chow LSN, Lo KW


Protein

The HYAL2 protein contains a N-terminal signal peptide (1-20) and a epidermal growth factor (EGF)-like domain (365-469).

Description The 473 amino-acid peptide encodes the HYAL2 protein with a predicted molecular weight of 53.9 KDa. The protein is comprised of a N-terminal signal peptide (amino acids 1-20) and a epidermal growth factor (EGF)-like domain at amino acids 365-469 (by SMART prediction).

Expression High level of HYAL2 expression was detected in most tissues, including liver, kidney, lung and heart. Expression was low or absent in brain.

Localisation Originally shown to be lysosomal but subsequently proved to be a glycosylphosphatidylinositol (GPI)-anchored cell surface protein.

Function Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix (ECM). The level of hyaluronan is regulated by a balance between hyaluronan synthase and HYAL enzyme activities. Hyaluronan is suggested to be involved in embryonic development, cell proliferation, migration and wound healing. Although originally supposed to be active at pH 4.0, HYAL2 actually displayed minimal to undetectable hyaluronidase activity in subsequent studies. The hyaluronidase activity of HYAL2 remains controversial.

Homology HYAL2 belongs to a family of hyaluronoglucosaminidases. Other members include HYAL1, HYAL3, HYAL4 and Spam1.

Mutations Note: No germline or somatic mutation is reported.

Implicated in Possible in lung cancer and breast cancer Note: HYAL2 is located within a 120-kb minimal deletion region at 3p21.3 a chromosomal segment known to harbor multiple candidate tumor suppressor genes in breast and lung cancers. Nevertheless, HYAL2 does not possess tumor suppressor function, as evident by in vitro and in vivo studies in lung cancer models. HYAL2 serves as the cellular receptor that mediates entry of the Jaagsiekte sheep retrovirus (JSRV), and its receptor function is independent on its catalytic activity. The JSRV envelope (Env) protein is believed to be the active oncogene. The viral Env transforms epithelial cells through activation of RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor (MST1R), and followed by activating PI3K/Akt signaling cascade and MAPK signaling cascade. HYAL2 physically interacts and negatively regulates RON. JSRV infects the epithelial cells of the lower airway of sheep and goats, resulting in ovine pulmonary adenocarinoma, sharing features with human bronchioloalveolar carcinoma. Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.

Disease Lung cancer; bronchioloalveolar carcinoma; non-Hodgkin lymphoma; breast cancer.

Prognosis Increased level of HYAL2 deletions in sputum of Stage I non-small-cell lung cancer patients was associated with pack-years of smoking, but independent on patients' age, gender, histologic tumor type and tumor

HYAL2 (hyaluronoglucosaminidase 2) Chow LSN, Lo KW


size and location. HYAL2 mRNA expression was inversely correlated with lymphoma aggressiveness.

Oncogenesis HYAL2 mRNA expression was lost in lung cancer cell lines. However, expression of HYAL2 was retained in esophageal squamous carcinoma and nasopharyngeal carcinoma cell lines. Highly invasive breast cancer cell lines preferentially express HYAL2. Systemic administration of protamine-complexed vectors expressing HYAL2 inhibited lung metastatic foci in nu/nu mice. Intratumoral injection of same construct failed to suppress primary tumor growth or induce apoptosis, suggesting HYAL2 may function at the level of metastasis.

References Lepperdinger G, Strobl B, Kreil G. HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. J Biol Chem 1998;273(35):22466-22470.

Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI, Minna JD. Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Oncogene 1998;16(24):3151-3157.

Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI, Miller AD. Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc Natl Acad Sci USA 2001;98(8):4443-4448.

Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD. Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Cancer Res 2002;62(9):2715-2720.

Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, Lerman MI. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc Natl Acad Sci USA 2003;100(8):4580-4585.

Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP. RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. Int J Cancer 2004;109(6):839-847.

Bertrand P, Courel MN, Maingonnat C, Jardin F, Tilly H, Bastard C. Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness. Int J Cancer 2005;113(2):207-212.

Udabage L, Brownlee GR, Nilsson SK, Brown TJ. The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. Exp Cell Res 2005;310(1):205-217.

Li R, Todd NW, Qiu Q, Fan T, Zhao RY, Rodgers WH, Fang HB, Katz RL, Stass SA, Jiang F. Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer. Clin Cancer Res 2007;13:482-487.

Vigdorovich V, Miller AD, Strong RK. Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus. J Virol 2007;81(7):3124-3129.

This article should be referenced as such: Chow LSN, Lo KW. HYAL2 (hyaluronoglucosaminidase 2). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):279-281.

Gene Section Review




PEBP1 (phosphatidylethanolamine binding protein 1) Sandy Beach, Kam C Yeung

Department of Cancer Biology and Biochemistry, College of Medicine, University of Toledo, Health Science Campus-(formerly Medical University of Ohio), 3035 Arlington Ave., Toledo, OH 43614, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/PEBP1ID44021ch12q24.html DOI: 10.4267/2042/38543


Identity Hugo: PEBP1 Other names: HCNP; HCNPpp; PBP; PEBP; PEBP-1; RKIP Location: 12q24.23

DNA/RNA Description The gene is composed of 4 exons spanning a region of 9,520 base pairs.

Transcription The mRNA contains 1507 nucleotides. Alternative splicing has not been described. In prostate cancer cell lines RKIP transcription is repressed by Snail through an E-box in its promoter. Promoter methylation does not seem to cause loss of RKIP expression.

Pseudogene RKIP has two putative pseudogenes located on chromosomes 2 and 14. These are intronless sequences with no verified expression to date.

Diagram of the RKIP gene. Exons are depicted as filled boxes and untranslated regions are unfilled boxes. Introns are represented as lines between exons. Intron, exon, and untranslated region sizes are described in base pairs.

Stereo view of the human RKIP structure prepared with Pymol (Delano, 2002). Pocket residues H86 (left), H118 (right), D70 (top) and Y120 (bottom) are indicated.

PEBP1 (phosphatidylethanolamine binding protein 1) Beach S, Yeung KC


Protein Note: RKIP belongs to a highly conserved family of phospholipid-binding proteins, which have been recognized and studied for several years as PEBP. These proteins are represented in eukaryotes, bacteria, and archae. One of the interesting properties of some PEBP family members is that they are cleaved at the N-terminus to release an undecapeptide which has been named hippocampal cholinergic neurostimulating peptide (HCNP).

Description RKIP is an 187 amino acid protein with a molecular mass of 21-23 kDa. The crystal structures of human, bovine and plant PEBPs are solved revealing no homologies to domains of known functions. The structure of RKIP features a b-fold formed by two anti-parallel b-sheets, a small C-terminal aba element, and a cavity at the surface, which could accommodate a small anion such as a phosphoryl group (see diagram above). Amino acids forming this cavity are conserved among all PEBP family members and constitute the PEB motif.

Expression RKIP and its mammalian homologs are widely expressed in tissues; it has been detected in lung, oviduct and ovary, mammary glands, uterus, prostate epithelium, thyroid, mesenteric lymph node, megakaryocytes of the heart; spleen, liver, and epididymis, testis, spermatids, Leydig cells, steroidogenic cells of the adrenal gland zona fasiculata, small intestine, plasma cells, and neural cells such as brain oliodendricytes, Schwann cells, and Pukinje cells.

Localisation RKIP is localized in the cytoplasm and at the plasma membrane.

Function RKIP inhibits the Raf/MEK/ERK cascade. Identified as a Raf-1 interacting protein in a yeast two-hybrid screen, RKIP was found to inhibit phosphorylation and activation of MEK by Raf-1. RKIP inhibits the phosphorylation of the N-region of Raf-1 by (21-activated kinase) Pak and Src family kinases thereby inhibiting activation of Raf-1. PKC phosphorylation of RKIP following GPCR stimulation causes its release from Raf-1. Classical and atypical PKCs can phosphorylate RKIP at serine 153 causing dissociation of the Raf-1 kinase domain and RKIP, indicating that PKC can mediate ERK activation through RKIP. Once free from Raf-1, RKIP was shown to bind GRK-2 and block its activity, promoting and enhancing G protein signaling and MEK/ERK signaling.

RKIP appears to support macrophage differentiation via inhibition of the NFKB pathway. RKIP inhibits the NF-kappaB pathway through interaction with NIK, TAK1, and IKK. RKIP was a novel effector of apoptosis signaling; this may occur by modulation of the NF-kappaB pathway and/or the regulation of the spindle checkpoint via Aurora B kinase and the spindle checkpoint by RKIP. RKIP regulation of Aurora kinase B and the spindle checkpoint through Raf-1/MEK/ERK signaling influences cell cycle fidelity. RKIP has serine protease activity. Purified RKIP was found to inhibit the serine proteases thrombin, chymotrypsin, and neuropsin. HCNP, the N-terminal fragment of RKIP, may play a role in phospholipid organization of the myelin sheath and septal cholinergic development of the hippocampus. HCNP can act on frog cardiac mechanical performance, exerting a negative inotropism. Results of these experiments suggest that RKIP/HCNP may be a new endocrine factor that regulates cardiac physiology. RKIP downregulation may be associated with the congenital heart disease manifested in Down syndrome. RKIP downregulation was found in the rat right ventricle and in the interventricular septum upon cardiac remodeling. RKIP has been found in the male reproductive tract with implications in the organization of sperm membranes during spermiogenesis. It has been identified as a decapacitation factor in mouse spermatozoa. RKIP and other proteins inhibited progesterone-induced acrosome reaction and zona pellucida binding of sperm.

Homology No significant sequence homology to other proteins. Humans have two known family members, RKIP and PEBP4. RKIP has high sequence identity to mouse, rat, bovine, and monkey phosphatidylethanolamine binding proteins.

Implicated in Breast cancer Oncogenesis Immunohistochemical examination of breast cancer lymph node metastases showed significant loss of RKIP protein expression compared to normal breast duct epithelia and primary tumors. There was a weak negative correlation between RKIP expression and apoptosis in breast tumors that did not have associated lymph node metastases. Low levels of RKIP may allow cancer cells to evade apoptosis. Breast cancer cell lines expressing low levels of RKIP undergo apoptosis following ectopic RKIP addition or Taxol treatment, which induced RKIP expression.



Prostate cancer Prognosis Decreased protein expression of RKIP may be a prognostic marker in prostate cancer, with low RKIP levels indicating early PSA failure.

Oncogenesis Low levels of RKIP may protect cancer cells against apoptosis. Tumorgenic prostate cancer cell lines expressing low levels of RKIP increase their RKIP expression following treatment with a chemotherapeutic drug, sensitizing the cells to apoptosis. Cell lines with higher RKIP expression can be made resistant to apoptosis when RKIP is knocked down. RKIP is downregulated in prostate cancer progression and metastasis. Modulation of RKIP expression in prostate cancer cell lines changes invasive ability in vitro as well as development of metastases in vivo, with loss of RKIP corresponding to increased invasiveness and metastatic spread. MEK/ERK activation was associated with low or decreased RKIP expression in vitro, and vice-versa. RKIP mRNA can activate interferon-inducible 2’,5’-oligoadenylate synthetases (OAS), leading to RNase L activation. RNase L deficiency in prostate cancer cell lines (PC3, Du145, LNCap) is associated with resistance to apoptosis through OAS activation.

Melanoma Note: RKIP mRNA and protein expression is reduced in melanoma cell lines versus normal melanocytes. AP-1 activation and ERK1/ERK2 phosphorylation decreased in Mel Im cells stably transfected with RKIP compared to control transfected cells. Immunohistochemical analyses showed reduced RKIP in primary melanoma versus normal normal skin, and further reduction in melanoma metastases. RKIP may act by inhibiting B-Raf kinase activity, as demonstrated in melanoma cell lines in vitro.

Hepatocellular carcinoma Note: Hepatocellular carcinoma cell lines and HCC liver tissue showed decreased RKIP expression as compared to primary human hepatocytes or adjacent peritumoral tissues. Low RKIP expression was correlated with increased ERK activation and modulation of RKIP expression antagonized MAPK signaling in vitro.

Colorectal cancer Note: Loss of RKIP, as studied in tissue microarrays of MMR-proficient and deficient colorectal cancer samples, was a marker of tumor progression and metastasis. Diminished RKIP expression was significantly positively associated with worse survival.

Insulinoma / Islet neoplasia Note: Insulinomas showed decreased or absent RKIP expression as compared to normal nearby islets. β-cell line HIT-TI5 proliferation, but not apoptotis, was inhibited by RKIP.

References Seddiqi N, Bollengier F, Alliel PM, Périn JP, Bonnet F, Bucquoy S, Jollès P, Schoentgen F. Amino acid sequence of the Homo sapiens brain 21-23-kDa protein (neuropolypeptide h3), comparison with its counterparts from Rattus norvegicus and Bos taurus species, and expression of its mRNA in different tissues. J Mol Evol 1994;39:655-660.

Moore C, Perry AC, Love S, Hall L. Sequence analysis and immunolocalisation of phosphatidylethanolamine binding protein (PBP) in human brain tissue. Brain Res Mol Brain Res 1996;37:74-78.

Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM, Kolch W. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 1999;401:173-177.

Kolch W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 2000;351 Pt 2:289-305. (Review).

Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol 2000;20:3079-3085.

Hengst U, Albrecht H, Hess D, Monard D. The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors. J Biol Chem 2001;276:535-540.

Kroslak T, Koch T, Kahl E, Hollt V. Human phosphatidylethanolamine-binding protein facilitates heterotrimeric G protein-dependent signaling. J Biol Chem 2001;276:39772-39778.

Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, McFerran B,Wyche J, Kolch W, Sedivy JM. Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation. Mol Cell Biol 2001;21:7207-7217.

Simister PC, Banfield MJ, Brady RL. The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family. Acta Crystallogr D Biol Crystallogr 2002;58:1077-1080.

Corbit KC, Trakul N, Eves EM, Diaz B, Marshall M, Rosner MR J. Activation of Raf-1 Signaling by Protein Kinase C through a Mechanism Involving Raf Kinase Inhibitory Protein. Biol Chem 2003;278:13061-13068.

Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET. Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 2003;95:878-889.

Lorenz K, Lohse MJ, Quitterer U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 2003;426:574-579.

Chatterjee D, Bai Y, Wang Z, Beach S, Mott S, Roy R, Braastad C, Sun Y, Mukhopadhyay A, Aggarwal BB, Darnowski J, Pantazis P, Wyche J, Fu Z, Kitagwa Y, Keller ET, Sedivy JM, Yeung KC. RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J Biol Chem 2004;279:17515-17523.



Jazirehi AR, Vega MI, Chatterjee D, Goodglick L, Bonavida B. Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Cancer Res 2004;64:7117-7126.

Keller ET, Fu Z, Brennan M. The role of Raf kinase inhibitor protein (RKIP) in health and disease. Biochem Pharmacol 2004;68:1049-1053. (Review).

Keller ET, Fu Z, Yeung K, Brennan M. Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. Cancer Lett 2004;207:131-137. (Review).

Odabaei G, Chatterjee D, Jazirehi AR, Goodglick L, Yeung K, Bonavida B. Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis. Adv Cancer Res 2004;91:169-200.

Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK. Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res 2004;64:5186-5192.

Yamazaki T, Nakano H, Hayakari M, Tanaka M, Mayama J, Tsuchida S. Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein. J Biol Chem 2004;279(31):32191-32195.

Zhang L, Fu Z, Binkley C, Giordano T, Burant CF, Logsdon CD, Simeone DM. Raf kinase inhibitory protein inhibits beta-cell proliferation. Surgery 2004;136:708-715.

Hagan S, Al-Mulla F, Mallon E, Oien K, Ferrier R, Gusterson B, Garcia JJ, Kolch W. Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res 2005;11:7392-7397.

Keller ET, Fu Z, Brennan M. The biology of a prostate cancer metastasis suppressor protein: Raf kinase inhibitor protein. J Cell Biochem 2005;94:273-278. (Review).

RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 2005;24(21):3535-3540.

Trakul N, Menard RE, Schade GR, Qian Z, Rosner MR. Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. J Biol Chem 2005;280(26):24931-24940.

Chen Q, Wang S, Thompson SN, Hall ED, Guttmann RP. Identification and characterization of PEBP as a calpain substrate. J Neurochem 2006;99:1133-1141.

Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR. Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 2006;23:561-574.

Fu Z, Kitagawa Y, Shen R, Shah R, Mehra R, Rhodes D, Keller PJ, Mizokami A, Dunn R, Chinnaiyan AM, Yao Z, Keller ET. Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. Prostate 2006;66:248-256.

Lee HC, Tian B, Sedivy JM, Wands JR, Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 2006;131:1208-1217.

Molinaro RJ, Jha BK, Malathi K, Varambally S, Chinnaiyan AM, Silverman RH. Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells. Nucleic Acids Res 2006;34:6684-6695.

Park S, Rath O, Beach S, Xiang X, Kelly SM, Luo Z, Kolch W, Yeung KC. Regulation of RKIP binding to the N-region of the Raf-1 kinase. FEBS Lett 2006;580:6405-6412.

Beach S, Tang H, Park S, Dhillon AS, Keller ET, Kolch W, Yeung KC. Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene 2007;.

Huang J, Mahavadi S, Sriwai W, Grider JR, Murthy KS. Cross-regulation of VPAC(2) receptor desensitization by M(3) receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2. Am J Physiol Gastrointest Liver Physiol 2007;292:G867-874.

Minoo P, Zlobec I, Baker K, Tornillo L, Terracciano L, Jass JR, Lugli A. Loss of raf-1 kinase inhibitor protein expression is associated with tumor progression and metastasis in colorectal cancer. Am J Clin Pathol 2007;127:820-827.

Rosner MR. MAP kinase meets mitosis: A role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation. Cell Div 2007;2:1. (Review).

Theroux S, Pereira M, Casten KS, Burwell RD, Yeung KC, Sedivy JM, Klysik J. Raf kinase inhibitory protein knockout mice: expression in the brain and olfaction deficit. Brain Res Bull 2007;71:559-567.

This article should be referenced as such: Beach S, Yeung KC. PEBP1 (phosphatidylethanolamine binding protein 1). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):282-285.





LMO2 (LIM domain only 2 (rhombotin-like 1)) Pieter Van Vlierberghe, Jean-Loup Huret

ErasmusMC/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rotterdam, The Netherlands (PVV); Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)


Online updated version: http://AtlasGeneticsOncology.org/Genes/RBTN2ID34.html DOI: 10.4267/2042/38544

This article is an update of: Bilhou-Nabera C. RBTN2 (rhombotin-2). Atlas Genet Cytogenet Oncol Haematol.1998;2(4):117-118. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: LMO2 Other names: RBTN2 (rhombotin-2); RHOM2; RBTNL1 (rhombotin-like-1); TTG2 (T-cell translocation gene 2); LMO2 (LIM domain only 2) Location: 11p13 Local order: telomere LMO1 - NUP98 (11p15) - CD59 - FSHB - LMO2 - PAX6 - PDHX (11p13) centromere.

DNA/RNA Description LMO2 belongs to a multigene family, extremely well conserved during evolution, encoding proteins containing two cystein-rich regions referred to as LIM domains: LMO1 (11p15), LMO2 (11p13), LMO3 (12p); 6 exons.

Transcription 3 transcripts: LMO2-a and LMO2-b encode the same 158-amino-acid protein; LMO2-c encodes a 151-amino-acid protein.

Protein Description Small cystein rich protein with two tandemly arranged Zinc binding LIM domain motifs: named Lom2; 158 amino acids; 18 kDa; 48 % amino-acid identity with LMO1 protein. LMO2 contains two transcription activating domains (one in N-term, in a prolin-rich 19 amino acid region, one in C-term) and two LIM domains as transcription

repressing domains, selectively inhibiting the N-term activation domain (no effect on the C-term domain).

Expression Early expressed during development, in all tissues (roughly consistent level in central nervous system, low level in thymus). Strongly expressed in the precursors of mixed erythrocyte/macrophage/mast, erythrocyte, megakaryocyte, neutrophil and macrophage colonies, undetectable in the mature progeny. Expressed in early B-cells, in leukemias of both the myeloid and lymphoid lineages. Nuclear marker in normal germinal center B-cells. Also expressed in endothelial cells. High expression in the brain; expressed in the hippocampus during development.

Localisation Nuclear.

Function Hematopoiesis: LMO2 directly interacts with the basic-loop-helix protein TAL1/SCL and the GATA DNA protein GATA1. They form a transcriptional complex: LMO2 has no direct evidence in DNA binding capacity but could act as a bridging molecule bringing together different DNA binding factors (TAL1, LDB1, E12/E47, GATA1) that are essential for hematopoiesis (e.g. in the erythroid complex). This interaction is critical for the regulation of red blood cell development in early stages of hematopoiesis. TAL1 interacts specifically with the LIM domains of LMO2, which in turn binds LDB1. Because LMO2 can also bind to GATA2, a complex LMO2-GATA2 might occur at earlier stages of hematopoiesis when Gata1 is not

LMO2 (LIM domain only 2 (rhombotin-like 1)) Van Vlierberghe P, Huret JL


expressed. Lmo2 has a central role in adult hematopoietic pathway regulation, on bone marrow pluripotential precursor stem cell mainly. LMO2 and TAL1 are able to partially suppress myeloid differentiation. LMO2 also interacts with retinoblastoma-binding protein 2 and elf-2 (ets transcription factor). LMO2-c expression is regulated by GATA1 and PU.1; LMO2-c acts as an antagonist of LMO2-a/b, therefore blocking the transactivation of LMO2-a/b. In the brain, hBEX2, LMO2, NSCL2 and LDB1 could form a similar complex.

Implicated in

t(11;14)(p13;q11)/T-cell leukaemia → LMO2/ TCRD-A Disease Childhood T-cell ALL ; found in 5-10% of T-cell ALL.

Cytogenetics A variant translocation t(7;11)(q35;p13) has been described.

Abnormal Protein It was previously believed that LMO2 is activated after chromosomal translocation by association either the T-cell receptor a/T-cell receptor d (14q11) or T-cell receptor b gene (7q35). Chromosome breakpoints occur 25 kb upstream LMO2 gene, in a presumed transcriptional start site, inducing truncation of the promoter/control region and leading to inappropriate Lmo2 level especially in T-cells (abnormal T-cell differentiation). However, it becomes now very likely that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD enhancer, is the main determinant for LMO2 activation in the majority of t(11;14)(p13;q11) translocations.

del(11)(p12p13) T-cell leukaemia Disease Childhood T-cell ALL; found in about 5% of T-cell ALL.

Cytogenetics Cryptic deletion that varies in size.

Abnormal Protein LMO2 is activated through a cryptic intrachromosomal deletion, del(11)(p12p13), in which a negative regulatory element (NRE), situated upstream of the LMO2 gene, is deleted. Removal of this NRE causes activation of the proximal promoter of the LMO2 gene leading to its ectopic expression.

Germinal center B-cell lymphomas Disease Diffuse large-B-cell lymphomas, follicular lymphomas, Burkitt lymphomas, less often in other haematological malignancies.

Prognosis LMO2 expression, together with BCL6, FN1, CCND2, SCYA3, and BCL2 expressions, is a predictor of outcome in diffuse large-B-cell lymphoma.

Prostate cancer Note: Expression of LMO2 is higher in prostate tumours samples than in the normal epithelium. Moreover, overexpression of LMO2 is significantly associated with advanced tumour stage, as well as with the development of distant metastasis.

Oncogenesis LMO2 may play an important role in prostate cancer progression, possibly via repression of E-cadherin expression.

References Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH. The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci USA 1991;88(10):4367-4371.

Royer-Pokora B, Loos U, Ludwig WD. TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene 1991;6(10):1887-1893.

Dong WF, Billia F, Atkins HL, Iscove NN, Minden MD. Expression of rhombotin 2 in normal and leukaemic haemopoietic cells. Br J Haematol 1996;93(2):280-286.

Wadman IA, Osada H, Grütz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J 1997;16(11):3145-3157.

Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH. The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc Natl Acad Sci USA 1998;95(7):3890-3895.

Anguita E, Hughes J, Heyworth C, Blobel GA, Wood WG, Higgs DR. Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. EMBO J 2004;23(14):2841-2852.

Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, Levy R. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004;350(18):1828-1837.

Hammond SM, Crable SC, Anderson KP. Negative regulatory elements are present in the human LMO2 oncogene and may contribute to its expression in leukemia. Leuk Res 2005;29(1):89-97.

LMO2 (LIM domain only 2 (rhombotin-like 1)) Van Vlierberghe P, Huret JL


Han C, Liu H, Liu J, Yin K, Xie Y, Shen X, Wang Y, Yuan J, Qiang B, Liu YJ, Peng X. Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex. Nucleic Acids Res 2005;33(20):6555-6565.

Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J, Passier M, van Wering ER, Veerman AJP, Kamps WA, Meijerink JPP, Pieters R. The

cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood 2006;108(10):3520-3529.

Dik WA, Nadel B, Przybylski GK, Asnafi V, Grabarczyk P, Navarro JM, Verhaaf B, Schmidt CA, Macintyre EA, van Dongen JJ, Langerak AW. Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL. Blood 2007;110(1):388-392.

Hansson A, Zetterblad J, van Duren C, Axelson H, Jönsson JI. The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation. Biochem Biophys Res Commun 2007;364(3):675-681.

Lécuyer E, Larivière S, Sincennes MC, Haman A, Lahlil R, Todorova M, Tremblay M, Wilkes BC, Hoang T. Protein stability and transcription factor complex assembly determined by the SCL-lmo2 interaction. Biol Chem 2007;282(46):33649-33658.

Ma S, Guan XY, Beh PS, Wong KY, Chan YP, Yuen HF, Vielkind J, Chan KW. The significance of LMO2 expression in the progression of prostate cancer. J Pathol 2007;211(3):278-285.

Natkunam Y, Zhao S, Mason DY, Chen J, Taidi B, Jones M, Hammer AS, Hamilton Dutoit S, Lossos IS, Levy R. The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. Blood 2007;109(4):1636-1642.

Wang Q, Zhang M, Wang X, Yuan W, Chen D, Royer-Pokora B, Zhu T. A novel transcript of the LMO2 gene, LMO2-c, is regulated by GATA-1 and PU.1 and encodes an antagonist of LMO2. Leukemia 2007;21(5):1015-1025.

Yang Z, Jiang H, Zhao F, Shankar DB, Sakamoto KM, Zhang MQ, Lin S. A highly conserved regulatory element controls hematopoietic expression of GATA-2 in zebrafish. BMC Dev Biol 2007;7:97.


Van Vlierberghe P, Huret JL. LMO2 (LIM domain only 2 (rhombotin-like 1)). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):286-288.





RNF7 (RING finger protein-7) Yi Sun

Department of Radiation Oncology, University of Michigan, 4304 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/RNF7ID44108ch3q22.html DOI: 10.4267/2042/38545


Identity Hugo: RNF7 Other names: CKBBP1; RBX2; ROC2; SAG (Sensitive to Apoptosis Gene) Location: 3q22-24

DNA/RNA Description The gene encoding RNF7/SAG consists of four exons

and three introns.

Transcription About 0.8 kb mRNA with 342 bp open reading frame; three alternative splicing variants; induced by redox compound, tumor promoter (TPA), and hypoxia.

Pseudogene Two pseudogenes, SAGp1 and SAGp2.

A) Location. B) Local order.

RNF7 (RING finger protein-7) Sun Y


Protein

Description 113 amino acids; 14 kDa protein; contains a RING domain (Cys-X2-Cys-X9-39-Cys-X1-3-His-X2-3-Cys/His-X2-Cys-X4-48-Cys-X2-Cys) at the C-terminus (50-102); Subjected to CK2 phosphorylation at Thr-10.

Expression Ubiquitously expressed with the highest expression in heart, skeleton muscle, and testis in humans.

Localisation Both cytoplasm and nucleus.

Function 1) In vitro test tube assays using purified protein showed that RNF7/SAG scavenges hydrogen peroxide at the expense of self oligomerization; has thiol-linked peroxidase activity; inhibits peroxynitrite-induced DNA damage. When complexed with the components of SCF E3 ubiquitin ligase, SAG has E3 ubiquitin ligase activity.

2) In cultured cells, SAG over-expression inhibits apoptosis induced by redox, nitric oxide, ischemia/hypoxia, neurotoxin, MPP, and UV-irradiation (unpublished data). SAG over-expression also promotes the S-phase entry and cell growth under serum starved conditions and inhibits TPA-induced neoplastic transformation. Silencing SAG expression by anti-sense or siRNA inhibits tumor cell growth, enhanced apoptosis induced by etoposide and TRAIL, and enhances TPA-induced neoplastic transformation. 3) In whole animals, SAG over-expression via injection of SAG expressing recombinant adenovirus protects mouse brain tissues from ischemia/hypoxia-induced damage. Targeted expression of SAG in mouse skin inhibits tumor formation at the early stage, but enhances tumor growth at the later stage in a SAG-transgenic DMBA-TPA carcinogenesis model. 4) In yeast, SAG is a growth essential gene whose targeted deletion causes death, which can be rescued by human SAG.

RNF7 (RING finger protein-7) Sun Y


Homology SAG is an evolutionarily conserved gene with 96% protein sequence identity between human and mouse, 70% identify between human and C-elegans and 50% between human and yeast. Two family members are found in human and mouse, four in Drosophila, three in C-elegans, one in Arabidopsis and in yeast.

Mutations Germinal Not known.

Somatic Not known.

Implicated in Lung and colon cancer Disease SAG/RNF7 over-expression was found in lung cancer and a subset of colon cancer tissues.

Prognosis Lung cancer patients with SAG/RNF7 over-expression have a worse prognosis.

Oncogenesis Targeted over-expression of SAG/RNF7 in mouse skin by K14 promoter inhibits tumor formation, but enhances tumor growth in DMBA-TPA-induced skin carcinogenesis.

References Duan H, Wang Y, Aviram M, Swaroop M, Loo JA, Bian J, Tian Y, Mueller T, Bisgaier CL, Sun, Y. SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol Cell Biol 1999;19:3145-3155.

Sun Y. Alteration of SAG mRNA in human cancer cell lines: Requirement for the RING finger domain for apoptosis protection. Carcinogenesis 1999;20:1899-1903.

Swaroop M, Bian J, Aviram M, Duan H, Bisgaier CL, Loo JA, Sun Y. Expression, purification, and biochemical characterization of SAG, a RING finger redox sensitive protein. Free Radicals Biol Med 1999;27:193-202.

Swaroop M, Wang Y, Miller P, Duan H, Jatkoe T, Madore SJ, Sun Y. Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: Chip profiling implicates its role in cell cycle regulation. Oncogene 2000;19:2855-2866.

Duan H, Tsvetkov LM, Liu Y, Song Y, Swaroop M, Wen R, Kung HF, Zhang H, Sun Y. Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. Mol Carcinog 2001;30(1):37-46.

Huang Y, Duan H, Sun Y. Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but its antisense transfection inhibits tumor cell growth. Mol Carcinog 2001;30:62-70.

Sasaki H, Yukiue H, Kobayashi Y, Moriyama S, Nakashima Y, Kaji M, Fukai I, Kiriyama M, Yamakawa Y, Fujii Y. Expression of the sensitive to apoptosis gene, SAG, as a prognostic marker in nonsmall cell lung cancer. Int J Cancer 2001;95(6):375-377.

Sun Y, Tan M, Duan H, Swaroop M. SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. Antioxid Redox Signal 2001;3(4):635-650. (Review).

Swaroop M, Gosink M, Sun Y. SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes. DNA Cell Biol 2001;20(7):425-434.

Yang GY, Pang L, Ge HL, Tan M, Ye W, Liu XH, Huang FP, Wu DC, Che XM, Song Y, Wen R, Sun Y. Attenuation of ischemia-induced mouse brain injury by SAG, a redox- inducible antioxidant protein. J Cereb Blood Flow Metab 2001;21(6):722-733.

Kim SY, Bae YS, Park JW. Thio-linked peroxidase activity of human sensitive to apoptosis gene (SAG) protein. Free Radic Res 2002;36:73-78.

Chanalaris A, Sun Y, Latchman DS, Stephanou A. SAG attenuates apoptotic cell death caused by simulated ischaemia/reoxygenation in rat cardiomyocytes. J Mol Cell Cardiol 2003;35(3):257-264.

Kim SY, Lee JH, Yang ES, Kil IS, Bae YS. Human sensitive to apoptosis gene protein inhibits peroxynitrite-induced DNA damage. Biochem Biophys Res Commun 2003;301:671-674.

Kim YS, Lee JY, Son MY, Park W, Bae YS. Phosphorylation of threonine-10 on CKBBP1/SAG/ROC2/Rbx2 by protein kinase CKII promotes the degradation of IkBa and p27kip1. J Biol Chem 2003;278:28462-28469.

Tan M, Gallegos JR, Gu Q, Huang Y, Li J, Jin Y, Lu H, Sun Y. SAG/ROC-SCFbeta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection. Neoplasia 2006;8(12):1042-1054.

Yang ES, Park JW. Regulation of nitric oxide-induced apoptosis by sensitive to apoptosis gene protein. Free Radic Res 2006;40(3):279-284.

Gu Q, Bowden, T.G., Normolle, D., and Sun, Y. SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage dependent targeting of c-Jun/AP1 and IkB/NF-kB. J Cell Biol 2007;178:1009-1023.

Gu Q, Tan M, Sun Y. SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Cancer Res 2007;67(8):3616-3625.

He H, Tan M, Pamarthy D, Wang G, Ahmed K, Sun Y. CK2 phosphorylation of SAG at Thr10 regulates SAG stability, but not its E3 ligase activity. Mol Cell Biochem 2007;295(1-2):179-188.

Kim SY, Kim MY, Mo JS, Park JW, Park HS. SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. Neurosci Lett 2007;413(2):132-136.

Tan M, Gu Q, He H, Pamarthy D, Semenza GL, Sun Y. SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1alpha ubiquitination and degradation. Oncogene 2008;27(10):1404-1411.


Sun Y. RNF7 (RING finger protein-7). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):289-291.





STARD13 (star-related lipid transfer (START) domain containing 13) Thomas Ho-Yin Leung, Judy Wai Ping Yam, Irene Oi-lin Ng

Departments of Pathology, Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong


Online updated version: http://AtlasGeneticsOncology.org/Genes/STARD13ID44051ch13q13.html DOI: 10.4267/2042/38546


Identity Hugo: STARD13 Other names: DLC2 (Deleted in Liver Cancer 2); FLJ37385; GT650 Location: 13q13.3

DNA/RNA Note: GeneLoc location for GC13M032575: Start: 32,575,307bp from pter; End: 32,757,892; Size: 182,585; Orientation: minus strand.

Description DLC2 was identified due to striking sequence homology to DLC1. It localizes to a small region of 13q12.3, which is a locus frequently deleted in hepatocellular carcinoma (HCC) as well as in other

cancers. Physical mapping of DLC2 in human genome revealed that it is in close proximity to the BRCA2 locus and flanked by microsatellite markers D13S171 and D13S267. The human DLC2 gene spans a region of 182 kb and contains 14 coding exons. Transcription The mRNA of DLC2 is 5886 bp long with an open reading frame of 3342 bp. Using bioinformatic analysis, 4 isoforms of DLC2, namely, DLC2alpha (5886 bp), DLC2beta (5810 bp), DLC2gamma (5784 bp), and DLC2delta (943 bp) have been identified. These 4 isoforms are generated by alternative splicing of the 5' end of the transcript. Northern blot analysis detected 7.2- and 4.2-kb DLC2 transcripts in all tissues examined, with the highest expression in heart, skeletal muscle, kidney, and pancreas.

Genomic characterization of human DLC2. (A) chromosomal map location of human DLC2 at 13q 12.3. Arrows underneath the gene symbols indicate the orientation of transcription. RFC3, replication factor C subunit 3; KL, Klotho; AS3, androgen shutoff 3; BRCA2, breast cancer 2, early onset; Tel, telomeric; Cen, centromeric. (B) genomic organization of human DLC2 locus. Non-coding (open boxes) and coding (filled boxes) are shown. (Ching YP,et al. J Biol Chem 2003).

STARD13 (star-related lipid transfer (START) domain containing 13) Leung THY, et al.


Protein Description DLC2alpha encodes a 1113-amino acid protein which has a calculated molecular mass of 125 kD. DLC2 contains an N-terminal sterile alpha motif (SAM) domain for protein-protein interactions, followed by an ATP/GTP-binding motif, a GTPase-activating protein (GAP) domain, and a C-terminal STAR-related lipid transfer (START) domain. The 4 isoforms of DLC2, DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta, encode proteins of 1113, 1105, 995, and 135 amino acids, respectively. DLC2alpha and DLC2beta encode a protein containing three functional domains, SAM, RhoGAP and START domains. DLC2alpha and DLC2beta differ by only a few N-terminal amino acids. DLC2gamma contains the RhoGAP and START domains, but lacks the N-terminal SAM domain, whereas DLC2delta contains only the SAM domain. Co-immunoprecipitation assay of ectopically expressed DLC2 in cells revealed that DLC1 forms homodimers in vivo and the region 160-672 residues is responsible for the interaction. Expression DLC2 is ubiquitously expressed in human tissues and is more abundant in heart, skeletal muscle, kidney and pancreas.

Localisation DLC2alpha, DLC2beta and DLC2gamma are predominantly localized in the cytoplasm in mouse

fibroblast and human HCC cells. Cellular fractionation and immunofluorescence microscopy revealed that DLC2 localizes to cytoplasmic speckles overlapping with mitochondria and in structures in close proximity to lipid droplets. The START domain of DLC2 has been demonstrated to be responsible for mitochondria targeting of DLC2.

Function DLC2 has been implicated to be a tumor suppressor protein. DLC2 has growth suppressive and anti-metastatic effects on HCC cell line, HepG2 and breast cancer cell line, MCF7. The RhoGAP domain has been demonstrated to be responsible for its biological functions and the RhoGAP activity has been demonstrated in vitro and in vivo. Recombinant DLC2 showed GAP activity specific for small GTPases, RhoA and Cdc42. Using GST-Rhoteckin pull down assay, in vivo RhoA activity has been shown to be negatively regulated by DLC2. However, in cells transfected with DLC2 RhoGAP mutant, the in vivo RhoA activity remained unchanged. Moreover, DLC2 inactivates RhoA activity via its RhoGAP domain and leads to the inhibition of actin stress fiber formation. Ectopic expression of DLC2 changed mouse fibroblast morphology from angular and spindle-shaped to round-shaped with dendritic cellular protrusions. Cells express DLC2 RhoGAP mutants did not exhibit morphological change and the actin stress fiber formation in these cells is unaffected. Introduction of human DLC2 into mouse fibroblasts suppressed Ras signaling and Ras-induced cellular transformation in a GAP-dependent manner. Overexpression of DLC2 also

A. DLC2 is a multifunctional protein. Diagram of protein domains in DLC2. SAM, sterile alpha motif; ATP/GTP binding, ATP/GTP-binding site motif A; GAP, RhoGAP domain; START, StAR-related lipid transfer domain. (Ching YP,et al. J Biol Chem 2003). B. Functional domains of the DLC2 isoforms. DLC2alpha and DLC2beta each contains a SAM, a RhoGAP, and a START domain, but they differ in their N-terminal sequence. The difference in the amino acid sequence was located at the first 60 aa in DLC2alpha and the first 52 aa in DLC2beta. DLC2gamma contains a RhoGAP and a START domain. DLC2delta only contains a SAM domain. (Leung TH, et al. Proc Nat Acad Sci USA. 2005).

STARD13 (star-related lipid transfer (START) domain containing 13) Leung THY, et al.


suppressed cell proliferation, motility and anchorage-independent growth in human hepatoma cells. Collectively, down regulation of RhoA activity in HCC cell line by DLC2 resulted in change of cell morphology, migration rate, proliferation rate and transforming ability. Several proteins were identified as interacting partners of DLC2 by yeast two-hybrid screening. These proteins include SWI/SNF, alpha-tubulin, HMG CoA reductase, and TAX1 binding protein (TAX1BP1).

Homology DLC family members: DLC1 is located at chromosome 8p22; DLC3 is located at chromosome Xq13; DLC2 shares 51% and 52% amino acid identities with DLC1 and DLC3, respectively.

Implicated in Cancer Note: DLC2, with its RhoGAP domain, is able to inhibit the activity of RhoA, which is believed to play a significant role in cell transformation in many cancer types. Down regulation of DLC2 mRNA expression has been reported in various types of cancer including liver, breast, lung, ovarian, renal, uterine, gastric, colon and rectal tumors. DLC2 localizes to a small region of 13q12.3 commonly deleted in HCC. DLC2 is flanked by microsatellite markers D13S171 and D13S267. Loss of heterozygosity on these two markers is frequently found in HCC. Allelic losses at markers D13S171 and D13S267 are detected in 33.3% and 40.7% of the informative cases, respectively. RT-PCR analysis of DLC2 mRNA in 45 HCC samples revealed that 17.8% of the cases showed significant underexpression (more than 2-fold) of DLC2 mRNA when compared with the corresponding non-tumorous liver tissues from the same patients. Studies in human cancers have suggested that small GTPases of the Rho family are critically involved tumorigenesis. Suppression of RhoA activity may be able to reverse the transformation phenotype in cancers. RhoGAP activity of DLC2 has been demonstrated both in vitro and in vivo. Anchorage-independent growth of cancer cells is a hallmark of cellular transformation. Stable expression of DLC2 in liver cancer cell line

effectively abolished the anchorage-independent growth ability of the cells. This indicated that DLC2 is capable of reducing the transforming phenotype and supports the view that DLC2 is a functional tumor suppressor.

References Ching YP, Wong CM, Chan SF, Leung THY, Ng DCH, Jin DY, Ng IOL. Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma. J Biol Chem 2003;278:10824-10830.

Nagaraja GM, Kandpal RP. Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. Biochem Biophys Res Commun 2004;313:654-665.

Popescu NC, Durkin ME. Rho GTPase activating protein cDNA on chromosome 13q12 is the deleted in liver cancer (DLC2) gene. Biochem Biophys Res Commun 2004;315:781.

Leung THY, Ching YP, Yam JWP, Wong CM, Yau, TO, Jin, DY, Ng IOL. Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proc Nat Acad Sci USA 2005;102:15207-15212.

Ng DC, Chan SF, Kok KH, Yam JW, Ching YP, Ng IO, Jin DY. Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. FEBS Lett 2006;580:191-198.

Ullmannova V, Popescu NC. Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol 2006;29:1127-1132.

Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC. DLC-1: a Rho GTPase-activating protein and tumor suppressor. J Cell Mol Med 2007;11(5):1185-1207.

Kwan JJ, Donaldson LW. The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle. BMC Struct Biol 2007;22:7-34.

Li H, Fung KL, Jin DY, Chung SS, Ching YP, Ng IO, Sze KH, Ko BC, Sun H. Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2. Proteins 2007;67:1154-1166.

Qian X, Li G, Asmussen HK, Asnaghi L, Vass WC, Braverman R, Yamada KM, Popescu NC, Papageorge AG, Lowy DR. Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities. Proc Natl Acad Sci USA 2007;104:9012-9017.


Leung THY, Yam JWP, Ng IOL. STARD13 (star-related lipid transfer (START) domain containing 13). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):292-294.

Gene Section Short Communication




TTL (twelve-thirteen translocation leukemia) Jean-Loup Huret

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


Online updated version: http://AtlasGeneticsOncology.org/Genes/TTLID529ch13q14.html DOI: 10.4267/2042/38547


Identity Other names: FLJ21437; LOC646982; TTL/TEL; TTL-T; TTL-B1; TTL-B2 Location: 13q14.11 Note: Not to be confused with: TTL : tubulin tyrosine ligase (2q13), nor with 'transthyretin-like (TTL) gene family', a family to which belongs TTR (transthyretin, 18q12).

DNA/RNA Description Start at 39,822,377 bp from pter; the gene spans 119,929 bases on minus strand.

Transcription Three splicing forms, namely: TTL-T, TTL-B1 and -B2. TTL-T is 2090 bp long and composed of exons 1-8. The longest open-reading frame contains exons 4, 5, and part of exon 6; it encods a 133 amino acids peptid. TTL-B1 transcript is 3450 bp long and is composed of exons 4, 5, and part of exon 9. TTL-B2, 3588 bp long is composed of exons 4, 5, and part of exon 8a.

Protein Note: This gene/protein remains poorly known: there has been no study on it since the princeps paper by Qiao et al (2003).

Expression Ubiquitous expression (lung, liver, spleen, thymus, and bone marrow); major expression in brain and testis.

Homology TTL has no homology to known genes.

Implicated in t(12;13)(p13;q14) in B-cell acute lymphoblastic leukaemia (B-ALL) → ETV6/TTL Note: Only one case to date.

Hybrid/Mutated Gene Both reciprocal transcripts, TTL/ETV6 and ETV6/TTL, were detected. ETV6/TTL fusion transcript. The other transcript, TTL/ETV6, comprises 5' TTL exons 1 to 5 or to 8a, fused to ETV6 from exon 2. The predicted 530 amino acids fusion protein consists mostly of ETV6 with both HLH and ETS domains, and could have modified transcriptional activities. On the other hand, a loss of function of ETV6 and/or of TTL could play the critical role in leukemogenesis.

References Qiao Y, Ogawa S, Hangaishi A, Yuji K, Izutsu K, Kunisato A, Imai Y, Wang L, Hosoya N, Nannya Y, Sato Y, Maki K, Mitani K, Hirai H. Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;q14), and its implication in leukemogenesis. Leukemia 2003 Jun;17(6):1112-20.


Huret JL. TTL (twelve-thirteen translocation leukemia). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):295.

Gene Section Review




ZFP36L1 (zinc finger protein 36, C3H type-like 1) Deborah J Stumpo, Perry J Blackshear

Laboratory of Neurobiology, NIEHS MD A2-05, 111 Alexander Drive, Research Triangle Park, NC 27709, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/ZFP36L1ID42866ch14q22.html DOI: 10.4267/2042/38548


Identity Hugo: ZFP36L1 Other names: Berg36; BRF1; cMG1; ERF1; TIS11B Location: 14q24.1 Note: The rat clone of ZFP36L1, cMG1, was the first cloned member of the tristetraprolin (TTP, TIS11, NUP475, GOS24) family of CCCH tandem zinc finger proteins. There are 4 mammalian members of this family, TTP, ZFP36L1, ZFP36L2 (TIS11D, ERF2, BRF2), and ZFP36L3. ZFP36L3 is the only family member that is rodent-specific. These proteins have been shown to bind (via their conserved tandem zinc finger domain) directly to class II AU-rich elements (ARE) in the 3'-untranslated region (UTR) of mRNA leading to deadenylation and destabilization of the mRNA.

DNA/RNA

Diagram of the human ZFP36L1 gene. Exons are represented by gray boxes; intron by the hatched box. The translation start site is indicated by the arrow and the translation stop site by the double line. The dark box represents the CCCH tandem zinc finger domain.

Description The human ZFP36L1 has 2 exons spanning 5411 bp on chromosome 14 (NC_000014.7; NT_026437.11). The first exon, which is small (186 bp), is separated from the larger second exon (2834 bp) by a 2388 bp intron.

Transcription 3022 bp human transcript (NM_004926.2) with 1014 bp (338 amino acids) of coding region.

Pseudogene None known.

Protein Description Human ZFP36L1 is a 338 amino acid protein with a predicted molecular weight of 36.3 kDa.

Expression In the adult mouse, expression appears to be ubiquitous. Based on northern blots, mRNA expression is highest in mouse kidney, spleen, ovary and lung, with lower levels of expression in thymus and heart, and still lower levels in brain, liver and testis. In the embryonic mouse, mRNA was barely detectable at embryonic day 7.5 (E7.5), but increased dramatically by E9.5 and E10.5. In situ hybridization histochemistry demonstrated that there was high level expression in the allantois at E8.0, immediately before fusion with the chorion. Expression is also seen in mouse embryonic stem cells.

Localisation Transfection studies using a GFP-tagged protein have shown diffuse cytoplasmic expression. There is good evidence that the protein can shuttle between the nucleus and the cytoplasm in a CRM1 (nuclear export receptor)-dependent, leptomycin B-inhibitable manner.

Function ZFP36L1 is a member of the TTP (ZFP36) family of CCCH tandem zinc finger proteins. These proteins have been shown to bind to target mRNAs through their AU-rich elements present in the 3'-untranslated regions of the mRNA. The binding of these proteins to mRNA leads to deadenylation and destabilization of the mRNA. All four family members have been shown to bind directly

ZFP36L1 (zinc finger protein 36, C3H type-like 1) Stumpo DJ, Blackshear PJ


to single stranded RNA probes (RNA gel shift assays), destabilize target mRNA (co-transfection assays), and deadenylate ARE-containing RNA probes (cell-free deadenylation assays). Physiological target mRNAs have been identified for TTP which include tumor necrosis factor alpha (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2b (IL-2), and immediate early response gene 3 (IER3, IEX-1, gly96). To date, one physiological target mRNA has been identified for ZFP36L1; however, this target mRNA is not destabilized by ZFP36L1 (see below). Two reports of ZFP36L1 knockout mice have been published. In one report, knockout embryos died around embryonic day 11 mainly due to failure of chorioallantoic fusion. When fusion did occur, there was increased apoptosis throughout the neural tube, as well as placental failure due to atrophy of the trophoblast layers. In a second report, knockout embryos also died at mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, the extraembryonic mesoderm failed to invaginate the trophoblast layer. This phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A (in the embryo and in mouse embryonic fibroblasts). This elevated level of expression was not due to increased stability of the VEGF-A mRNA, but rather due to enhanced association with polyribosomes. This is in contrast to a prior report using co-transfection studies showing that ZFP36L1 was able to bind to two AU-rich motifs in the 3' UTR of VEGF mRNA that led to destabilization of the mRNA. Mouse ZFP36L1 has been shown to interact with 14-3-3 proteins in a phosphorylation-dependent manner. This interaction causes ZFP36L1 to be sequestered in the cytoplasm preventing it from regulating mRNA decay. Several studies have suggested that ZFP36L1 may function as a pro-apoptotic protein.

Homology Four members of the TTP family of CCCH tandem zinc finger proteins, TTP (ZFP36), ZFP36L1, ZFP36L2 and the rodent-specific ZFP36L3, have been identified. They all share a highly conserved tandem zinc finger domain.

Mutations Note: Eight polymorphisms have been identified. The functional significance of these polymorphisms has not been determined. 1) G change into T at base 644 in the 5' UTR. 2) AG change into GC at base 706 in the first coding region. 3) G change into A at base 729 in the intron. 4) C change into CC at base 772 in the intron.

5) A change into G at base 804 in the intron. 6) G change into C at base 845 in the intron. 7) G change into A at base 3685 in the second coding region. 8) C change into A at base 3915 in the second coding region.

Implicated in Cisplatin sensitivity in head and neck squamous cell carcinoma (HNSCC) Note: A common feature in HNSCC is cisplatin sensitivity. Microarray analysis identified mouse ZFP36L1 to be differentially expressed by cisplatin treatment. Cisplatin-sensitive HNSCC cell lines expressed elevated levels of ZFP36L1 compared to cisplatin-resistant HNSCC cell lines. Downregulation of ZFP36L1 (using antisense oligonucleotides) in cisplatin-sensitive cell lines made the cells cisplatin-resistant. Conversely, overexpression of ZFP36L1 reverted cisplatin-resistant cells to cisplatin-sensitive cells. There was an inverse correlation between the expression levels of ZFP36L1 and the human inhibitor of apoptosis protein-2, cIAP2 (Birc3, baculoviral IAP repeat-containing 3). Increased expression of ZFP36L1 also correlated with increased caspase-3 activity and increased cisplatin-induced apoptosis. These results suggested that expression of ZFP36L1 enhanced cisplatin sensitivity in HNSCC cells by reducing cIAP2 mRNA levels.

t(8;21) translocation Note: The AML1-MTG8 fusion transcription factor generated by t(8;21) translocation is thought to affect the normal regulation of genes that are needed for differentiation and proliferation of hematopoietic progenitors leading to acute myelogenous leukemia (AML). ZFP36L1 was identified as an up-regulated gene in t(8;21) leukemic cells suggesting that it may be important to AML1-MTG8-mediated leukemogenesis.

Human T-lymphotropic virus 1 (HTLV-1) Note: ZFP36L1 expression is also up-regulated in human T-lymphotropic virus 1(HTLV-1)-infected cells. HTLV-1 is associated with adult T-cell leukemia/lymphoma and the Tax oncoprotein encoded by the 3' region of HTLV-1 has been proposed to dysregulate the expression of many genes that are important for cell proliferation. The Tax transactivator was shown to bind to two ZFP36L1 upstream elements (a novel transcription factor-binding site labeled BRF1 Tax-responsive site or BTRS and a second consensus cAMP-responsive site or CRE).

Various cancers Note: Increased expression of ZFP36L1 has been seen in several cancers including lymph node (+) primary breast tumors and hepatocellular carcinomas. Increased

ZFP36L1 (zinc finger protein 36, C3H type-like 1) Stumpo DJ, Blackshear PJ


expression has also been demonstrated in a number of the NCI 60 panel of human cancer cell lines. These include the mammary gland cancer cell lines BT549, MDA-MB-231, and NCI/ADR-RES; ovarian cell lines OVCAR-5, OVCAR-8 and SK-OV-3; lung cell line NCI-H226; skin cell lines LOXMVI, M14, MALME-3M, and SK-MEL-2; brain cell lines SF268 and SF295; prostate cell line PC-3; kidney cell lines A498, ACHN, CAKI-1, SN12C, TK10, and UO31; and colon cell line HT29.

References Gomperts M, Pascall JC, Brown KD. Identification of a mRNA rapidly induced in an intestinal epithelial cell line by epidermal growth factor. Biochem Soc Trans 1990;18(4):568-569.

Varnum BC, Ma QF, Chi TH, Fletcher B, Herschman HR. The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat. Mol Cell Biol 1991;11(3):1754-1758.

Bustin SA, Nie XF, Barnard RC, Kumar V, Pascall JC, Brown KD, Leigh IM, Williams NS, McKay IA. Cloning and characterization of ERF-1, a human member of the Tis11 family of early-response genes. DNA Cell Biol 1994;13(5):449-459.

Ning ZQ, Norton JD, Li J, Murphy JJ. Distinct mechanisms for rescue from apoptosis in Ramos human B cells by signaling through CD40 and interleukin-4 receptor: role for inhibition of an early response gene, Berg36. Eur J Immunol 1996;26(10):2356-2363.

Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 1998;281(5379):1001-1005.

Bustin SA, McKay IA. The product of the primary response gene BRF1 inhibits the interaction between 14-3-3 proteins and cRaf-1 in the yeast trihybrid system. DNA Cell Biol 1999;18(8):653-661.

Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood 2000;95(6):1891-1899.

Johnson BA, Geha M, Blackwell TK. Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival. Oncogene 2000;19(13):1657-1664.

Lai WS, Carballo E, Thorn JM, Kennington EA, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. J Biol Chem 2000;275(23):17827-17837.

Shimada H, Ichikawa H, Nakamura S, Katsu R, Iwasa M, Kitabayashi I, Ohki M. Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF. Blood 2000;96(2):655-663.

Johnson BA, Stehn JR, Yaffe MB, Blackwell TK. Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms. J Biol Chem 2002;277(20):18029-18036.

Phillips RS, Ramos SB, Blackshear PJ. Members of the tristetraprolin family of tandem CCCH zinc finger proteins exhibit CRM1-dependent nucleocytoplasmic shuttling. J Biol Chem 2002;277(13):11606-11613.

Blackshear PJ, Phillips RS, Vazquez-Matias J, Mohrenweiser H. Polymorphisms in the genes encoding members of the tristetraprolin family of human tandem CCCH zinc finger proteins. Prog Nucleic Acid Res Mol Biol 2003;75:43-68.

Li B, Fink T, Ebbesen P, Liu XD, Zachar V. Expression of butyrate response factor 1 in HTLV-1-transformed cells and its transactivation by tax protein. Arch Virol 2003;148(9):1787-1804.

Ciais D, Cherradi N, Bailly S, Grenier E, Berra E, Pouyssegur J, Lamarre J, Feige JJ. Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Oncogene 2004;23(53):8673-8680.

Stumpo DJ, Byrd NA, Phillips RS, Ghosh S, Maronpot RR, Castranio T, Meyers EN, Mishina Y, Blackshear PJ. Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family. Mol Cell Biol 2004;24(14):6445-6455.

Blackshear PJ, Phillips RS, Ghosh S, Ramos SB, Richfield EK, Lai WS. Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins. Biol Reprod 2005;73(2):297-307.

Lee SK, Kim SB, Kim JS, Moon CH, Han MS, Lee BJ, Chung DK, Min YJ, Park JH, Choi DH, Cho HR, Park SK, Park JW. Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines. Int J Cancer 2005;117(1):32-40.

Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR. Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol 2005;174(2):953-961.

Bell SE, Sanchez MJ, Spasic-Boskovic O, Santalucia T, Gambardella L, Burton GJ, Murphy JJ, Norton JD, Clark AR, Turner M. The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression. Dev Dyn 2006;235(11):3144-3155.

Benjamin D, Schmidlin M, Min L, Gross B, Moroni C. BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites. Mol Cell Biol 2006;26(24):9497-9507.

Lai WS, Parker JS, Grissom SF, Stumpo DJ, Blackshear PJ. Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts. Mol Cell Biol 2006;26(24):9196-9208.

Zindy PJ, L'Helgoualc'h A, Bonnier D, Le Béchec A, Bourd-Boitin K, Zhang CX, Musso O, Glaise D, Troadec MB, Loréal O, Turlin B, Léger J, Clément B, Théret N. Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis. Hepatology 2006;44(5):1296-1307.

Abba MC, Sun H, Hawkins KA, Drake JA, Hu Y, Nunez MI, Gaddis S, Shi T, Horvath S, Sahin A, Aldaz CM. Breast cancer molecular signatures as determined by SAGE: correlation with lymph node status. Mol Cancer Res 2007;5(9):881-890.

Carrick DM, Blackshear PJ. Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines. Arch Biochem Biophys 2007;462(2):278-285.


Stumpo DJ, Blackshear PJ. ZFP36L1 (zinc finger protein 36, C3H type-like 1). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):296-298.

Gene Section Review




ZNF384 (zinc finger protein 384) Paolo Gorello, Roberta La Starza, Cristina Mecucci

Hematology, University of Perugia, via Brunamonti, 06122 Perugia, Italy


Online updated version: http://AtlasGeneticsOncology.org/Genes/ZNF384ID42881ch12p13.html DOI: 10.4267/2042/38549


Identity Hugo: ZNF384 Other names: CAGH1; CAGH1A; CIZ; ERDA2; NMP4; NP; TNRC1 Location: 12p13.31 Local order: centromere 5'-ZNF384- 3' telomere.

DNA/RNA Note: GeneLoc location for GC12M006646: Start: 6,645,904 bp from pter; End: 6,668,930 bp from pter; Size: 23,026 bases (23 kb); Orientation: minus strand

Transcription Transcript Variant: different alternative splicing isoforms are described.

Protein Note: Similarity: belongs to the Kruppel C2H2-type zinc-finger protein family; contains 8 C2H2-type zinc fingers.

Description Nucleocytoplasmic shuttling protein and transcription factor which appear to bind and regulate the promoter of MMP1, MMP3, MMP7 and COL1A1. Multiple transcript variants encoding several protein isoforms have been found.

Localisation Nucleus.

The diagram shows all genes (including ZNF384), with their orientation from centromere to telomere, which are localized in a region going from 6,590 Kbp to 6,720 Kbp at 12p13.

Schematic representation of CIZ protein. LZ: leucine-rich domain SR: serine rich domain PR: Proline rich domain NLS: Nuclear Localization signal ZFs: Kruppel-type C2H2 zinc finger domains QA: Gln-Ala repeat (See also Martini et al., Cancer Research 2002).

ZNF384 (zinc finger protein 384) Gorello P, et al.


Implicated in Acute lymphoblastic leukemia with t(12;17)(p13;q11) → TAF15/ZNF384 Disease pro-B Acute lymphoblastic leukemia with expression

of myeloid antigens (ANPEP/CD13 and/or CD33, and less frequently FUT4/CD15); acute myeloid leukemia.

Prognosis Relatively good prognosis.

Abnormal Protein TAF15-ZNF384

A) schematic representation of the reciprocal t(12;17)(p13;q11) translocation; B) Break-a-part FISH: RP11-369N23 maps telomeric to the 3' ZNF384 while RP11-101F21 partially overlaps with the 5' end of ZNF384 (RP11 clones belong to the Peter De Jong library and were kindly provided by M Rocchi).

Schematic representation of the TAF15-ZNF384 fusion protein. SYQG, Ser-Tyr-Gln-Gly transactivating domain; RGG, Arg-Gly-Gly rich region, (RNA binding domain); LZ, leucine-rich domain; SR, serine rich domain; PR, Proline rich domain; NLS, Nuclear Localization signal; ZFs, Kruppel-type C2H2 zinc finger domains QA: Gln-Ala repeat (see also Martini et al., Cancer Res 2002).



Acute lymphoblastic leukemia with t(12;19)(p13;p13) → E2A/ZNF384 Disease pro-B Acute Lymphoblastic Leukemia with expression of myeloid antigens.


Cytogenetics The t(12;19)(p13;p13) is cryptic.

Abnormal Protein

ZNF384-E2A

Acute lymphoblastic leukemia with t(12;22)(p13;q12) → EWSR1/ZNF384 Disease pro-B Acute Lymphoblastic Leukemia with expression of myeloid antigens; biphenotypic leukemia.


Abnormal Protein EWSR1-ZNF384

A) schematic representation of the reciprocal t(12;19)(p13;p13) translocation; B) Break-a-part FISH: RP11-369N23 maps telomeric to the 3'ZNF384 while RP11-101F21 partially overlaps with the 5' end of ZNF384 (RP11 clones belong to the Peter De Jong library and were kindly provided by M Rocchi).

Schematic representation of the EWSR1-ZNF384 fusion protein. SYQG, Ser-Tyr-Gln-Gly transactivating domain; LZ, leucine-rich domain; SR, serine rich domain; PR, Proline rich domain; NLS, Nuclear Localization signal; ZFs, Kruppel-type C2H2 zinc finger domains; QA, Gln-Ala repeat (see also Martini et al., Cancer Res 2002).



Schematic representation of the reciprocal t(12;22)(p13;q12) translocation producing the EWSR1-ZNF384 fusion gene.

Breakpoints

References Bidwell JP, Torrungruang K, Alvarez M, Rhodes SJ, Shah R, Jones DR, Charoonpatrapong K, Hock JM, Watt AJ. Involvement of the nuclear matrix in the control of skeletal genes: the NMP1 (YY1), NMP2 (Cbfa1), and NMP4 (Nmp4/CIZ) transcription factors. Crit Rev Eukaryot Gene Expr 2001;11(4):279-297. (Review). Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A, Somers R, Aventin A, Foa R, Hagemeijer A, Mecucci C, Marynen P. Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res 2002;62(19):5408-5412.

Krane SM. Identifying genes that regulate bone remodeling as potential therapeutic targets. J Exp Med 2005;201(6):841-843. (Review).

La Starza R, Aventin A, Crescenzi B, Gorello P, Specchia G, Cuneo A, Angioni A, Bilhou-Nabera C, Boqué C, Foà R, Uyttebroeck A, Talmant P, Cimino G, Martelli MF, Marynen P, Mecucci C, Hagemeijer A. CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. Leukemia 2005;19(9):1696-1699.

Fan Z, Tardif G, Boileau C, Bidwell JP, Geng C, Hum D, Watson A, Pelletier JP, Lavigne M, Martel-Pelletier J. Identification in human osteoarthritic chondrocytes of proteins binding to the novel regulatory site AGRE in the human matrix metalloprotease 13 proximal promoter. Arthritis Rheum 2006;54(8):2471-2480.

Janssen H, Marynen P. Interaction partners for human ZNF384/CIZ/NMP4--zyxin as a mediator for p130CAS signaling? Exp Cell Res 2006;312(7):1194-1204.


Gorello P, La Starza R, Mecucci C. ZNF384 (zinc finger protein 384). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):299-302.





CD53 (CD53 molecule) Pedro A Lazo

Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, campus Miguel de Unamuno, E-37007 Salamanca, Spain

Published in Atlas Database: December 2007

Online updated version: http://AtlasGeneticsOncology.org/Genes/CD53ID983ch1p13.html DOI: 10.4267/2042/38550


Identity Hugo: CD53 Other names: TSPAN25; Tetraspanin-25; Tspan-25; tetraspanin-25; CD53 glycoprotein; CD53 tetraspan antigen; MOX44 Location: 1p13.3 Local order: Telomere-KCNA3--Q8NHC3---CD53---C1orf103---TMEM77---CEPT1---DENND2D-Centromere.

DNA/RNA Description Gene size: 26,77 Kbp; 8 exons.

Transcription Transcript length: 1,567 bps.

Protein Note: Size: 219 amino acids; 24341 Da; Four transmembrane domains. Subcellular location: Plasma Membrane; endosomes.

Localisation Plasma membrane; endosomes; exoxomes.

Function Modifier of signal transduction.

Homology Member of the tetraspanin protein family.

Map of chromosomal region 1p13.3

Exon-Intron structure of human CD53 gene.

CD53 (CD53 molecule) Lazo PA


The CD53 protein has four transmembrane domains. Several residues are conserved and define the tetraspanin protein family. The protein is glycosylated (green) in its second extracellular loop. Internally the protein is palmitoylated (red lines). EC: extracellular.

Location of breakpoint in chromosome region 1p13.3 in a case of T-ALL with a t(1;22)(p13;q13). The CD53 gene is not structurally altered. It is not known if its level of expression is affected.

Implicated in T-cell acute lymphoblastic leukemia Cytogenetics t(1;22)(p13;q13)

Abnormal Protein None.

References Gonzalez ME, Pardo-Manuel de Villena F, Fernandez-Ruiz E, Rodriguez de Cordoba S, Lazo PA. The human CD53 gene, coding for a four transmembrane domain protein, maps to chromosomal region 1p13. Genomics 1993;18:725-728.

Korínek V, Horejsí V. Genomic structure of the human CD53 gene. Immunogenetics 1993;38:272-279.

Olweus J, Lund-Johansen F, Horejsi V. CD53, a protein with four membrane-spanning domains, mediates signal transduction in human monocytes and B cells. J Immunol 1993;151:707-716.

Taguchi T, Bellacosa A, Zhou JY, Gilbert DJ, Lazo PA, Copeland NG, Jenkins NA, Tsichlis PN, Testa JR. Chromosomal localization of the Ox-44 (CD53) leukocyte antigen gene in man and rodents. Cytogenet Cell Genet 1993;.64:217-221.

Gallego MI, Varas F, Lazo PA. HindIII RFLP in the human CD53 gene on 1p13. Hum Mol Genet 1994;3:1711.

Rasmussen AM, Blomhoff HK, Stokke T, Horejsi V, Smeland EB. Cross-linking of CD53 promotes activation of resting human B lymphocytes. J Immunol 1994;153:4997-5007.

CD53 (CD53 molecule) Lazo PA


Mannion BA, Berditchevski F, Kraeft SK, Chen LB, Hemler ME. Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). J Immunol 1996;157:2039-2047.

Szöllósi J, Horejsí V, Bene L, Angelisová P, Damjanovich S. Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. J Immunol 1996;157:2939-2946.

Mollinedo F, Fontán G, Barasoain I, Lazo PA. Recurrent infectious diseases in human CD53 deficiency. Clin Diagn Lab Immunol 1997;4:229-231.

Nichols TC, Guthridge JM, Karp DR, Molina H, Fletcher DR, Holers VM. Gamma-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes. Eur J Immunol 1998;28:4123-4129.

Beinert T, Münzing S, Possinger K, Krombach F. Increased expression of the tetraspanins CD53 and CD63 on apoptotic human neutrophils. J Leuk Biol 2000;67:369-373.

Hernández-Torres J, Yunta M, Lazo PA. Differential cooperation between regulatory sequences required for human CD53 gene expression. J Biol Chem 2001;276:35405-35413.

Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 2003;19:397-422. (Review).

Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ, Fero M, Pollack JR, Van De Rijn M, Brooks JD. Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Am J Pathol 2003;162:925-932.

Yunta M, Lazo PA. Apoptosis protection and survival signal by the CD53 tetraspanin antigen. Oncogene 2003;22:1219-1224.

Barrena S, Almeida J, Yunta M López A, Díaz-Mediavilla J, Orfao A, Lazo PA. Discrimination of biclonal B-cell chronic

lymphoproliferative neoplasias by tetraspanin antigen expression. Leukemia 2005:19: 1708-1709.

Barrena S, Almeida J, Yunta M, López A, Fernández-Mosteirín N, Giralt M, Romero M, Perdiguer L, Delgado M, Orfao A, Lazo PA. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 2005;19:1376-1383.

Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 2005;6:801-811. (Review).

Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO, Israel MA. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Nat Acad Sci USA 2005;102:5814-5819.

West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP, Montgomery K, Zhu S, Patel R, Hernandez-Boussard T, Goldblum JR, Brown PO, van de Vijver M, van de Rijn M. Determination of stromal signatures in breast carcinoma. PLoS biology 2005;3:e187.

Berger R, Bernard OA. Interleukin-2 receptor beta chain locus rearrangement in a T-cell acute lymphoblastic leukemia. Pathol Biol (Paris) 2007;55:56-58.

Lazo PA. Functional implications of tetraspanin proteins in cancer biology. Cancer science 2007;98:1666-1677. (Review).

Månsson R, Lagergren A, Hansson F, Smith E, Sigvardsson M. The CD53 and CEACAM-1 genes are genetic targets for early B cell factor. Eur J Immunol 2007;37:1365-1376.


Lazo PA. CD53 (CD53 molecule). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):303-305.

Gene Section Review




EVI1 (ecotropic viral integration site 1 (EVI1) and myelodysplastic syndrome 1 (MDS1)-EVI1) Rotraud Wieser

Medizinische Universitaet Wien, Department fuer Medizinische Genetik, Waehringerstr. 10, A-1090 Wien, Austria


Online updated version: http://AtlasGeneticsOncology.org/Genes/EVI103q26ID19.html DOI: 10.4267/2042/38551

This article is an update of: Chakraborty S, Buonamici S, Senyuk V, Nucifora G. EVI1-MDS1/EVI1 (ecotropic viral integration site 1 (EVI1) and myelodysplastic syndrome 1 (MDS1)-EVI1). Atlas Genet Cytogenet Oncol Haematol.2003;7(3):160-161. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: EVI1 Other names: PRDM3 Location: 3q26.2

DNA/RNA Description The human EVI1 gene spans approximately 65 kb of genomic DNA. 14 of its 16 exons are coding (Fig. 1A). Transcription can initiate from alternative exons 1a, 1b,

1c, 1d, or 3L (Fig. 1B), and several alternative splice variants of the EVI1 mRNA have been described (Delta324, -Rp9, Delta105; Fig. 1A). The human MDS1 gene consists of 4 exons spread over a genomic region of more than 500 kb. MDS1 exon 4 is located less than 2 kb upstream of EVI1 exon1a. The MDS1-EVI1 mRNA presumably results from splicing of the second exon of MDS1 to the second exon of EVI1 (Fig. 1B).

Transcription Telomere to centromere.

Figure 1. Genomic locus of the human EVI1 gene and EVI1 mRNA variants. Asterisk, translation initiation codon; diamond, translation stop codon. (This figure was reprinted from Gene 396, R. Wieser, 'The oncogene and developmental regulator EVI1: Expression, biochemical properties, and biological functions', pages 346-357, Copyright Elsevier (2007), with permission from Elsevier. Gene homepage: http://www.sciencedirect.com/science/journal/03781119).

EVI1 (ecotropic viral integration site 1 (EVI1) and myelodysplastic syndrome 1 (MDS1)-EVI1) Wieser R


Figure 2. A) EVI1 and B) MDS1/EVI1 protein domains and EVI1 interacting proteins. Black boxes, zinc finger motifs; RD, repression domain, with binding motifs for the transcriptional corepressor CtBP depicted as black bars; ac, acidic region; PR, PR domain. This figure was reprinted from Gene 396, R. Wieser, 'The oncogene and developmental regulator EVI1: Expression, biochemical properties, and biological functions', pages 346-357, Copyright Elsevier (2007), with permission from Elsevier. Gene homepage: http://www.sciencedirect.com/science/journal/03781119.

Protein Description Exon 3 of the human EVI1 gene contains two closely spaced ATG codons, either of which may serve as the translation initiation site. Depending on which ATG is used, proteins of 1051 or 1041 amino acids will be formed. EVI1 contains two domains of seven and three zinc finger motifs, respectively, a repression domain between the two sets of zinc fingers, and an acidic domain of unknown function at its C-terminus. It is a 145 kDa protein that is capable of binding to DNA in a sequence specific manner, and that interacts with transcriptional coactivators (P/CAF, CBP) and corepressors (CtBP, HDAC) as well as other sequence specific transcription factors (GATA1, Smad3). Predicted translation of MDS1-EVI1 adds 188 amino acids to the N-terminus of EVI1. 63 of these additional amino acids are derived from the untranslated second exon and the untranslated part of the third exon of EVI1, and the remaining 125 from the MDS1 gene. MDS1-EVI1 contains a PR domain, which is about 40% homologous to the N-terminus of the retinoblastoma-binding protein, RIZ, and the PRDI-BF1 transcription factor. Some biological functions of MDS1/EVI1 are different from, or even antagonistic to, those of EVI1.

Expression In human tissues/organs, the EVI1 mRNA is expressed abundantly in kidney, lung, pancreas, stomach, ovaries, uterus, and prostate, to a lesser extent in the small intestine, colon, thymus, spleen, heart, brain, testis, and placenta, and at very low levels in skeletal muscle and bone marrow. The pattern of expression of MDS1-EVI1 is very similar to that of EVI1. In the adult mouse, the Evi1 mRNA is expressed, at

varying levels, in the kidney, lung, stomach, ovary, uterus, intestine, thymus, spleen, heart, brain, and liver. In the mouse embryo, Evi1 mRNA levels are high in the urinary system and Mullerian ducts, the lung, the heart, and the emerging limb buds. Similar Evi1 expression patterns were also observed in Xenopus, chicken, and zebrafish.

Localisation Nuclear; in part in speckles.

Function Because of the spatially and temporally restricted expression of EVI1, it has been suggested that this gene plays an important role in development and could be involved in organogenesis, cell migration, cell growth, and differentiation. In the mouse, homozygous disruption of the 6th exon of the Evi1 gene lead to embryonic lethality, with widespread hypocellularity, reduced body size, small or absent limb buds, a pale yolk sac and placenta, abnormal development of the nervous system and the heart, and massive haemorrhaging. EVI1 is thought to exert its biological functions mainly by acting as a transcription factor. In addition, however, EVI1 has been reported to inhibit c-jun N-terminal kinase, and to stimulate PI3K/AKT signalling.

Homology EVI1 orthologs are present in many species. Evi1 proteins from other mammals share more than 90% amino acid sequence identity with the human protein, and Xenopus Evi1 is 77% identical to its human counterpart. MDS1-EVI1 shares an overall homology with the C. elegans Egl 43 protein that includes the PR domain at the N-terminus and the two zinc-finger domains. An MDS1/EVI1 ortholog, hamlet, is also present in Drosophila.



Figure3. Normal and leukemia-associated EVI1 protein variants.

Implicated in t(3;3)(q21;q26) or inv(3)(q21q26) Note: 3q21q26 syndrome. Chromosomal rearrangements located either 5' or 3' of the EVI1 gene can activate its transcription in haematopoietic cells. Usually, t(3;3)(q21;q26) breakpoints are located 5' of EVI1, and inv(3)(q21q26) breakpoints 3' of it. Nevertheless, in both cases aberrant expression of the EVI1 gene may be due to its juxtaposition to the enhancer of the constitutively expressed housekeeping gene ribophorin 1 at 3q21.

Disease Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS), and Chronic Myelogenous Leukemia (CML).

Prognosis Patients with EVI1 rearrangements have elevated platelet counts, marked hyperplasia with dysplasia of megakaryocytes, and a poor prognosis.

Cytogenetics Rearrangements at 3q26 may occur as a sole anomaly, but are often associated with monosomy 7 or deletion of the long arm of chromosome 7, and, less frequently, deletion in chromosome 5.

Oncogenesis Inappropriate expression of EVI1 in haematopoietic cells alters differentiation into granulocytes, erythrocytes and megakaryocytes. EVI1 promotes the proliferation of certain cell types, but inhibits the growth of others. It interferes with growth inhibition by TGF-b and with apoptosis elicited by a variety of stimuli. In a murine bone marrow transduction/transplantation model, EVI1 caused a

disease resembling human myelodysplastic syndrome. Additional coexpression of Hoxa9 and Meis 1 lead to overt leukemia.

t(3;21)(q26;q22) Disease Therapy-related MDS/AML and CML during the blast crisis.

Prognosis Poor.

Cytogenetics Complex.

Abnormal Protein AML1 -MDS1-EVI1.

Oncogenesis AML1-MDS1-EVI1 is a chimeric transcription factor that interferes with AML1 functions in a dominant negative manner, but shares some biological effects with EVI1.

t(3;12)(q26;p13) Disease CML during the blast crisis and MDS in transformation.

Prognosis Poor.

Cytogenetics Complex.

Abnormal Protein Overexpression of a fusion protein between the amino terminus of TEL, which does not contain any functional domains, and the entire MDS1/EVI1 protein is driven by the TEL promoter.



AML without 3q26 rearrangements. Note: EVI1 may also be overexpressed in AML, MDS, or CML in blast crisis in the absence of any cytogenetically detectable 3q26 rearrangements.

Disease AML, MDS, CML.

Prognosis Poor (AML).

Oncogenesis As above.

Breakpoints Note: Other chromosomal rearrangements that results in the inappropriate expression of EVI1 include t(2;3)(p13;q26), t(2;3)(q23;q26), t(3;7)(q27;q22), t(3;8)(q26;q24), t(3;13)(q26;q13-14), and t(3;17)(q26;q22).

References Morishita K, Parkar DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN. Retroviral activation of a novel gene encoding a zinc finger protein in IL-3 dependent myeloid leukemia cell lines. Cell 1988;54:831-840.

Bordereaux D, Fichelson S, Tambourin P, Gisselbrecht S. Alternative splicing of the Evi-1 zinc finger gene generates mRNAs which differ by the number of zinc finger motifs. Oncogene 1990;5:925-927.

Morshita K, Parganas E, Douglass EC, Ihle JN. Unique expression of the Evi-1 gene in an endrometrial carcinoma cell line: sequence of cDNAs and structure of alternatively spliced transcripts. Oncogene 1990;5:963-971.

Perkins AS, Mercer JA, Jenkins NA, Copeland NG. Patterns of Evi-1 expression in embryonic and adult tissues suggest that Evi-1 plays an important regulatory role in mouse development. Development 1991;111:479-487.

Nucifora G, Birn DJ, Espinosa R 3rd, Erickson P, LeBeau MM, Roulston D, McKeithan TW, Drabkin H, Rowley JD. Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood 1993;81:2728-2734.

Bartholomew C, Clark AM. Induction of two alternatively spliced evi-1 proto-oncogene transcripts by cAMP in kidney cells. Oncogene 1994;9:939-942.

Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M, Hirai H. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J 1994;13:504-510.

Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN, Rowley JD. Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Proc Natl Acad Sci USA 1994;91:4004-4008.

Russell M, List A, Greenberg P, Woodward S, Glinsmann B, Parganas E, Ihle J, Taetle R. Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood 1994;84:1243-1248.

Suzukawa K, Parganas E, Gajjar A, Abe T, Takahashi S, Tani K, Asano S, Asou H, Kamada N, Yokota J, et al. Identification of a breakpoint cluster region 3' of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26). Blood 1994;84:2681-2688.

Levaltier X, Penther D, Bastard C, Troussard X. t(2;3)(p23;q26) in a patient with AML M2. Br J Haematol 1996;92:1027.

Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud N, Marynen P. Fluorescence in situ hybridization analysis of t(3;12)(q26;p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Blood 1996;88:682-689.

Yufu Y, Sadamura S, Ishikura H, Abe Y, Katsuno M, Nishimura J, Nawata H. Expression of EVI1 and the retinoblastoma genes in acute myelogenous leukemia with t(3;13)(q26;q13-14). Am J Hematolol 1996;53:30-34.

Hoyt PR, Bartholomew C, Davis AJ, Yutzey K, Gamer LW, Potter SS, Ihle JN, Mucenski ML. The Evi1 proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development. Mech Dev 1997;65:55-70.

Nucifora G. The EVI1 gene in myeloid leukemia. Leukemia 1997;11:2022-2031. (Review).

Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P. Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer Res 1997;57:564-569.



Jółkowska J, Witt M. The EVI-1 gene-its role in pathogenesis of human leukemias. Leuk Res 2000;24:553-558. (Review).

Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, Ogawa S, Moriguchi T, Nishida E, Yazaki Y, Hirai H. The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J 2000;19:2958-2968.

Chakraborty S, Senyuk V, Sitailo S, Chi Y, Nucifora G. Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles. J Biol Chem 2001;276:44936-44943.

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

Voutsadakis IA, Maillard N. Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: Case report and review of the literature. Am J Hematol 2003;72:135-137.

Vinatzer U, Mannhalter C, Mitterbauer M, Gruener H, Greinix H, Schmidt HH, Fonatsch C, Wieser R. Quantitative comparison of the expression of EVI1 and its presumptive antagonist, MDS1/EVI1, in patients with myeloid leukemia. Genes Chromosomes Cancer 2003;36:80-89.

Wieser R, Schreiner U, Rieder H, Pirc-Danoewinata H, Grüner H, Loncarevic IF, Fonatsch C. Interphase fluorescence in situ hybridization assay for the detection of rearrangements of the EVI-1 locus in chromosome band 3q26 in myeloid malignancies. Haematologica 2003;88:25-30.

Buonamici S, Li D, Chi Y, Zhao R, Wang X, Brace L, Ni H, Saunthararajah Y, Nucifora G. EVI1 induces myelodysplastic syndrome in mice. J Clin Invest 2004;114:713-719.

Stevens-Kroef M, Poppe B, van Zelderen-Bhola S, van den Berg E, van der Blij-Philipsen M, Geurts van Kessel A, Slater R, Hamers G, Michaux L, Speleman F, Hagemeijer A. Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: report of 21 new cases, clinical, cytogenetic and molecular genetic features. Leukemia 2004;18:1108-1114.

Aytekin M, Vinatzer U, Musteanu M, Raynaud S, Wieser R. Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends. Gene 2005;356:160-168.

Du Y, Jenkins NA, Copeland NG. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 2005;106:3932-3939.

Kilbey A, Alzuherri H, McColl J, Calés C, Frampton J, Bartholomew C. The Evi1 proto-oncoprotein blocks endomitosis in megakaryocytes by inhibiting sustained cyclin-dependent kinase 2 catalytic activity. Br J Haematol 2005;130:902-911.

Mead PE, Parganas E, Ohtsuka S, Morishita K, Gamer L, Kuliyev E, Wright CV, Ihle JN. Evi-1 expression in Xenopus. Gene Expr Patterns 2005;5:601-608.

Yuasa H, Oike Y, Iwama A, Nishikata I, Sugiyama D, Perkins A, Mucenski ML, Suda T, Morishita K. Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression. EMBO J 2005;24:1976-1987.

Alzuherri H, McGilvray R, Kilbey A, Bartholomew C. Conservation and expression of a novel alternatively spliced Evi1 exon. Gene 2006;384:154-162.

Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006;12:401-409.

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

Van Campenhout C, Nichane M, Antoniou A, Pendeville H, Bronchain OJ, Marine JC, Mazabraud A, Voz ML, Bellefroid EJ. Evi1 is specifically expressed in the distal tubule and duct of the Xenopus pronephros and plays a role in its formation. Dev Biol 2006;294:203-219.

Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D. t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Cancer 2006;106:1730-1738.

Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol 2007;136:806-813.

Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T, Miyata S,Nakamura T. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 2007;109:3998-4005.

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


Wieser R. EVI1 (ecotropic viral integration site 1 (EVI1) and myelodysplastic syndrome 1 (MDS1)-EVI1). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):306-310.





KIF14 (kinesin family member 14) Brigitte L Thériault, Timothy W Corson

Division of Applied Molecular Oncology, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, ON, Canada (BLT); Department of Molecular, Cellular and Developmental Biology, Yale (TWC)


Online updated version: http://AtlasGeneticsOncology.org/Genes/KIF14ID44138ch1q32.html DOI: 10.4267/2042/38552


Identity Hugo: KIF14 Other names: KIAA0042; HUMORFW; MGC142302 Location: 1q32.1 Local order: Genes flanking KIF14 at 1q32.1 are (centromeric to telomeric): ZNF281 (zinc finger protein 281), KIF14, DDX59 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 59).

DNA/RNA Description Gene spans 68.5 kbp on the minus strand at 1q32.1.

Transcription One known 6586 base transcript, 30 exons. The KIF14 promoter is bound by p130/ E2F4 under growth arrest conditions; further details of transcriptional regulation are currently lacking.

Protein Description KIF14 is a 186 kDa, 1648 aa protein, containing kinesin motor and forkhead-associated (FHA) domains. It is a member of the N-3 family of kinesins. High-throughput studies have identified phosphorylations on Tyr-196; Ser-1200 and Ser-1292, and ubiquitination on Lys-275.

Expression KIF14 was cloned from an immature myeloid cell line, KG-1. By qRT-PCR, KIF14 is expressed at low levels in normal adult tissues and at higher levels in placenta

and fetal tissues; highest expression is in fetal thymus and liver. KIF14 expression varies with the cell cycle, with highest expression at G2-M.

Localisation In HeLa cells, KIF14 is localized to the cytoplasm during interphase, and becomes tightly localized to the midbody and central spindle during cytokinesis.

Function KIF14 is a mitotic kinesin motor protein with ATPase activity. It interacts with protein regulator of cytokinesis 1 (PRC1) and is essential for localizing citron kinase to the mitotic spindle. KIF14 knockdown results in failure of cytokinesis, leading to multinucleation and/or apoptosis, but no chromosome segregation defects.

Homology There are KIF14 orthologs in several mammalian species. The closest Drosophila melanogaster gene, with 40% amino acid identity, is nebbish/tiovivo, encoding Klp38B (kinesin-like protein 38B). Klp38B is a mitotic kinesin that binds to chromatin and microtubules in the formation of the bipolar spindle and attachment of chromosomes to the spindle, and/or acts in cytokinesis.

Mutations Germinal None yet identified.

Somatic None yet identified.

KIF14 (kinesin family member 14) Thériault BL, Corson TW


Schematic representation of the KIF14 protein (not to scale). KIF14 contains two major effector domains. The first is a highly conserved 274 aa kinesin motor domain containing an ATP-binding site (aa 447-454) which is involved in microtubule-dependent ATPase activity, and a microtubule binding site (aa 455-628) involved in ATP-dependent protein transport. The second is a 67 aa forkhead-associated (FHA) domain (aa 825-891) which has similarity to the SMAD Mad Homology 2 (MH2) domain, and is involved in mediating protein-protein interactions with phosphoproteins, although no such interactions have been documented for KIF14. In addition to the highly conserved N-type neck region (N) adjacent to the motor domain, KIF14 also contains 4 other C-terminal regions predicted to form coiled-coil structures (1-4). Phosphorylation sites have been identified on Tyr-196, Ser-1200 and Ser-1292 (P), and a ubiquitination site identified on Lys-275 (U). The kinesin motor and FHA domains are flanked by a 354 aa N-terminal extension, and a 758 aa C-terminal stalk and tail region. The N-terminal extension is involved in the binding of PRC1 (protein-regulating cytokinesis 1), a protein crucial for the proper formation of the central spindle structure during cytokinesis. Citron kinase has been shown to interact with the C-terminal stalk and tail of KIF14, and this interaction is required for proper localization of KIF14 to the mitotic spindle.

Implicated in Retinoblastoma Prognosis KIF14 mRNA and protein expression is greatly increased in tumors versus normal adult and fetal retina. mRNA expression is higher in older patients' tumors than younger.

Cytogenetics KIF14 lies in a 'hotspot' of genomic gain at 1q31.3-1q32.1. Low-level genomic gain (3-5 copies) of the gene is observed in 50% of tumors. High-level amplification has been observed in one tumor (along with, but independent of, MYCN amplification).

Breast carcinoma Prognosis mRNA expression increases with grade, and is higher in ductal than lobular carcinoma, and in estrogen receptor (ER) negative over ER positive tumors. Expression correlates with proliferation, and overexpression is prognostic for poor overall and disease-free survival.

Cytogenetics KIF14 lies in a 'hotspot' of genomic gain at 1q31.3-1q32.1. Low-level genomic gain of the gene is observed in 50% of breast cancer cell lines.

Non-small-cell lung carcinoma Prognosis mRNA expression decreases with differentiation, and is higher in squamous cell than adenocarcinoma. Overexpression is independently prognostic for poor

disease-free survival, and prognostic for poor overall survival.

Oncogenesis Knockdown of KIF14 decreases proliferation of H1299 NSCLC cells, and decreases their ability to form colonies in soft agar.

Hepatocellular carcinoma Cytogenetics Low-level gain of the KIF14 locus is seen in 58% tumors.

To be noted Note: Numerous microarray studies indexed in Oncomine document overexpression of KIF14 in other cancers, including brain tumors, seminoma, prostate and tongue cancers.

References Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S. Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res 1994;1:223-229.

Molina I, Baars S, Brill JA, Hales KG, Fuller MT, Ripoll P. A chromatin-associated kinesin-related protein required for normal mitotic chromosome segregation in Drosophila. J Cell Biol 1997;139:1361-1371.

Ohkura H, Török T, Tick G, Hoheisel J, Kiss I, Glover DM. Mutation of a gene for a Drosophila kinesin-like protein, Klp38B, leads to failure of cytokinesis. J Cell Sci 1997;110:945-954.

Durocher D, Taylor IA, Sarbassova D, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB. The molecular basis of FHA domain:phosphopeptide binding specificity and

KIF14 (kinesin family member 14) Thériault BL, Corson TW


implications for phospho-dependent signaling mechanisms. Mol Cell 2000;6:1169-1182.

Miki H, Setou M, Kaneshiro K, Hirokawa N. All kinesin superfamily protein, KIF, genes in mouse and human. Proc Natl Acad Sci USA 2001;98:7004-7011.

Corson TW, Huang A, Tsao MS, Gallie BL. KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers. Oncogene 2005;24:4741-4753.

Zhu C, Zhao J, Bibikova M, Leverson JD, Bossy-Wetzel E, Fan J-B, Abraham RT, Jiang W. Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. Mol Biol Cell 2005;16:3187-3199.

Carleton M, Mao M, Biery M, Warrener P, Kim S, Buser C, Marshall CG, Fernandes C, Annis J, Linsley PS. RNA interference-mediated silencing of mitotic kinesin KIF14 disrupts cell cycle progression and induces cytokinesis failure. Mol Cell Biol 2006;26:3853-3863.

Corson TW, Gallie BL. KIF14 mRNA expression is a predictor of grade and outcome in breast cancer. Int J Cancer 2006;119:1088-1094.

Gruneberg U, Neef R, Li X, Chan EHY, Chalamalasetty RB, Nigg EA, Barr FA. KIF14 and citron kinase act together to promote efficient cytokinesis. J Cell Biol 2006;172:363-372.

Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB, Gallie BL. Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. Genes Chromosomes Cancer 2007;46:118-129.

Corson TW, Zhu CQ, Lau SK, Shepherd FA, Tsao MS, Gallie BL. KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin Cancer Res 2007;13:3229-3234.

Madhavan J, Coral K, Mallikarjuna K, Corson TW, Amit N, Khetan V, George R, Biswas J, Gallie BL, Kumaramanickavel G. High Expression of KIF14 in Retinoblastoma: Association with Older Age at Diagnosis. Invest Ophthalmol Vis Sci 2007;48:4901-4906.


Thériault BL, Corson TW. KIF14 (kinesin family member 14). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):311-313.

Gene Section Review




NTRK2 (neurotrophic tyrosine kinase, receptor, type 2) Nadia Gabellini

University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3, 35121, Padua, Italy


Online updated version: http://AtlasGeneticsOncology.org/Genes/NTRK2ID41589ch9q21.html DOI: 10.4267/2042/38553


Identity Hugo: NTRK2 Other names: GP145-TrkB; TRKB; Trk-B Location: 9q21.33 Local order: NTRK2 is located between solute carrier family 28, sodium-coupled nucleoside transporter member 3 (SLC28A3) and ATP/GTP binding protein 1 (AGTPBP1).

DNA/RNA Table 1: NTRK2 exons and size (bp).

Description NTRK2 gene is comprised between 86,473,286-86,828,325 bp of chromosome 9, with plus strand orientation. The start codon is located on exon 5. Alternative stop codons are placed on terminal exons 16, 19 and 24. Transcription According to AceView (NCBI), six alternative promoters may control transcription of the complex NTRK2 locus. There are at least 18 mRNA variants supported by cDNA clones, potentially encoding 12 complete proteins. Variants may include 8 different terminal exons with alternative polyadenylation sites. Truncation at the 5' end or 3' end, alternative splicing, intron retention, occurrence of 5 cassette exons, and different exon boundaries introduce additional differences. Five confirmed mRNA variants (a, b, c, d, e) are reported (NCBI accessions: NM_006180.3; NM_001007097.1; NM_001018064.1; NM_001018065.1; NM_001018066.1). The mRNA variant (a) encodes the full-length protein; variant (c) is slightly shorter excluding the small internal exon 17. Of particular importance are the truncated isoforms

lacking the catalytic tyrosine kinase domain generated by the inclusion of alternate terminal exon 16 (b) or exon 19 (d) and (e).

Pseudogene None.

Protein Note: Three TrkB isoforms are reported by UniProt/Swiss-Prot: 1. The long isoform TrkB, including the tyrosine kinase domain (ID Q16620-1; variant c). 2. The truncated isoform TrkB-T1 lacking the tyrosine kinase domain (ID Q16620-2; variant b). 3. The truncated isoform TrkB-T-Shc lacking the tyrosine kinase domain but retaining the Shc site (ID Q16620-3; variant e).

Description The unprocessed precursor of the full-length TrkB (a) consists of 838 AA. Variant (c) excludes 16 AA of unknown function, located downstream of the transmembrane segment. The N-terminal portion (AA 32-430) is potentially extracellular and includes several N-glycosylation sites (AA 67, 121, 254). It follows a single transmembrane segment (AA 432-454). The C-terminal portion is cytosolic (AA 455-822) and comprises the Protein Kinase domain. This region includes the ATP binding site (AA 544-552) and several sites of autophosphorylation such as Tyr-516/702/706/707/817 (AA position refers to variant c). The truncated Trkb-T1 (b) is composed of 477 AA. TrkB-T-Shc variants d and e consist of 553 AA and 537 AA, respectively. Truncated isoforms TrkB-T1 and TrkB-T-Shc include C-terminal sequence variations of 10 and 9 AA, respectively.

NTRK2 (neurotrophic tyrosine kinase, receptor, type 2) Gabellini N


Figure 1: The horizontal bar represents NTRK2 gene (355,039 bp). Vertical bars depict the exons 1-24 (red: translated regions, blue: 5' and 3' UTR regions).

The predicted domains of TrkB (variant c): Signal Peptide (SP, AA 1-31); Leucine Rich Repeat N-Terminal domain (LRRNT, AA 31-65); Leucine-rich Repeats (LRR, AA 72-93, 96-117, 116-138); Leucine Rich Repeat C-Terminal domain (LRRCT, AA 148-195); Immunoglobulin C-2 Type 1 domain (IGC2-1, AA 197-282); Immunoglobulin C-2-type 2 domain (IGC2-2, AA 295-365); Transmembrane (TM, AA 431-454); the Protein Kinase domain (TyrKc, AA 538-807). In addition the site of interaction with SHC1 (Shc, AA 516) and with Phospho-Lipase C-gamma-1 (AA PLC-gamma, 817) are indicated.

Expression NTRK2 gene is preferentially expressed in brain, spinal cord, cranial and spinal ganglia. Expression is most prominent in the following brain regions: amygdale, caudate nucleus, cerebellum, choroid plexus, corpus callosum, cortex, hippocampus, hypothalamus and thalamus. In addition, a variety of cranial structures such as eyes, ophthalmic nerves, various facial districts and vestibular system indicate significant expression. Lower expression is described in several other tissues such as heart, kidney, lung, ovaries, pancreas, pituitary gland, prostate, salivary glands, skeletal muscle, spleen, thymus and thyroid. Isoforms TrkB and TrkB-T1 are expressed in brain as well as in several peripheral areas, whereas TrkB-T-Shc is primarily expressed in brain. AceView (NCBI) analysis of cDNA clones supports the expression pattern suggested by the evaluation of mRNA described above. In addition suggests elevated expression in several tumor tissues.

Localisation Neuronal activity promotes TrkB translocation from intracellular vesicles to the plasma membrane where it becomes available for neurotrophins. The N-terminal segment is extracellular and is involved in neurotrophin binding and cell adhesion. A single transmembrane segment is located in the central portion of the polypeptide. The C-terminal segment is intracellular and comprises the protein kinase domain.

Function TrkB specifically binds brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5. It can also bind neurotrophin-3 with low affinity but it excludes nerve growth factor (NGF). Neurotrophin binding triggers receptor dimerization and consequent trans-phosphorylation of tyrosine residues of the TyrKc domain. Phosphorylated receptor undergoes conformational changes, which promote the recruitment of intracellular substrates such SHC1, PI-3



kinase, and PLC-gamma-1. The signaling cascades consequently activated support neuronal survival during development and following injuries, promote neuronal differentiation and maintenance, control short-term and long-term synaptic activity. TrkB can also form heterodimers with the pan-neurotrophin receptor p75NTR or with truncated TrkB. This influences the establishment of specific connections with signaling pathways.

Homology TrkB belongs to the large family of protein kinase comprising a conserved kinase domain. It is included in the subfamily of tyrosine protein kinase. For the presence of a highly conserved intracellular TyrKc domain it is most related to growth factor receptors, and particularly to the neurotrophic factor receptors TrkA and TrkC. The homology with tyrosine kinase receptors is extended to the IGC-2 and LRRs domains, however, these are also present in cell-adhesion molecules.

Mutations Germinal Heterozygous missense mutations leading to substitution of highly conserved residues have been linked to Obesity, Hyperphagia and Developmental Delay. Recurrent SNPs of the NTRK2 locus are associated with Eating Disorders (Anorexia and Bulimia nervosa).

Somatic Tumor-specific mutations in the kinase domain have been identified in Colorectal Cancer cells.

Implicated in Various diseases Disease Obesity, Hyperphagia and Developmental Delay. Neuroblastomas, Pancreatic Ductal Adenocarcinomas, Wilms's tumors, Colorectal Cancer.

Oncogenesis Overexpression of full-length TrkB is generally associated with malignant transformation. Excessive TrkB signaling through MAPK, PI3K and mTOR pathways support tumor development and metastasis. In highly malignant tumors the overexpression of TrkB enhances angiogenesis and invasive potential by upregulating VEGF and matrix proteases. Furthermore TrkB overcomes apoptosis caused by loss of cell-matrix interactions (anoikis), which is a natural barrier to metastasis. In contrast with the oncogenic activity of TrkB, the truncated isoforms TrkB-T1 and TrkB-T-Shc, lacking

the tyrosine kinase domain, behave as dominant-negative inhibitors and counteract tumor growth.

To be noted Note: NTRK2 gene is comprised in the region, del(9q), commonly deleted in acute myeloid leukemia, this disease is believed to arise by heterozygous loss of tumor suppressor genes. Numerous structural abnormalities of the region 9q22 are associated with cancer cases reported by The Cancer Genome Anatomy Project (CGAP).

References Klein R, Parada LF, Coulier F, Barbacid M. trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development.v. EMBO J 1989;8:3701-3709.

Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203-212. (Review).

Schneider R, Schweiger M. A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors. Oncogene 1991;6:1807-1811.

Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J, Burton LE, Stanton BR, Kaplan DR, Hunter T, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 1991;65:895-903.

Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C, Glass DJ, Masiakowski P, Furth ME, Valenzuela DM, et al. trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell 1991;65:885-893.

Middlemas DS, Meisenhelder J, Hunter T. Identification of TrkB autophosphorylation sites and evidence that phospholipase C-gamma 1 is a substrate of the TrkB receptor. J Biol Chem 1994;269:5458-5466.

Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 1994;14:759-767.

Nakagawara A, Liu XG, Ikegaki N, White PS, Yamashiro DJ, Nycum LM, Biegel JA, Brodeur GM. Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2). Genomics 1995, 25:538-546.

Aoyama M, Asai K, Shishikura T, Kawamoto T, Miyachi T, Yokoi T, Togari H, Wada Y, Kato T, Nakagawara A. Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants. Cancer Lett 2001;164:51-60.

Stoilov P, Castren E, Stamm S. Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun 2002;290:1054-1065.

Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003;300:949.

Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004;430:1034-1039.

Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS. A de novo



mutation affecting human TrkB associated with severe obesity and developmental delay. Nature Neurosci 2004;7:1187-1189.

Hecht M, Schulte JH, Eggert A, Wilting J, Schweigerer L. The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. Carcinogenesis 2005;26:2105-2115.

Nykjaer A, Willnow TE, Petersen CM. p75NTR--live or let die. Curr Opin Neurobiol 2005;15:49-57. (Review).

Ribases M, Gratacos M, Badia A, Jimenez L, Solano R, Vallejo J, Fernandez-Aranda F, Estivill X. Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, harm avoidance and minimum body mass index. Mol Psychiatry 2005;10:851-860.

Sclabas GM, Fujioka S, Schmidt C, Li Z, Frederick WA, Yang W, Yokoi K, Evans DB, Abbruzzese JL, Hess KR, Zhang W, Fidler IJ, Chiao PJ. Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 2005;11:440-449.

Sweetser DA, Peniket AJ, Haaland C, Blomberg AA, Zhang Y, Zaidi ST, Dayyani F, Zhao Z, Heerema NA, Boultwood J, Dewald GW, Paietta E, Slovak ML, Willman CL, Wainscoat JS, Bernstein ID, Daly SB. Delineation of the minimal commonly

deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 2005;44:279-291.

Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 2006;66:4249-4255.

Geiger TR, Peeper DS. Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res 2007;67:6221-6229.

Han L, Zhang Z, Qin W, Sun W. Neurotrophic receptor TrkB: Is it a predictor of poor prognosis for carcinoma patients?. Med Hypotheses 2007;68:407-409.


Gabellini N. NTRK2 (neurotrophic tyrosine kinase, receptor, type 2). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):314-317.





PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)) Dina Stepanova, Jonathan Chernoff

Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/PAK1ID41633ch11q13.html DOI: 10.4267/2042/38554


Identity Hugo: PAK1 Other names: Alpha-PAK; MGC130000; MGC130001; P65-PAK; PAK-1; PAKalpha Location: 11q13.5 Local order: centromere - MYO7A - GDPD4 - LOC387791 - PAK1 - DFFZp434E1119 - FLJ38894 - AQP11. Note: PAK1 encodes a serine/threonine specific protein kinase that is a member of the PAK branch of the STE20 family. PAK1 plays a role in cell survival, polarity, and motility, and may have oncogenic function when overexpressed.

DNA/RNA

The alignment of PAK1 mRNA to its genomic sequence.

Description The PAK1 gene contains 14 exons. The sizes of the exons 1-14 are 189, 100, 129, 147, 37, 119, 174, 63, 48,

112, 117, 99, 196, 137, and 86 bps. Exon 2 contains the translation initation ATG, and a few additional codons. Exon 13 contains the stop codon. Other features of the PAK1 gene, such as promoters or enhancer elements, have not been described.

Transcription PAK1 expression is particularly high in the brain. Other tissues which have reasonably high levels of PAK1 expression include spleen and skeletal muscle. The mRNA size is 1945 bps.

Protein Description PAK1 is a highly conserved serine/threonine protein kinase of 545 amino acids and is a member of the PAK group of the STE20 family of serine/threonine protein kinases. Pak1 is active in a monomeric form; the non-active form is an autoinhibited homodimer. Pak1 contains a regulatory N-terminal regulatory domain and non-classical SH3-binding site for the PIX family of proteins (PXP). Pak1 binds to activated forms of the GTPases Cdc42 and Rac. Pak1 homodimerizes through a motif adjacent to the p21-binding domain, and is autoinhibited.

Upon binding to Cdc42 or Rac, Pak1 is activated and autophosphorylates. Pak1 has dozens of substrates,

activating cytoskeletal and transcription pathways that enhance cell motility, proliferation, and survival.

PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)) Stepanova D, Chernoff J


Expression PAK1 is highly expressed in epithelium of tongue and larynx and in thyroid gland, expression also found in central nervous system (brain).

Localisation Under basal conditions, Pak1 localizes to the cytosol. Upon growth factor stimulation, Pak1 is recruited to the plasma membrane as well as the nucleus.

Function Cell survival and proliferation

Homology Similar to STE20 in budding yeast and PAK1 in fission yeast. Human PAK1 complements both these yeast genes.

Mutations Note: No mutations in the PAK1 gene have been reported.

Implicated in Cancers Disease There is emerging evidence that the Pak family may play a key role in several human malignancies, including breast, ovarian, head and neck, colon, thyroid, and renal cancer. In human breast cancer, the expression level of Pak1 correlates with the tumor grade, with higher expression in less differentiated ductal carcinomas of the breast (grade III tumors) than in grade II and grade I tumors. Pak1 overexpression is also associated with tamoxifen resistance in breast cancer. In human tumors, Pak1 is not itself activated by mutation: rather, Pak1 is

overexpressed by unknown mechanisms. Pak1 may also play a role in transformation by Kaposi's sarcoma-associated herpes virus, which induces Kaposi's sarcoma and primary effusion lymphomas.

Prognosis Recently, it has been shown that the level of phosphorylated (activated) Pak1 Level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. As noted above, Pak1 expression may also correlate with tamoxifen resistance in breast cancer.

References Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 1994;46:40-46.

Sells MA, Chernoff J. Emerging from the Pak: the p21-activated protein kinase family. Trends Cell Biol 1997;7:162-167. (Review).

Bagrodia S, Cerione RA. Pak to the future. Trends Cell Biol 1999;9:350-355. (Review).

Dan I, Watanabe NM, Kusumi A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 2001;11(5):220-230. (Review).

Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol 2002;34:713-717. (Review).

Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003;72:743-781. (Review).

Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci 2004;117:4343-4354. (Review).

Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. Nat Rev Cancer 2006;6:459-471. (Review).


Stepanova D, Chernoff J. PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):318-319.

Gene Section Review




POU4F1 (POU class 4 homeobox 1) Vishwanie Budhram-Mahadeo, David S Latchman

Medical Molecular Biology Unit, Institute of Child Health, 30 Guilford St, London WC 1N1 EH, UK


Online updated version: http://AtlasGeneticsOncology.org/Genes/POU4F1ID44173ch13q31.html DOI: 10.4267/2042/38555


Identity Hugo: POU4F1 Other names: BRN3A; Brn-3a; FLJ13449; Oct-T1; RDC-1 Location: 13q31.1 Local order: Gene orientation: minus strand. Note: Member of class IV POU domain transcription factor.

DNA/RNA Description The gene is about 4,468 bases encoded by two exons separated by a short intron.

Transcription 5', upstream promoter drives expression of longer Brn-3a transcript encoding for Brn-3a(l) protein which includes exons 1 and 2. Regulatory sequences within the intron control expression of short Brn-3a transcript entirely from exon 2, which encodes Brn-3a(s) protein.

Protein Description Protein product for Brn-3a(l) is 423 amino acids with estimated molecular weight of about 42.9 kDa whereas Brn-3a(s) protein is 339 amino acids; about 32 kDa.

Expression Nervous System: Originally isolated from brain cDNA, Brn-3a is expressed in specific neurons of midbrain and hindbrain in CNS and in peripheral sensory neurons (trigeminal ganglia, dorsal root ganglia, spinal cord). It is first seen in neural crest cells that are destined to form sensory neurons and expression persists in mature

neurones. Brn-3a is also expressed in retinal ganglion cells and vestibular somatosensory cells, where it cooperates with Brn-3b and Brn-3c respectively to determine cell fate. Non-neuronal cell: Brn-3a is also expressed in T-cells, heart, testis, ovary, breast epithelium. Cancers: implicated in neuroblastoma, Ewing sarcoma, cervical cancers, prostate cancers.

Localisation Nuclear.

Function Brn-3a proteins act as transcription factors to regulate the expression of target genes, which can alter cell fate. In neuron, Brn-3a protects cells from apoptosis (by transactivating anti-apoptotic genes while repressing expression of pro-apoptotic proteins -see below). Brn-3a also enhances differentiation of neuronal cells in vitro and in-vivo by its ability to transactivate multiple neuronal target promoters. Brn-3a is required for the generation of proprioceptors in trigeminal ganglia. The POU domain found at the C' terminal end of Brn-3a proteins is a bipartite DNA binding domain that can recognize and bind with high affinity and specificity to specific DNA sequences present in the promoters of target genes. DNA consensus sites recognized by Brn-3a include a core A/T rich octamer sequence e.g. ATAATTAAT with the POU-homeodomain (POU-HD) facilitating high affinity binding, whilst the POU-specific (POU-s) domain enhances specificity. The POU domain of Brn-3a protein also has transactivation function and since Brn-3a(l) and Brn-3a(s) are identical in this region, both proteins can regulate specific subsets of target genes that require POU domain transactivation function e.g. neurofilament, SNAP 25, synaptophysin, Hsp-27.

POU4F1 (POU class 4 homeobox 1) Budhram-Mahadeo V, Latchman DS


Schematic diagram showing the two isoforms of Brn3-a protein that can be derived from the Brn-3a gene as a result of alternative promoter usage (P1 and P2). AD refers to N-terminal activation domain present only in Brn-3a(l). POU domain found at the C' terminal of the protein is common to both Brn-3a(l) and Brn-3a(s). However, some Brn-3a target genes require the N' terminal transactivation domain that is found only in Brn-3a(l) protein and therefore these target genes can only be activated by Brn-3a(l) protein e.g. Bcl-2, Bcl-XL, alpha-internexin. Other target genes regulated by Brn-3a include TrkA, neuroD1 and neuroD4, Nav1.7 sodium channel, Doppel glycoprotein, iNOS, p53, NGFI-A, Hsp-27, tyrosine hydroxylase. Brn-3a also auto-regulate its own expression. In addition to its direct effects on specific target genes, Brn-3a can also alter gene expression by its interaction with other cellular factors. For example, Brn-3a interacts physically with p53 protein, and modifies its effects on specific target genes that regulate cell fate. Thus Brn-3a cooperates with p53 to increase the expression of the cell cycle regulator, p21cip1/waf1 whilst antagonising p53 mediated expression of pro-apoptotic target genes, Bax and Noxa. Brn-3a other interacting partner includes Rin1 (on target gene, Egr1), HIPK1 (alters TrkA expression), EWS - Fli1 fusion protein (represses Brn-3a mediated effects on survival / differentiation genes). In addition to cellular target genes, Brn-3a also controls expression of viral genes such as those encoding the human papilloma virus (HPV) immediate early E6/E7 gene (required for HPV transformation of cervical cells) by binding to and transactivating the viral promoter. It is thought that the ability of Brn-3a to transactivate this promoter contributes to its effects in transformation of cervical cancer cells.

Homology High homology with other POU4 family members in the POU domain (C' terminal end of the protein), and in the POU4 box (region of homology within the N' terminal transactivation domain, present only in Brn-3a(l)). Family members include mammalian POU4f2 (Brn-3b), POU4f3 (Brn-3c), drosophila I-POU and nematode, unc-86.

Implicated in Normal development of sensory neurons in CNS and PNS Note: Loss of Brn-3a by homologous recombination in mice resulted in significant loss of sensory neurons

(e.g. in the midbrain, trigeminal ganglia, dorsal root ganglia) during development. Mutants die within the first day of birth. Studies using cultured neural crest cells demonstrate that Brn-3a expressing cells are destined for sensory lineage. Brn-3a is required for the survival of these cells and achieves this partly by inhibiting expression of p53 mediated, pro-apoptotic target genes. Neural crest cells cultured from Brn-3a knockout mice, undergo significant apoptosis as a result of increased expression of p53 pro-apoptotic target genes, bax and Noxa.

Neuroblastomas Oncogenesis Brn-3a mRNA is significantly reduced in neuroblastoma tumour biopsies. Studies undertaken using neuroblastoma cell lines showed that Brn-3a is expressed at low levels when the cells are actively proliferating. However, when cells are induced to cease dividing and undergo differentiation, Brn-3a is significantly increased in cells. Forced over-expression of Brn-3a protects cells from apoptosis but also induces differentiation and neurite outgrowth. Therefore, the significant decrease of Brn-3 in neuroblastoma tumours may contribute to the oncogenic changes in the cells.

Neuroendocrine tumours Oncogenesis Brn-3a was shown to be elevated in highly aggressive neuroendocrine tumours SCCL tumours and ACTH producing pituitary tumours.

Ewing sarcoma Oncogenesis Brn-3a was detected in some Ewing sarcomas, which are tumours derived from primitive neural ectodermal lineage. These tumours are characterised by rearrangement of genes encoding the Ewing sarcoma (EWS) protein, and members of the Ets family of transcription factors. The most common fusion protein, EWS/Fli1, produces cellular transformation. Brn-3a interacts with the EWS/Fli1 fusion protein, and this interaction prevents Brn-3a mediated transactivation of genes required for cell cycle arrest e.g. p21cip1/waf1 and neurite outgrowth e.g. SNAP-25.



Cervical cancer Oncogenesis Brn-3a is expressed at high levels in high-grade cervical intra-epithelial neoplasia (CIN 3) compared to normal cervical biopsies. In this context, Brn-3a may contribute to tissue formation by binding to regulatory regions of Human Papilloma Viruses, HPV-16 and HPV18 and regulate expression of their oncogenic E6 and E7 genes.

Prostate cancer Oncogenesis Brn-3a was also detected in prostate cancers with up to 50% of tumours showing significant increase in expression of Brn-3a short isoforms.

Systemic lupus erythematosus Note: Brn-3a is elevated in approximately 43% of patients with SLE and this correlates with enhanced levels of auto-antibodies to the protein. Increased Brn-3a also correlates with enhanced expression of HSP 90 protein in serum of SLE patients.

References He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG. Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature 1989;340(6228):35-41.

Collum RG, Fisher PE, Datta M, Mellis S, Thiele C, Huebner K, Croce CM, Israel MA, Theil T, Moroy T, et al. A Novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system. Nucleic Acids Res 1992;20(18):4919-4925.

Lillycrop KA, Budhram VS, Lakin ND, Terrenghi G, Wood JN, Polak JM, Latchman DS. A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells. Nucleic Acids Res 1992;20(19):5093-5096.

Bhargava AK, Li Z, Weissman SM. Differential expression of four members of the POU family of proteins in activated and phorbol 12-myristate 13-acetate-treated Jurkat T cells. Proc Natl Acad Sci USA 1993;90(21):10260-10264.

Budhram-Mahadeo V, Theil T, Morris PJ, Lillycrop KA, Möröy T, Latchman DS. The DNA target site for the Brn-3 POU family transcription factors can confer responsiveness to cyclic AMP and removal of serum in neuronal cells. Nucleic Acids Res 1994;22(15):3092-3098.

Budhram-Mahadeo V, Lillycrop KA, Latchman DS. The levels of the antagonistic POU family transcription factors Brn-3a and Brn-3b in neuronal cells are regulated in opposite directions by serum growth factors. Neurosci Lett 1995;185(1):48-51.

Budhram-Mahadeo V, Morris PJ, Lakin ND, Theil T, Ching GY, Lillycrop KA, Moroy T, Liem RK, Latchman DS. Activation of the alpha-internexin promoter by the Brn-3a transcription factor is dependent on the N-terminal region of the protein. J Biol Chem 1995;270(6):2853-2858.

Fedtsova NG, Turner EE. Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors. Mech Dev 1995;53(3):291-304.

Lakin ND, Morris PJ, Theil T, Sato TN, Möröy T, Wilson MC, Latchman DS. Regulation of neurite outgrowth and SNAP-25

gene expression by the Brn-3a transcription factor. J Biol Chem 1995;270(26):15858-15863.

Lillycrop KA, Liu YZ, Theil T, Möröy T, Latchman DS. Activation of the herpes simplex virus immediate-early gene promoters by neuronally expressed POU family transcription factors. Biochem J 1995;307 (Pt 2):581-584.

Milton NG, Bessis A, Changeux JP, Latchman DS. The neuronal nicotinic acetylcholine receptor alpha 2 subunit gene promoter is activated by the Brn-3b POU family transcription factor and not by Brn-3a or Brn-3c. J Biol Chem 1995;270(25):15143-15147.

Budhram-Mahadeo V, Morris PJ, Lakin ND, Dawson SJ, Latchman DS. The different activities of the two activation domains of the Brn-3a transcription factor are dependent on the context of the binding site. J Biol Chem 1996;271(15):9108-9113.

Latchman DS. Activation and repression of gene expression by POU family transcription factors. Philos Trans R Soc Lond B Biol Sci 1996;351(1339):511-515. (Review).

Liu YZ, Dawson SJ, Latchman DS. Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells. J Mol Neurosci 1996;7(1):77-85.

McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG. Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature 1996;384(6609):574-577.

Milton NG, Bessis A, Changeux JP, Latchman DS. Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors. Biochem J 1996;317 (Pt 2):419-423.

Morris PJ, Lakin ND, Dawson SJ, Ryabinin AE, Kilimann MW, Wilson MC, Latchman DS. Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors. Brain Res Mol Brain Res 1996;43(1-2):279-285.

Smith MD, Latchman DS. The functionally antagonistic POU family transcription factors Brn-3a and Brn-3b show opposite changes in expression during the growth arrest and differentiation of human neuroblastoma cells. Int J Cancer 1996;67(5):653-660.

Turner EE, Fedtsova N, Rosenfeld MG. POU-domain factor expression in the trigeminal ganglion and implications for herpes virus regulation. Neuroreport 1996;7(18):2829-2832.

Xiang M, Gan L, Zhou L, Klein WH, Nathans J. Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Proc Natl Acad Sci USA 1996;93(21):11950-11955.

Leblond-Francillard M, Picon A, Bertagna X, de Keyzer Y. High expression of the POU factor Brn3a in aggressive neuroendocrine tumors. J Clin Endocrinol Metab 1997;82(1):89-94.

Smith MD, Dawson SJ, Latchman DS. The Brn-3a transcription factor induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Mol Cell Biol 1997;17(1):345-354.

Smith MD, Morris PJ, Dawson SJ, Schwartz ML, Schlaepfer WW, Latchman DS. Coordinate induction of the three neurofilament genes by the Brn-3a transcription factor. J Biol Chem 1997;272(34):21325-21333.

Xiang M, Gan L, Li D, Zhou L, Chen ZY, Wagner D, O'Malley BW Jr, Klein W, Nathans J. Role of the Brn-3 family of POU-domain genes in the development of the auditory/vestibular, somatosensory, and visual systems. Cold Spring Harb Symp Quant Biol 1997;62:325-336. (Review).

Latchman DS. The Brn-3a transcription factor. Int J Biochem Cell Biol 1998;30(11):1153-1157. (Review).



Gay RD, Dawson SJ, Murphy WJ, Russell SW, Latchman DS. Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter. Biochim Biophys Acta 1998;1443(3):315-322.

Ndisang D, Morris PJ, Chapman C, Ho L., Singer A, Latchman DS. The HPV-activating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions. J Clin Invest 1998;101(8):1687-1692.

Smith MD, Dawson SJ, Boxer LM, Latchman DS. The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression. Nucleic Acids Res 1998;26(18):4100-4107.

Wyatt S, Ensor L, Begbie J, Ernfors P, Reichardt LF, Latchman DS. NT-3 regulates expression of Brn3a but not Brn3b in developing mouse trigeminal sensory neurons. Brain Res Mol Brain Res 1998;55(2):254-264.

Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS. P53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J Biol Chem 1999;274(21):15237-15244.

Huang EJ, Zang K, Schmidt A, Saulys A, Xiang M, Reichardt LF. POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression. Development 1999;126(13):2869-2882.

Ndisang D, Budhram-Mahadeo V, Latchman DS. The Brn-3a transcription factor plays a critical role in regulating human papilloma virus gene expression and determining the growth characteristics of cervical cancer cells. J Biol Chem 1999;274(40):28521-28527.

Smith MD, Ensor EA, Stohl L, Wagner JA, Latchman DS. Regulation of NGFI-A (Egr-1) gene expression by the POU domain transcription factor Brn-3a. Brain Res Mol Brain Res 1999;74(1-2):117-125.

Trieu M, Rhee JM, Fedtsova N, Turner EE. Autoregulatory sequences are revealed by complex stability screening of the mouse brn-3.0 locus. J Neurosci 1999;19(15):6549-6558.

Ndisang D, Budhram-Mahadeo V, Singer A, Latchman DS. Widespread elevated expression of the human papilloma virus (HPV)-activating cellular transcription factor Brn-3a in the cervix of women with CIN3 (cervical intraepithelial neoplasia stage 3). Clin Sci (Lond) 2000;98(5):601-602.

Budhram-Mahadeo V, Moore A, Morris PJ, Ward T, Weber B, Sassone-Corsi P, Latchman DS. The closely related POU family transcription factors Brn-3a and Brn-3b are expressed in distinct cell types in the testis. Int J Biochem Cell Biol 2001;33(10):1027-1039.

Eng SR, Gratwick K, Rhee JM, Fedtsova N, Gan L, Turner EE. Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice. J Neurosci 2001;21(2):541-549.

Ensor E, Smith MD, Latchman DS. The BRN-3A transcription factor protects sensory but not sympathetic neurons from programmed cell death/apoptosis. J Biol Chem 2001;276(7):5204-5212.

Fedtsova N, Turner EE. Signals from the ventral midline and isthmus regulate the development of Bn3.0-expressing neurons in the midbrain. Mech Dev 2001;105(1-2):129-144.

Huang EJ, Liu W, Fritzsch B, Bianchi LM, Reichardt lf, Xiang M. Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding of inner ear sensory neurons. Development 2001;128(13):2421-2432.

Ndisang D, Budhram-Mahadeo V, Pedley B, Latchman DS. The Brn-ea transcription factor plays a key role in regulating the growth of cervical cancer cells in vivo. Oncogene 2001;20(35):4899-4903.

Smith MD, Melton La, Ensor EA, Packham G, Anderson P, Kinloch RA, Latchman DS. Brn-3a activates the expression of

Bcl-x(L) and promotes neuronal survival in vivo as well as in vitro. Mol Cell Neurosci 2001;17(3):460-470.

Budhram-Mahadeo V, Morris PJ, Latchman DS. The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1). Oncogene 2002;21(39):6123-6131.

Budhram-Mahadeo V, Morris P, Ndisang D, Irshad S, Lozano G, Pedley b, Latchman DS. The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells. Neurosci Lett 2002;334(1):1-4.

Frass B, Vassen L, Moroy T. Gene expression of the POU factor Brn-3a is regulated by two different promoters. Biochim Biophys Acta 2002;1579(2-3):207-213.

Ichikawa H, Mo Z, Xiang M, Sugimoto T. Effect of Brn-3a deficiency on nociceptors and low-threshold mechanoreceptors in the trigeminal ganglion. Brain Res Mol Brain Res 2002;104(2):240-245.

Perez-Sanchez C, Budhram-Mahadeo VS, Latchman DS. Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter. Nucleic Acids Res 2002;30(22):4872-4880.

Thomas GR, Latchman DS. The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription. Cancer Biol Ther 2002;1(4):428-432.

Ma L, Lei L, eng SR, Turner E, Parada LF. Brn3a regulation of TrkA/NGF receptor expression in developing sensory neurons. Development 2003;130(15):3525-3534.

Calissano M, Ensor E, Brown DR, Latchman DS. Doppel expression is regulated by the Brn-3a and Brn-3b transcription factors. Neuroreport 2004;15(3):483-486.

Eng SR, Lanier J, Fedtsova N, Turner EE. Coordinated regulation of gene expression by Brn-3a in developing sensory ganglia. Development 2004;131(16):3859-3870.

Farooqui-Kabir SR, Budhram-Mahadeo V, Lewis H, Latchman DS, Marber MS, Heads RJ. Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a. Cell Death Differ 2004;11(11):1242-1244.

Faulkes DJ, Ensor E, Le Rouzic E, Latchman DS. Distinct domains of Brn-3a regulate apoptosis and neurite outgrowth in vivo. Neuroreport 2004;15(9):1421-1425.

Gascoyne DM, Thomas GR, Latchman DS. The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1. Oncogene 2004;23(21):3830-3840.

Hudson CD, Podesta J, Henderson D, Latchman DS, Budhram-Mahadeo V. Coexpression of Brn-3a POU protein with p53 in a population of neuronal progenitor cells is associated with differentiation and protection against apoptosis. J Neurosci Res 2004;78(6):803-814.

Thomas GR, Faulkes DJ, Gascoyne D, Latchman DS. EWS differentially activates transcription of the Brn-3a long and short isoform mRNAs from distinct promoters. Biochem Biophys Res Commun 2004;318(4):1045-1051.

Calissano M, Faulkes D, Latchman DS. Phosphorylation of the Brn-3a transcription factor is modulated during differentiation and regulates its functional activity. Brain Res Mol Brain Res 2005;141(1):10-18.

Hudson CD, Morris PJ, Latchman DS, Budhram-Mahadeo VS. Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate. J Biol Chem 2005;280(12):11851-11858.

Ichikawa H, Mo Z, Xiang M, Sugimoto T. Brn-3a deficiency increases tyrosine hydroxylase-immunoreactive neurons in the dorsal root ganglion. Brain Res 2005;1036(1-2):192-195.



Ichikawa H, Qiu F, Xiang M, Sugimoto T. Brn-3a is required for the generation of proprioceptors in the mesencephalic trigeminal tract nucleus. Brain Res 2005;1053(1-2):203-206.

Ichikawa H, Schultz S, Hollt V, Mo Z, Xiang M, Sugimoto T. Effect of Brn-3a deficiency on primary nociceptors in the trigeminal ganglion. Neurosci Res 2005;51(4):445-451.

Ripley BJ, Rahman Ma, Isenberg DA, Latchman DS. Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90. Arthritis Rheum 2005;52(4):1171-1179.

Diss JK, Faulkes DJ, Walker MM, Patel A, Foster CS, Budhram-Mahadeo V, Djamgoz MB, Latchman DS. Brn-3a neuronal transcription factor functional expression in human prostate cancer. Prostate Cancer Prostatic Dis 2006;9(1):83-91.

Ndisang D, Faulkes DJ, Gascoyne D, Lee SA, Ripley BJ, Sindos M, Singer A, Budhram-Mahadeo V, Cason J, Latchman DS. Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a. Oncogene 2006;25(1):51-60.

Lanier J, Quina LA, Eng SR, Cox E, Turner EE. Brn3a target gene recognition in embryonic sensory neurons. Dev Biol 2007;302(2):703-716.


Budhram-Mahadeo V, Latchman DS. POU4F1 (POU class 4 homeobox 1). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):320-324.





PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)) Wael El-Rifai, Abbes Belkhiri

Department of Surgery, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/PPP1R1BID44096ch17q12.html DOI: 10.4267/2042/38556


Identity Hugo: PPP1R1B Other names: DARPP-32; DARPP32; FLJ20940; t-DARPP Location: 17q12

DNA/RNA Description DARPP-32 gene is located at 17q12. Both full length

DARPP-32 and its transcriptional splice variant (t-DARPP) consist of seven exons where only exon 1 is unique in each of the two transcripts.

Transcription 2 alternative transcripts.

Pseudogene Unknown.

Genomic localization of DARPP-32, with FISH using BAC clone CTD-2019C10 (Research Genetics) that contains DARPP-32, using fluorescent in situ hybridization (FISH) on a normal metaphase spread. Arrows indicate the green FITC hybridization signals. The ideogram of chromosome 17 together with the inverted DAPI banding and FISH hybridization signals on the two chromosome 17. The FISH signals localize to chromosome band 17q12-q21.

PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B El-Rifai W, Belkhiri A (dopamine and cAMP regulated phosphoprotein, DARPP-32))


This schematic illustration shows the genomic structure of DARPP-32 and its transcriptional splice variant that encodes a truncated DARPP-32 protein (t-DARPP). The sequence length of the mRNA of DARPP-32 is 1,841 bp, including the untranslated 3' and 5' ends. The length of the transcriptional splice variant of DARPP-32 that encodes a truncated DARPP-32 protein (t-DARPP) is 1,502 bp. DARPP-32 and t-DARPP share an identical sequence from exon 2 to the 3' end. Each of them has seven exons. Each of DARPP-32 and t-DARPP transcripts has its own unique exon 1, where exon1 in DARPP-32 includes 548 bp whereas exon1 in t-DARPP consists of unique 207 bp that does not match with exon1 of DARPP-32.

Protein Description DARPP-32 encodes a protein of 204 amino acids (about 32 kD), whereas t-DARPP encodes a 168 amino acid protein (about 28 kD). DARPP-32 contains four phosphorylation sites at Thr34, Thr75, Ser102, and Ser137, whereas t-DARPP lacks the Thr34 phosphorylation site of DARPP-32. The schematic illustration, shown above, demonstrates the phosphorylation sites of DARPP-32 and t-DARPP shown in yellow color.

Expression DARPP-32 protein is highly expressed in medium-sized spiny neurons of the neostriatum. DARPP-32 was characterized as a major target for dopamine and protein kinase A signaling. Modulation of DARPP-32 phosphorylation state provides a molecular mechanism for integrating signals through several neurotransmitters and steroid hormones that stimulate dopaminoceptic neurons in various regions of the brain. Activation of PKA or PKG leads to phosphorylation of DARPP-32 at Thr34 and subsequently converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). Cdk5 can also phosphorylate DARPP-32 at Thr75 and this converts DARPP-32 into a PKA inhibitor. Expression of t-DARPP in the brain was not reported. Protein and mRNA expression of both DARPP-32 and t-DARPP are expressed at varying levels in several

types of normal epithelial tissues outside the brain. DARPP-32 and t-DARPP are over-expressed in carcinomas of the breast, prostate, colon, and stomach compared with normal tissue samples. The observation that DARPP-32 and t-DARPP are frequently over-expressed in common subtypes of human cancers suggests that these proteins may play a role in tumorigenesis. The expression of t-DARPP has been shown to increase the AKT kinase activity and regulate the levels of BCL2 in cancer cells. This effect is believed to mediate resistance to drug-induced apoptosis.

Localisation Cytosolic.

Homology Unknown.

Mutations Note: Unknown

Implicated in Dopaminergic disorders Disease DARPP-32 plays a key role in cognitive function, and multiple brain functions. DARPP-32 is a key mediator of the biochemical, electrophysiological, transcriptional, and behavioral effects of dopamine. In this respect, DARPP-32 plays a critical role in

PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B El-Rifai W, Belkhiri A (dopamine and cAMP regulated phosphoprotein, DARPP-32))


dopaminoceptive neurons in the neostriatum (and likely in other brain regions) in signal transduction pathways regulated by a variety of neurotransmitters, neuromodulators, and neuropeptides. Abnormal signaling through DARPP-32 has been implicated in several major neurologic and psychiatric disorders. DARPP-32 may be involved in the pathogenesis of schizophrenia and plays a role in mediating the actions of a broad range of drugs of abuse.

Cancers Oncogenesis Over-expression of DARPP-32 and t-DARPP are associated with gastric cancer, and confer a potent anti-apoptotic function in cancer cells through a p53 -independent mechanism that involves preservation of mitochondrial membrane potential and increased Bcl2 expression levels. t-DARPP transcriptionally up-regulates Bcl2 by an Akt-dependent mechanism through activation of CREB/ATF-1 transcription factors in gastric cancer. DARPP-32 is frequently over-expressed in multiple human adenocarcinomas suggesting that DARPP-32 proteins may be important in tumorigenesis. Decreased expression of DARPP-32, however, in oral premalignant and malignant lesions was observed, and thereby suggested that DARPP-32 may be a tumor suppressor in this particular malignancy. In addition, phosphorylation of DARPP-32 at Thr34 or Thr75 appears to regulate breast cancer cell migration downstream of the receptor tyrosine kinase DDR1.

References Hemmings HCJr., Greengard P, Tung HY, Cohen P. DARPP32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 1984;310:503-505.

Greengard P. Neuronal phosphoproteins. Mediators of signal transduction. Mol Neurobiol 1987;1:81-119. (Review).

Greengard P, Browning MD. Studies of the physiological role of specific neuronal phosphoproteins. Adv Second Messenger Phosphoprotein Res 1988;21:133-146. (Review).

Halpain S, Girault JA, Greengard P. Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Nature 1990;343:369-372.

Ouimet CC, Greengard P. Distribution of DARPP-32 in the basal ganglia: an electron microscopic study. J. Neurocytol 1990;19:39-52.

Brené S, Lindefors N, Ehrlich M, Taubes T, Horiuchi A, Kopp J, Hall H, Sedvall G, Greengard P, Persson H. Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue. J Neurosci 1994;14:985-998.

Nishi A, Snyder GL, Greengard P. Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci 1997;17:8147-8155.

Fienberg AA, Hiroi N, Mermelstein PG, Song WJ, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, et al. DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science 1998;281:838-842.

Greengard P, Nairn AC, Girault JA, Ouimet CC, Snyder GL, Fisone G, Allen PB, Fienberg A, Nishi A. The DARPP-32/protein phosphatase-1 cascade: a model for signal integration. Brain Res Brain Res Rev 1998;26:274-284. (Review).

Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC, Jr., Nairn AC, Greengard P. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 1999;402:669-671.

Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 1999;23:435-447. (Review).

Mayerhofer A, Hemmings HC Jr., Snyder GL, Greengard P, Boddien S, Berg U, Brucker C. Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro. J Clin Endocr Metab 1999;84:257-264.

Mani SK, Fienberg AA, O'Callaghan JP, Snyder GL, Allen PB, Dash PK, Moore AN, Mitchell AJ, Bibb J, Greengard P, O'Malley BW. Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science 2000;287:1053-1056.

El-Rifai W, Smith MFJr., Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HFJr., Powell SM. Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. Cancer Res 2002;62:4061-4064.

Lindskog M, Svenningsson P, Pozzi L, Kim Y, Fienberg AA, Bibb JA, Fredholm BB, Nairn AC, Greengard P, Fisone G. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature 2002;418:774-778.

Beckler A, Moskaluk CA, Zaika A, Hampton GM, Powell SM, Frierson HFJr., El-Rifai W. Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein in common adenocarcinomas. Cancer 2003;98:1547-1551.

Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, Greengard P. The role of DARPP-32 in the actions of drugs of abuse. Neuropharmacology 2004;47 Suppl 1:14-23. (Review).

Belkhiri A, Zaika A, Pidkovka N, Knuutila S, Moskaluk C, and El-Rifai W. Darpp-32: a novel anti-apoptotic gene in upper gastrointestinal carcinomas. Cancer Res 2005;65:6583-6592.

García-Jiménez C, Zaballos MA, and Santisteban P. DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation. Mol Endocrinol 2005;19:3060-3072.

Wang MS, Pan Y, Liu N, Guo C, Hong L, Fan D. Overexpression of DARPP-32 in colorectal adenocarcinoma. Int J Clin Pract 2005;59:58-61.

Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 2007;117:672-682.

Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W. t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. Cancer Res 2008;68(2):395-403.


El-Rifai W, Belkhiri A. PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):325-327.

Gene Section Review




RMRP (RNA component of mitochondrial RNA processing endoribonuclease) Pia Hermanns, Kerstin Reicherter, Brendan Lee

Centre for Pediatrics and Adolescent Medicine, pediatric genetics section, Freiburg University Hospital, Germany (PH, KR); Howard Hughes Medical Institute (BL); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA (BL)


Online updated version: http://AtlasGeneticsOncology.org/Genes/RMRPID44001ch9p21.html DOI: 10.4267/2042/38557


Identity Hugo: RMRP Other names: CHH; RMRPR Location: 9p21-p12

DNA/RNA Note: RMRP is the RNA component of the RNase MRP protein complex. It functions as a RNA and is not translated into a protein.

Transcription The RMRP gene is transcribed by the DNA dependent RNA polymerase III. The gene contains typical sequence elements of a RNA Pol III type 3 promoter. The core sequence elements such as the PSE element and a TATA box can be found upstream of the transcription initiation site of the RMRP gene. In addition, transcription factor binding sites like a SP1 binding element and an octamer (recruits the transcription factor Oct-1) sequence could serve as distal sequence elements (DSE) to enhance the

transcription of RMRP similar to the DSE element of the human U6 snRNA gene. Expression: RMRP is strongly and ubiquitously expressed in mouse embryos (as an example an E15.5 mouse embryo is shown). In bone Rmrp is more strongly expressed in hypertrophic chondrocytes and pericondrium than in the zone of proliferating chondrocytes. There is also very strong expression in the epiphysis. In humans RMRP shows also a very strong expression in adult tissues. A little weaker expression is observed in skeletal muscle when compared to the GAPDH hybridization control. In Xenopus laevis oocytes RMRP is stronger expressed in developmental stages with a higher content of mitochondria. Function: RMRP has been mostly studied in yeast and multiple functions have been attributed to this ribonucleoprotein complex, called RNase MRP. The yeast orthologues gene is called nme1. Firstly, it plays a role in mitochondrial DNA replication. It cleaves the RNA primer of RNA/DNA hybrid. This hybrid formation initiates the mitochondrial DNA replication.

Figure 1: Cartoon of the RMRP genomic gene structure. The RMRP gene is an intronless gene that is 267 bp long (violet). The promoter region contains a SP1 binding site (blue), an octamer (red), a proximal sequence element (PSE) (green) and a TATA box (yellow).

RMRP (RNA component of mitochondrial RNA processing endoribonuclease) Hermanns P, et al.


Figure 2: Expression pattern of the Rmrp gene. A: in situ hybridization of an E15.5 mouse embryo. B: adult human Multiple tissue Northern Blot. Rmrp is ubiquitously expressed in human and mouse. H: hypertrophic chondrocytes. It is also involved in the RNA primer formation. Secondly, RMRP is involved in the progression of the cell cycle at the end of mitosis. Some nme1 mutants arrest in the late cycle of mitosis. These mutants present morphologically as large budded cells with dumbbell-shaped nuclei, and also exhibit extended spindles. This cell cycle arrest might be due to an increased level of CLB2. In wild type yeast strains the 5'UTR of CLB2 is cleaved by the RNase MRP complex. This causes a rapid degradation of the CLB2 mRNA, which leads to a cell cycle progression. Thirdly, RMRP also plays a role in the ribosomal RNA

processing. In yeast, it cleaves pre-ribosomal RNA at the A3 site thus helps the maturation of the short and active form of the 5.8S rRNA. Homology: RNase P is also a ribonucleoprotein endoribonuclease that is mainly involved in tRNA precursor maturation. RNase P and RNase MRP have eight proteins in common. The protein RPR2p is unique to the RNase P complex. In yeast two RNase MRP specific proteins have been identified; snm1 and rmp1. The loss of function of snm1 leads to a defect in the chromosome segregation during mitosis. But the exact mechanism is not understood yet.



Figure 3: Cartoon of the ribosomal RNA processing. If Rnase MRP cleaves the 27SA2 rRNA at the A3 site, this leads to the formation of the short form of the 5.8S rRNA (5.8SS). In a second, less effective alternative pathway, the 27SA2 rRNA is directly cleaved at the B1L site that leads at the end to the formation of the long form of the 5.8S rRNA (5.8SL).

Mutations Note: So far 93 different mutations have been identified in CHH patients. These include 24 promoter mutations that are either duplications, triplications or insertions that occur exclusively between the TATA box and the transcription start site. The size of the promoter mutations varies between 6 and 24 bp. In vitro studies have shown that these promoter mutations decrease the level of the RMRP transcript but do not abolish the RNA transcription completely. 69 different mutations in the 267 bp long transcript have been found up to now. 57 of these are single base pair substitutions spread out over the entire transcript. Also 11 small insertions, duplications and deletions have been found. The largest deletion identified so far involves the last 10 bp of the RMRP transcript. The mutations lead to a significant decrease of the RMRP RNA level in CHH, despite the nature of the mutation. These mutations might influence the secondary structure of the RNA, the binding of the proteins to the RNA or the RNA stability itself. The most frequently found mutation among CHH patients is a 70 A>G transition mutation with an ancient founder origin established in Finland and is the only mutation found in Amish CHH patients. Patients

either carry two mutations in the RMRP transcript or are compound heterozygous for a promoter mutation and a transcript mutation. Interestingly, none of the patients exhibit two promoter mutations. In addition 11 polymorphisms and 17 rare sequence variants have been observed. This is very remarkable considering the small size of the RMRP gene. So far no complete deletion of the entire RMRP gene has been observed. This suggests that complete loss of RMRP function might be incompatible with life. This is also supported by the fact that the knock out of the yeast NME1 gene is lethal.

Implicated in Cartilage Hair Hypoplasia (CHH) Prognosis The adult height ranges between 111 and 151 cm in males and between 104 and 137 cm in females. Around 20% of Cartilage Hair Hypoplasia patients exhibit recurrent to severe infections. These patients show evidence of immune deficiency in vivo and in vitro.

Oncogenesis A predisposition to certain cancers primarily lymphomas has been reported.



References Chang DD, Clayton DA. A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. EMBO J 1987;6:409-417.

Topper JN, Clayton DA. Characterization of human MRP/Th RNA and its nuclear gene: Full length MRP/Th RNA is an active endoribonuclease when assembled as an RNP. Nucleic Acids Res 1990;18:793-799.

Schmitt ME, Clayton DA. Yeast site-specific ribonucleoprotein endoribonuclease MRP contains an RNA component homologous to mammalian RNase MRP RNA and essential for cell viability. Genes Dev 1992;6(10):1975-1985.

Chu S, Archer RH, Zengel JM, Lindahl L. The RNA of RNase MRP is required for normal processing of ribosomal RNA. Proc Natl Acad Sci USA 1994;91:659-663.

Schmitt ME, Clayton DA. Characterization of a unique protein component of the yeast RNase MRP: an RNA-binding protein with a zinc-cluster domain. Genes Dev 1994;8:2617-2628.

Lygerou Y, Allmang C, Tollervey D, Séraphin B. Accurate Processing of a Eukaryotic Precursor Ribosomal RNA by Ribonuclease MRP in Vitro. Science 1996;272:268-270.

Lee DY, Clayton DA. RNase mitochondrial RNA processing correctly cleaves a novel R loop at the mitochondrial DNA leading-strand origin of replication. Genes Dev 1997;1:582-592.

Shadel GS, Buckenmeyer GA, Clayton DA, Schmitt ME. Mutational analysis of the RNA component of Saccharomyces cerevisiae RNase MRP reveals distinct nuclear phenotypes. Gene 2000;245:175-184.

Ridanpää M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Mäkitie O, Kaitila I, de la Chapelle A. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 2001;104(2):195-203.

Bonafé L, Schmitt K, Eich G, Giedion A, Superti-Furga A. RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet 2002;61(2):146-151.

Cai T, Aulds J, Gill T, Cerio M, Schmitt ME. The Saccharomyces cerevisiae RNase mitochondrial RNA processing is critical for cell cycle progression at the end of mitosis. Genetics 2002;161:1029-1042.

Ridanpää M, Sistonen P, Rockas S, Rimoin DL, Mäkitie O, Kaitila I. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A--->G mutation of the untranslated RMRP. Eur J Hum Genet 2002;10(7):439-447.

Schramm L, Hernandez N. Recruitment of RNA polymerase III to its target promoters. Genes Dev 2002;16:2593-2620.

Nakashima E, Mabuchi A, Kashimada K, Onishi T, Zhang J, Ohashi H, Nishimura G, Ikegawa S. RMRP mutations in

Japanese patients with cartilage-hair hypoplasia. Am J Med Genet A 2003;123(3):253-256.

Ridanpää M, Jain P, McKusick VA, Francomano CA, Kaitila I. The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases. Am J Med Genet C Semin Med Genet 2003;121(1):81-83.

Gill T, Cai T, Aulds J, Wierzbicki S, Schmitt ME. RNase MRP Cleaves the CLB2 mRNA To Promote Cell Cycle Progression: Novel Method of mRNA Degradation. Mol Cell Biol 2004;24:945-953.

Welting TJM, vn Venrooij WJ, Purijn GJM. Mutual interactions between subunits of the human RNase MRP ribonucleoportein complex. Nucleic Acids Res 2004;32(7):2138-2146.

Bonafé L, Dermitzakis ET, Unger S, Greenberg CR, Campos-Xavier BA, Zankl A, Ucla C, Antonarakis SE, Superti-Furga A, Reymond A. Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genet 2005;1(4):e47.

Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum Mol Genet 2005;14(23):3723-3740.

Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, Ruschendorf F, Sticht H, Spranger J, Muller D, Zweier C, Schmitt ME, Reis A, Rauch A. Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator. Am J Hum Genet 2005;77(5):795-806.

Hermanns P, Tran A, Munivez E, Carter S, Zabel B, Lee B, Leroy JG. RMRP mutations in cartilage-hair hypoplasia. Am J Med Genet A 2006;140(19):2121-2130.

Hirose Y, Nakashima E, Ohashi H, Mochizuki H, Bando Y, Ogata T, Adachi M, Toba E, Nishimura G, Ikegawa S. Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia. J Hum Genet 2006;51(8):706-710.

Muñoz-Robles J, Allende LM, Clemente J, Calleja S, Varela P, Gonzalez L, de Pablos P, Paz E, Morales P. A novel RMRP mutation in a Spanish patient with cartilage-hair hypoplasia. Immunobiology 2006;211(9):753-757.

Martin AN, Li Y. RNase MRP RNA and human genetic diseases. Cell Res 2007;17(3):219-226.

Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A. Type and Level of RMRP Functional Impairment Predicts Phenotype in the Cartilage Hair Hypoplasia - Anauxetic Dysplasia Spectrum. Am J Med Genet 2007;81(3):519-529.


Hermanns P, Reicherter K, Lee B. RMRP (RNA component of mitochondrial RNA processing endoribonuclease). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):328-333.

Gene Section Review




TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) Jiangping Wu, Bing Han

CHUM Research Center, University of Montreal, Canada


Online updated version: http://AtlasGeneticsOncology.org/Genes/TNFRSF6BID42628ch20q13.html DOI: 10.4267/2042/38558


Identity Hugo: TNFRSF6B Other names: DCR3 (decoy receptor 3); DJ583P15.1.1; M68; TR6 (TNF receptor family member 6) Location: 20q13.3

DNA/RNA Description DNA sequence is located on chromosome 20. Transcription consists of 7 exons and 6 introns, spanning 3.6kb. A shorter transcription variance (M68E) has been identified, and is transcribed from 3 exons and 2 introns spanning 1.9kb as illustrated above. The difference occurs at the 5' untranslated region, but the two transcripts encode the same isoform. Mice do not have a gene orthologue to human TNFRSF6B. TNFRSF68B mRNA in Northen blot presents as a 1.2-knt band.

Protein Description TNFRSF6B protein is 300-amino acid long, and has a

molecular weight of 35 kD. Although TNFRSF6B belongs to the TNFR superfamily, it lacks the transmembrane and cytosolic domains in its sequence, and is a secreted protein. It contains 4 TNFR cystein-rich regions, as illustrated above. TNFRSF6B can be easily cleaved between Arg218 and Ala219 in biological fluids and solutions. It has thus a very short (about 20 min) half-life in serum and in vivo. Mutation of arginine residue at position 218 to glutamine makes TNFRSF6B resistant to proteolysis, and significantly prolongs its half-life. TNFRSF6B can bind to the TNF family members FasL, LIGHT and TL1A. It does not bind to other known TNF family members. Human TNFRSF6B can bind to mouse FasL, LIGHT and TL1A. This allows human DcR3/TNFRSF6B to function in mouse models both in vitro and in vivo. The role of TNFRSF6B in apoptosis is obvious. FasL is a well-known molecule involved in apoptosis. LIGHT is a ligand for HVEM and LTbetaR, in addition to being a ligand for TNFRSF6B. LIGHT can induce apoptosis in cells expressing both HVEM and LTbetaR, or LTbetaR alone. TL1A, a member of the TNF family, can evoke apoptosis via its receptor, DR3. Consequently, the interaction of TNFRSF6B with FasL, LIGHT, and TL1A blocks apoptosis mediated by Fas, HVEM, LTbetaR and DR3.

TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) Wu J, Han B


A) Domains and Motifs. B) TNFRSF6B X-ray crystography.

Expression Normal tissue and cells express low-level TNFRSF6B, and healthy individuals have near-background serum TNFRSF6B levels. About 60% of malignant tumors of various tissue origins overexpress TNFRSF6B, and these patients have elevated serum TNFRSF6B levels. Serum TNFRSF6B levels of tumor patients are positively correlated to the degree of tumor malignancy and status of metastasis. It is hypothesized that malignant tumor cells secrete TNFRSF6B as a way to achieve survival advantage by blocking multiple apoptosis pathways. Hepatocytes in liver cirrhosis have augmented TNFRSF6B expression and patients with liver cirrhosis have increased serum TNFRSF6B levels. TNFRSF6B expression is low in resting T cells but is augmented in activated T cells, which probably represents a fine-tuning mechanism to balance the need for clonal expansion and subsequent massive activation-induced T cell death. About 40% of systemic lupus erythematosus patients have elevated serum TNFRSF6B levels. TNFRSF6B expression in rheumatoid arthritis fibroblast-like synoviocytes is increased by TNFalpha. Localisation TNFRSF6B is a secreted protein, and is thus detected in body fluids. However, it can also be detected in cytoplasm before it is secreted.

Function As TNFRSF6B can block ligands from interacting with Fas, HVEM, LTbetaR, and DR3, all of which mediate

apoptosis, it is thus can effectively inhibit apoptosis in many cell types. It is believed that many types of malignant tumors gain survival advantage by secreting TNFRSF6B which blocks tumor cell apoptosis. Syngeneic islets transplanted to diabetes recipients survive better in the presence of administered exogenous human TNFRSF6B, due to the blockage of FasL-, LIGHT- and TL1A-triggered islets apoptosis. Transgenic expression of human TNFRSF6B in NOD mouse islets reduces diabetes pathogenesis, again, due to anti-apoptotic effect of TNFRSF6B. The forward signaling from FasL to Fas, and from LIGHT to HVEM can provide costimulation signals to resting T cells. Blocking of these two signaling pathways reduces T cell responses to antigens. As LIGHT and FasL, although being ligands, are also transmembrane proteins, and are capable of reversely transducing costimulating signals into T cells, TNFRSF6B can also block such reverse signaling. The end result is that TNFRSF6B can reduce several costimulation pathways in T cells and inhibit T cell immune responses, such as cytokine secretion and proliferation in vitro, and cardiac allograft rejection in vivo in mouse models. When human TNFRSF6B is linked to a transmembrane domain and is expressed on the mouse tumor cell surface, it can effectively trigger T cell costimulation via LIGHT and FasL reverse signaling, and cause effective tumor vaccination in mouse models. When human TNFRSF6B is transgenically expressed in mice, it causes a systemic lupus erythrematosus-like syndrome. The expression of TNFRSF6B in bone



marrow-derived cells is sufficient to induce this phenotype. Recombinant human TNFRSF6B ameliorates an autoimmune crescentic glomerulonephritis model in mice. TNFRSF6B can influence dendritic cells which in turn drive T cells to differentiate into Th2 cells. TNFRSF6B can inhibit actin polymerization of T cells upon mitogen stimulation, and repress T-cell pseudopodium formation, which is known to be important for cell-cell interaction. As a consequence, T-cell aggregation after activation is suppressed by either soluble or solid phase TNFRSF6B. Human T cells pretreated with soluble or solid-phase TNFRSF6B are compromised in migration in vitro and in vivo toward CXCL12. Mechanistically, a small GTPase Cdc42 fails to be activated after TNFRSF6B pretreatment of human T cells, and further downstream, p38 mitogen-activated protein kinase activation, actin polymerization, and pseudopodium formation are all down-regulated in the treated T cells. Phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide are impaired in TNFRSF6B-treated macrophages.

Mutations Note: Not reported yet.

Implicated in Malignant tumors Disease Oncogenesis: TNFRSF6B is overexpressed in about 60% of various malignant tumors. Its anti-apoptotic effect provides the tumors a survival advantage, and its role in reducing T cell costimulation favors tumor evasion from the immune surveillance. No TNFRSF6B gene amplification in tumors has been identified. Diagnosis and prognosis: TNFRSF6B in sera or tumor can be used as a parameter for tumor diagnosis and prognosis. The degree of tumor malignancy is correlated to TNFRSF6B levels. When a TNFRSF6B-expressing tumor is resected, serum TNFRSF6B levels will decrease to near-zero level. The re-arising of serum TNFRSF6B in such patients will indicate tumor reoccurrence. Therapeutics: When TNFRSF6B is anchored on tumor cell surface, it can increase the antigenicity of the tumor, and such TNFRSF6B-expressing tumors can be used as tumor vaccine.

Systemic lupus erythematosus (SLE) Disease Pathogenesis: About 50% of SLE patients have elevated serum TNFRSF6B levels, and the levels

augment during SLE flare-up. In animal models, human TNFRSF6B overexpression in mouse cells of hematopoietic origin leads to a SLE-like syndrome, suggesting a pathogenic role of TNFRSF6B in SLE. Diagnosis: Serum TNFRSF6B can be used as a diagnostic parameter for SLE and SLE disease activity. Therapeutics: Due to the pathogenic effect of TNFRSF6B on SLE, it is speculated that neutralizing TNFRSF6B might have therapeutic effect on a subpopulation of SLE patients, who are serum TNFSF6B positive.

Islet primary nonfunction during islet transplantation Disease Therapeutics: Due to the anti-apoptotic effect of TNFRSF6B, it can effectively protect islets from apoptosis during their isolation, transportation, and primary non-function after transplantation.

References Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998;396(6712):699-703.

Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 1999;274(20):13733-13736.

Bai C, Connolly B, Metzker ML, Hilliard CA, Liu X, Sandig V, Soderman A, Galloway SM, Liu Q, Austin CP, Caskey CT. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci USA 2000;97(3):1230-1235.

Ohshima K, Haraoka S, Sugihara M, Suzumiya J, Kawasaki C, Kanda M, Kikuchi M. Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. Cancer Lett 2000;160(1):89-97.

Otsuki T, Tomokuni A, Sakaguchi H, Aikoh T, Matsuki T, Isozaki Y, Hyodoh F, Ueki H, Kusaka M, Kita S, Ueki A. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin Exp Immunol 2000;119(2):323-327.

Maeda T, Hao C, Tron VA. Ultraviolet light (UV) regulation of the TNF family decoy receptors DcR2 and DcR3 in human keratinocytes. J Cutan Med Surg 2001;5(4):294-298.

Roth W, Isenmann S, Nakamura M, Platten M, Wick W, Kleihues P, Bähr M, Ohgaki H, Ashkenazi A, Weller M. Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 2001;61(6):2759-2765.

Zhang J, Salcedo TW, Wan X, Ullrich S, Hu B, Gregorio T, Feng P, Qi S, Chen H, Cho YH, Li Y, Moore PA, Wu J. Modulation of T-cell responses to alloantigens by TR6/DcR3. J Clin Invest 2001;107(11):1459-1468.

Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC, Chen L, Hsieh SL. Modulation of dendritic cell differentiation and maturation by decoy receptor 3. J Immunol 2002;168(10):4846-4853.



Mild G, Bachmann F, Boulay JL, Glatz K, Laffer U, Lowy A, Metzger U, Reuter J, Terracciano L, Herrmann R, Rochlitz C. DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer. Int J Cancer 2002;102(3):254-257.

Takahama Y, Yamada Y, Emoto K, Fujimoto H, Takayama T, Ueno M, Uchida H, Hirao S, Mizuno T, Nakajima Y. The prognostic significance of overexpression of the decoy receptor for Fas ligand (DcR3) in patients with gastric carcinomas. Gastric Cancer 2002;5(2):61-68.

Wan X, Zhang J, Luo H, Shi G, Kapnik E, Kim S, Kanakaraj P, Wu J. A TNF family member LIGHT transduces costimulatory signals into human T cells. J Immunol 2002;169(12):6813-6821.

Bridgham JT, Johnson AL. Characterization of chicken TNFR superfamily decoy receptors, DcR3 and osteoprotegerin. Biochem Biophys Res Commun 2003;307(4):956-961.

Shi G, Wu Y, Zhang J, Wu J. Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo. J Immunol 2003;171(7):3407-3414.

Tsuji S, Hosotani R, Yonehara S, Masui T, Tulachan SS, Nakajima S, Kobayashi H, Koizumi M, Toyoda E, Ito D, Kami K, Mori T, Fujimoto K, Doi R, Imamura M. Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. Int J Cancer 2003;106(1):17-25.

Wan X, Shi G, Semenuk M, Zhang J, Wu J. DcR3/TR6 modulates immune cell interactions. J Cell Biochem 2003;89(3):603-612.

Wortinger MA, Foley JW, Larocque P, Witcher DR, Lahn M, Jakubowski JA, Glasebrook A, Song HY. Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue. Immunology 2003;110(2):225-233.

Wroblewski VJ, McCloud C, Davis K, Manetta J, Micanovic R, Witcher DR. Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3(R218Q)], in cynomolgus monkeys and mice. Drug Metab Dispos 2003;31(4):502-507.

Wroblewski VJ, Witcher DR, Becker GW, Davis KA, Dou S, Micanovic R, Newton CM, Noblitt TW, Richardson JM, Song HY, Hale JE. Decoy receptor 3 (DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT. Biochem Pharmacol 2003;65(4):657-667.

Wu Y, Han B, Luo H, Roduit R, Salcedo TW, Moore PA, Zhang J, Wu J. DcR3/TR6 effectively prevents islet primary nonfunction after transplantation. Diabetes 2003;52(9):2279-2286.

Wu Y, Han B, Sheng H, Lin M, Moore PA, Zhang J, Wu J. Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients. Int J Cancer 2003;105(5):724-732.

Chang YC, Hsu TL, Lin HH, Chio CC, Chiu AW, Chen NJ, Lin CH, Hsieh SL. Modulation of macrophage differentiation and activation by decoy receptor 3. J Leukoc Biol 2004;75(3):486-494.

Chen J, Zhang L, Kim S. Quantification and detection of DcR3, a decoy receptor in TNFR family. J Immunol Methods 2004;285(1):63-70.

Gill RM, Hunt JS. Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis. Am J Pathol 2004;165(1):309-317.

Hsu MJ, Lin WW, Tsao WC, Chang YC, Hsu TL, Chiu AW, Chio CC, Hsieh SL. Enhanced adhesion of monocytes via reverse signaling triggered by decoy receptor 3. Exp Cell Res 2004;292(2):241-251.

Hwang SL, Lin CL, Cheng CY, Lin FA, Lieu AS, Howng SL, Lee KS. Serum concentration of soluble decoy receptor 3 in glioma patients before and after surgery. Kaohsiung J Med Sci 2004;20(3):124-127.

Kim S, McAuliffe WJ, Zaritskaya LS, Moore PA, Zhang L, Nardelli B. Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells. Infect Immun 2004;72(1):89-93.

Sung HH, Juang JH, Lin YC, Kuo CH, Hung JT, Chen A, Chang DM, Chang SY, Hsieh SL, Sytwu HK. Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice. J Exp Med 2004;199(8):1143-1151.

Yang CR, Hsieh SL, Teng CM, Ho FM, Su WL, Lin WW. Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A, a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action. Cancer Res 2004;64(3):1122-1129.

Yang CR, Wang JH, Hsieh SL, Wang SM, Hsu TL, Lin WW. Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells. Cell Death Differ 2004;11 Suppl 1:S97-107.

Wu YY, Chang YC, Hsu TL, Hsieh SL, Lai MZ. Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3. J Biol Chem 2004;279(42):44211-44218.

Wu SF, Liu TM, Lin YC, Sytwu HK, Juan HF, Chen ST, Shen KL, Hsi SC, Hsieh SL. Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. J Leukoc Biol 2004;75(2):293-306.

Arakawa Y, Tachibana O, Hasegawa M, Miyamori T, Yamashita J, Hayashi Y. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol 2005;109(3):294-298.

Hsu TL, Wu YY, Chang YC, Yang CY, Lai MZ, Su WB, Hsieh SL. Attenuation of Th1 response in decoy receptor 3 transgenic mice. J Immunol 2005;175(8):5135-5145.

Kim S, Fotiadu A, Kotoula V. Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Clin Immunol 2005;115(3):286-294.

Li H, Zhang L, Lou H, Ding I, Kim S, Wang L, Huang J, Di Sant'Agnese PA, Lei JY. Overexpression of decoy receptor 3 in precancerous lesions and adenocarcinoma of the esophagus. Am J Clin Pathol 2005;124(2):282-287.

Shen HW, Gao SL, Wu YL, Peng SY. Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. World J Gastroenterol 2005;11(38):5926-5930.

Shi G, Mao J, Yu G, Zhang J, Wu J. Tumor vaccine based on cell surface expression of DcR3/TR6. J Immunol 2005;174(8):4727-4735.

Yang CR, Hsieh SL, Ho FM, Lin WW. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J Immunol 2005;174(3):1647-1656.

Chang YC, Chan YH, Jackson DG, Hsieh SL. The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion. J Immunol 2006;176(1):173-180.

Fayad R, Brand MI, Stone D, Keshavarzian A, Qiao L. Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells. Eur J Immunol 2006;36(8):2215-2222.



Otsuki T, Miura Y, Nishimura Y, Hyodoh F, Takata A, Kusaka M, Katsuyama H, Tomita M, Ueki A, Kishimoto T. Alterations of Fas and Fas-related molecules in patients with silicosis. Exp Biol Med (Maywood) 2006;231(5):522-533. (Review).

Han B, Moore PA, Wu J, Luo H. Overexpression of human decoy receptor 3 in mice results in a systemic lupus erythematosus-like syndrome. Arthritis Rheum 2007;56(11):3748-3758.

Hayashi S, Miura Y, Nishiyama T, Mitani M, Tateishi K, Sakai Y, Hashiramoto A, Kurosaka M, Shiozawa S, Doita M. Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against Fas-induced apoptosis. Arthritis Rheum 2007;56(4):1067-1075.

Ho CH, Hsu CF, Fong PF, Tai SK, Hsieh SL, Chen CJ. Epstein-Barr virus transcription activator Rta upregulates decoy receptor 3 expression by binding to its promoter. J Virol 2007;81(9):4837-4847.

Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A. Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice. J Am Soc Nephrol 2007;18(9):2473-2485.

Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW. Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Gynecol Oncol 2007;106(1):112-118.

Tang CH, Hsu TL, Lin WW, Lai MZ, Yang RS, Hsieh SL, Fu WM. Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice. J Biol Chem 2007;282(4):2346-2354.

You RI, Chang YC, Chen PM, Wang WS, Hsu TL, Yang CY, Lee CT, Hsieh SL. Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3). Blood 2008;111(3):1480-1488.


Wu J, Han B. TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):334-338.

Gene Section Review




TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) Maria Grazia di Iasio, Elisabetta Melloni, Paola Secchiero, Silvano Capitani

Signal Transduction Unit, Laboratory of Cell Biology, Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy


Online updated version: http://AtlasGeneticsOncology.org/Genes/TNFSF10ID42632ch3q26.html DOI: 10.4267/2042/38559


Identity Hugo: TNFSF10 Other names: APO2L; Apo-2L; CD253; TL2; TRAIL; TRAIL-PEN Location: 3q26

DNA/RNA

Organization of the human TRAIL gene.

Description 5 exons; DNA size 17805 bp.

Transcription CDS: 846 nt; Krieg A. et al. (BJC 2003) reported two splice variants in neoplastic and non-neoplastic cells.

Pseudogene No known pseudogenes.

Protein Note: 281 AA, 32509 Da; TRAIL (TNF-Related Apoptosis-Inducing Ligand) was originally identified by two independent groups and characterized as a member of the TNF (Tumor Necrosis Factor) family of death-inducing ligands. TRAIL can bind to five different receptors found on a variety of cell types: four membrane-bound and one soluble receptor. Two of

these membrane receptors, TRAIL-R1/death receptor 4 (DR4) and TRAIL-R2/death receptor 5 (DR5), act as agonistic receptors, containing a cytoplasmic death domain through which TRAIL can transmit an apoptotic signal. The other two membrane receptors, TRAIL-R3/decoy receptor 1 (DcR1) and TRAIL-R4/decoy receptor 2 (DcR2), can also bind TRAIL, but act as antagonistic/regulatory receptors, lacking the death domain. In addition to these four transmembrane receptors, a fifth soluble antagonistic receptor, osteoprotegerin (OPG), has been identified (Diagram 1). Description The extra-cellular domain of the membrane-bound TRAIL forms a bell shaped homo-trimer, much like other ligands of the TNF family. However, there is a unique insertion loop of about 16-20 amino acids in soluble TRAIL near its amino-terminal end (Diagram 2). Unlike other members of the TNF superfamily, TRAIL carries a zinc ion at the trimer interface, coordinated by the single unpaired cysteine residue (Cys 230) of each monomer (Diagram 2). This zinc ion is essential for structural integrity of TRAIL, and substituting the Cys 230 with alanine or serine strongly affects the capacity of TRAIL to induce apoptosis. Three molecules of TRAIL assemble with three molecules of the transmembrane receptor as a hexameric complex (3:3).

Expression Membrane-bound TRAIL is expressed on the surface of activated immune cells, such as natural killer (NK)

TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10) di Iasio MG, et al.


Diagram 1. TRAIL receptor system. Diagram 2. Schematic representation of the structure of TRAIL protein.

cells, T cells, macrophages and dendritic cells, whereas soluble TRAIL is present in the sera of normal individuals as well as of patients affected by neoplastic disorders. Soluble TRAIL is also released in the culture supernatant of activated peripheral blood mononuclear cells (PBMC) in response to interferon induction, so that it apparently seems to function as an immune effector molecule, mediating antitumor cytotoxicity and immune regulation. Importantly, this biological role of TRAIL is consistent with its tumor selective properties, since it implies that normal tissues are constitutively protected from circulating immune cells bearing TRAIL. Besides, a significant level of TRAIL transcript has been detected in many human tissues including thymus, spleen, PBMC, prostate, ovary, small intestine, colon and placenta, but not in the brain and it is expressed constitutively in some cell lines.

Localisation TRAIL is a type II membrane protein of about 33-35 kD, which can be cleaved from the cell surface by the aspartic proteinase cathepsin E to form a soluble ligand of about 21 kD that retains biological activity.

Function The best-characterized biological activity of TRAIL is

to induce apoptotic cell death in a variety of neoplastic cells. Both full-length membrane expressed TRAIL and soluble TRAIL can rapidly induce apoptosis in a wide variety of human cancer cell lines and primary tumors (including hematological malignancies), showing minimal or absent cytotoxicity on normal cells, both in vitro and in vivo; thus TRAIL was identified as a potential tumor-specific cancer therapeutic. The wide expression of TRAIL and TRAIL-Rs in many normal tissues suggests that the physiological role of TRAIL is more complex than the simply induction of apoptosis in cancer cells. In this respect, several studies have demonstrated that the TRAIL-TRAIL receptors system elicit a physiological role in normal hematopoiesis (for example an anti-differentiative effect on erythroid maturation and a pro-maturative effect during megakaryocytopoiesis and in vascular physiology, promoting the survival, migration and proliferation of endothelial cells). It has also been demonstrated that TRAIL significantly counteracts the adhesion of peripheral blood derived monocytes and granulocytes to endothelial cells without inducing apoptosis in response to inflammatory cytokines in vitro, suggesting an anti-inflammatory activity of TRAIL. All these data are reviewed in Secchiero and Zauli, 2008.



Homology

GENE IDENTITY (%) SPECIES SYMBOL PROTEIN DNA HOMO SAPIENS TNFSF10 VS. PAN TROGLODYTES

TNFSF10 98.9 99.3

VS. MUS MUSCULUS TNFSF10 67.0 75.0 VS. RATTUS NORVEGICUS

TNFSF10 70.3 74.3

VS. GALLUS GALLUS TNFSF10 59.3 64.2 VS. DANIO RERIO TNFSF10L2 46.2 54.1

The homology of TRAIL with the other proteins of TNF family is reported below:

GENE IDENTITY (%) SPECIES SYMBOL PROTEIN

HOMO SAPIENS TNFSF10

HOMO SAPIENS TNF 23

HOMO SAPIENS RANKL 24

HOMO SAPIENS FASL 27

HOMO SAPIENS CD40L 23

HOMO SAPIENS CD137L NOT SIGNIFICANT

HOMO SAPIENS OX40L NOT SIGNIFICANT



HOMO SAPIENS LTA 22

HOMO SAPIENS LTB 21

HOMO SAPIENS APO3L NOT SIGNIFICANT

HOMO SAPIENS APRIL NOT SIGNIFICANT

HOMO SAPIENS TNFSF13B NOT SIGNIFICANT

HOMO SAPIENS TNFSF14 25

HOMO SAPIENS TNFSF15 34

HOMO SAPIENS TNFSF18 NOT SIGNIFICANT

Mutations

6 esonic variations. For details see: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=8743



Implicated in Myelodysplastic Syndromes (MDS) Note: The myelodysplastic syndromes comprise a heterogeneous group of clonal disorders, usually characterized by a normal or hypercellular marrow with dysplastic features leading to peripheral blood cytopenias and a variable incidence of transformation into acute myeloid leukemia (AML). Ineffective erythropoiesis is a common feature of MDS. One mechanism invoked to explain the apparent discrepancy between cellular marrow and peripheral blood cytopenias in patients with MDS is apoptosis, which occurs with increased frequency in MDS marrow.

Disease The decrease of mature erythrocytes, the major clinical feature of MDS, has been attributed to the increased expression and release at the bone marrow level of TRAIL, that selectively inhibits erythroid development by specifically targeting immature erythroblasts, impairing erythropoiesis and contributing to the degree of anemia.

B-Chronic Lymphocytic Leukemia (B-CLL) Note: B-CLL represents a quintessential example of human malignancies that are caused primarily by defects in apoptosis or programmed cell death. During the early stages of disease, mature B lymphocytes that constitute most B-CLL are largely quiescent G(0) phase cells, which accumulate not because they are dividing more rapidly than normal cells but because they survive longer than their normal counterparts due to defects in the apoptotic pathways. These noncycling CD5+/CD19+ B lymphocytes accumulate in the peripheral blood, marrow, spleen, and lymph nodes. Defects in apoptotic pathways contribute also to chemoresistance, rendering tumor cells less sensitive to the cytotoxic actions of currently available anticancer drugs, and can also promote resistance to cellular immune responses.

Disease In order to elucidate the expression of TRAIL and its biological potential function in B-CLL, it has been examined the expression of TRAIL in B-CLL PBMC in comparison with PBMC obtained from healthy blood donors as well as the susceptibility of B-CLL cells to soluble recombinant TRAIL and the potential effects of endogenous membrane-bound TRAIL on autologous B-CLL cell survival. It has been shown that TRAIL is overexpressed in B-CLL PBMC in comparison with normal B cells, but B-CLL cells are resistant to TRAIL-mediated apoptosis. Taken together, these findings suggest that an aberrant expression of TRAIL might contribute to the pathogenesis of B-CLL.

References Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3(6):673-682.

Bogdanović AD, Janković GM, Colović MD, Trpinać DP, Bumbasirević VZ. Apoptosis in bone marrow of myelodysplastic syndrome patients. Blood 1996;87(7):3064.

Gruss HJ. Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily. Int J Clin Lab Res 1996;26(3):143-59. (Review).

Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271(22):12687-12690.

Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281(5381):1305-1308. (Review).

Heaney ML, Golde DW. Myelodysplasia. N Engl J Med 1999;340(21):1649-1660.

Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 1999;4(4):563-571.

Hymowitz SG, O'Connell MP, Ultsch MH, Hurst A, Totpal K, Ashkenazi A, de Vos AM, Kelley RF. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 2000;39(4):633-640.

Reed JC, Kitada S, Kim Y, Byrd J. Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Semin Oncol 2002;.29(1 Suppl 2):10-24. (Review).

Krieg A, Krieg T, Wenzel M, Schmitt M, Ramp U, Fang B, Gabbert HE, Gerharz CD, Mahotka C. TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential. Br J Cancer 2003;88(6):918-927.

Secchiero P, Melloni E, Heikinheimo M, Mannisto S, Di Pietro R, Iacone A, Zauli G. TRAIL regulates normal erythroid maturation through an ERK-dependent pathway. Blood 2004;103(2):517-522.

Campioni D, Secchiero P, Corallini F, Melloni E, Capitani S, Lanza F, Zauli G. Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes. Am J Pathol 2005;166(2):557-563.

Melloni E, Secchiero P, Celeghini C, Campioni D, Grill V, Guidotti L, Zauli G. Functional expression of TRAIL and TRAIL-R2 during human megakaryocytic development. J Cell Physiol 2005;204(3):975-982.

Secchiero P, Corallini F, di Iasio MG, Gonelli A, Barbarotto E, Zauli G. TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release. Blood 2005;105(9):3413-3419.

Secchiero P, Tiribelli M, Barbarotto E, Celeghini C, Michelutti A, Masolini P, Fanin R, Zauli G. Aberrant expression of TRAIL in B chronic lymphocytic leukemia (B-CLL) cells. J Cell Physiol 2005;205(2):246-252.

Zauli G, Secchiero P. The role of the TRAIL/TRAIL receptors system in hematopoiesis and endothelialcell biology. Cytokine Growth Factor Rev 2006;17(4):245-257. (Review).

Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K. Cathepsin E Prevents Tumor Growth and Metastasis by Catalyzing the Proteolytic Release of Soluble



TRAIL from Tumor Cell Surface. Cancer Res 2007;67(22):10869-10878.

Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ. Targeting death-inducing receptors in cancer therapy. Oncogene 2007;26(25):3745-3757.

Corallini F, Rimondi E, Secchiero P. TRAIL and osteoprotegerin: a role in endothelial physiopathology? Front Biosci 2008;13:135-147. (Review).

Secchiero P, Zauli G. Tumor necrosis factor-related apoptosis-inducing ligand and the regulation of hematopoiesis. Current Opinion in Hematology 2008;15:42-48.


di Iasio MG, Melloni E, Secchiero P, Capitani S. TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):339-343.

Leukaemia Section Mini Review




dic(1;15)(p11;p11) Jean-Loup Huret


Published in Atlas Database: August 2007

Online updated version: http://AtlasGeneticsOncology.org/Anomalies/dic0115p11p11ID1159.html DOI: 10.4267/2042/38560


Identity

dic(1;15)(p11;p11) G-banding - Courtesy Catherine Roche-Lestienne, Olivier Theisen, Jean-Luc Lai.

dic(1;15)(p11;p11) Huret JL


Clinics and pathology Disease Myeloid malignancies

Phenotype / cell stem origin Myeloproliferative diseases (MPD) in 3 of 10 available cases (polycytemia vera (PV) in all 3 cases), myelodysplastic syndromes (MDS) in 6 cases (mainly refractory anaemia (RA): 5 cases; RARS in one case), acute myeloid leukaemia (AML) of M7 type in one case.

Epidemiology At least 10 cases; balanced sex ratio (5M/5F); median age was 47 years (range 15-81).

Kaplan-Meier on 10 cases of dic(1;15) from the literature; survivals (in months) were: 4, 14, 23+, 24+, 27, 40+, 93+, 96, 235.

Prognosis About 60% of cases were still alive 2 to 8 years after diagnosis (see figure1), but with a too short follow up of a too small cohort, no real conclusions can be drawn. It is likely that the prognosis depend more on the haematological diagnosis (AML versus MDS, vs MPD).

Cytogenetics Cytogenetics morphological Presents as-15, + dic(1;15) in most, if not all, cases. It therefore results in trisomy 1q; sole anomaly in about half cases, accompanied with del(5q) twice, +8 once, del(20q) once.

Genes involved and Proteins Note: Genes involved are unknown; the translocation breakpoints are likely to be in heterochromatic regions.

References Wurster-Hill D, McIntyre OR, Hsu LY, Hirschhorn K, Modan B, Pisciotta AV, Pierre R, Balcerzak SP, Murphy S, Weinfeld A. Cytogenetic studies in polycythemia vera. Semin Hematol 1976;13:13-32.

Mecucci C, Tricot G, Boogaerts M, Van den Berghe H. An identical translocation between chromosome 1 and 15 in two patients with myelodysplastic syndromes. Br J Haematol 1986;62:439-445.

Swolin B, Weinfeld A, Westin J. Trisomy 1q in polycythemia vera and its relation to disease transition. Am J Hematol 1986;22:155-167.

Mascarello JT, Osborn C, Kadota RP. A dysmorphic child with myelodysplasia characterized by a duplication of 1q and multiple duplications of 3q. Cancer Genet Cytogenet 1989;38:9-12.

Jotterand-Bellomo M, Parlier V, Schmidt PM, Beris P. Cytogenetic analysis of 54 cases of myelodysplastic syndrome. Cancer Genet Cytogenet 1990;46:157-172.

Michaux L, Dierlamm J, Mecucci C, Meeus P, Ameye G, Libouton JM, Verhoef G, Ferrant A, Louwagie A, Verellen-Dumoulin C, Van Den Berghe H. Dicentric (1;15) in myeloid disorders. Cancer Genet Cytogenet 1996;88:86-89.

Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, Bilhou-Nabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R; Groupe Français d'Hématologie Cellulaire. Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 2002;100:618-626.


Huret JL. dic(1;15)(p11;p11). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):344-345.

Leukaemia Section Short Communication




t(2;19)(p11;p13) Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0219p11p13ID1288.html DOI: 10.4267/2042/38561


Clinics and pathology Disease Acute myeloid leukaemia (AML)

Phenotype / cell stem origin One de novo AML (M2 type), and a therapy related AML (t-AML).

Epidemiology The de novo AML was a 11 year old girl; the t-AML case was a 58 year old female patient who had been treated for ovary carcinoma with melphalan 1.5 years before.

Prognosis No complete remission (CR) in the de novo case; CR was obtained but a relapse occurred and the patient died 3 months after diagnosis in the therapy related case.

Cytogenetics Cytogenetics morphological Sole anomaly in the de novo AML case; complex karyotype in the t-AML case, with -5 and other abnormalities.

Genes involved and Proteins Note: Genes involved are unknown.

References Larson RA, Wernli M, Le Beau MM, Daly KM, Pape LH, Rowley JD, Vardiman JW. Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine. Blood 1988;72:1333-1339.

Quilichini B, Zattara H, Cas E, Bastide-Alliez LA, Blachere A, Curtillet C, Fossat C, Michel G. Translocation t(2;19)(p11;p12-p13) in childhood with acute myeloid leukemia. Atlas Genet Cytogenet Oncol Haematol 2003;7(1):137-140.


Huret JL. t(2;19)(p11;p13). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):346.

Leukaemia Section Mini Review




t(3;4)(p21;q34) Adriana Zamecnikova

Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0304p21q34ID1433.html DOI: 10.4267/2042/38562


Identity

t(3;4)(p21;q34) G-banding

Clinics and pathology Disease Myeloid lineage, found in 1 myelodysplastic syndrome (MDS) and 1 Acute Myeloid Leukemia (AML).

Phenotype / cell stem origin MDS-RA and M1 AML by FAB criteria, a primitive myeloid progenitor is likely to be involved.

Etiology No known prior exposure.

Epidemiology Only 2 cases to date, a 69 year old female and a 31 year old male, sex ratio 1M/1F.

Clinics Elevated WBC (68x109l), 93% blasts in blood, lymphadenopaty, hepatosplenomegaly, high LDH in AML patient.

Cytology Positive for CD 34, HLDR, CD33, CD68, MPO in AML.

Treatment Chemotherapy followed by bone marrow transplantation in AML.

Evolution After the first cycle of therapy, persistent bone marrow infiltration with 11% blasts.

Prognosis Survival 6 month in MDS, 15 month+ in AML.

Cytogenetics Cytogenetics morphological May be misinterpreted as t(3;5) in suboptimal preparations.

Cytogenetics molecular FISH analysis is recommended to exclude the more frequent t(3;5).

t(3;4)(p21;q34) Zamecnikova A


FISH with WCP 3 and 4 and LSI BCL6 and 5q EGR1 probes.

Probes WCP 3 and 4 probes, locus specific BCl6 and 5q probes.

Additional anomalies t(3;4)(p21;q34) is part of a complex karyotype in MDS case associated with del(20q), sole abnormality in AML case.

Genes involved and Proteins Note: 3p21 is a recurrent breakpoint in MDS/AML and t-MDS/t-AML suggesting, 3p21 site is likely to contain a gene (genes) involved in the pathogenesis of t(3;4)(p21;q34). Frequent deletion or allelic loss of band 3p21 is common in solid tumors, indicating the presence of tumor suppressor genes on this chromosome arm. The association among structural chromosome 3 aberrations and fragile sites on 3p may indicate the importance of previous mutagen exposure in the etiology of these diseases. Although several cancer-related genes have been located to 3p21, no gene has yet been identified to be related with hematological malignancies. One of the candidate genes may be the AF3p21 gene, a novel fusion partner of the MLL gene described in a patient who had developed therapy-related leukemia with t(3;11)(p21;q23). AF3p21 encodes a protein localized

exclusively in the cell nucleus, suggesting the possibility that AF3p21 protein plays a role in signal transduction in the nucleus.

References Shi G, Weh HJ, Martensen S, Seeger D, Hossfeld DK. 3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia. Cytogenet Cell Genet 1996;74:295-299.

Sano K, Hayakawa A, Piao JH, Kosaka Y, Nakamura H. A novel SH3 protein encoded by the AF3p21 gene is fused to MLL in a therapy-related leukemia with t(3;11)(p21;q23). Blood 2000;95:1066-1068.

Hayakawa A, Matsuda Y, Daibata M, Nakamura H, Sano K. Genomic organization, tissue expression, and cellular localization of AF3p21, a fusion partner of MLL in therapy-related leukemia. Genes Chromosomes Cancer 2001;30:364-374.

Liu YC, Ito Y, Hsiao HH, Sashida G, Kodama A, Ohyashiki Jh, Ohyashiji K. Risk factor analysis in myelodysplastic syndrome patients with del(20q): prognosis revisited. Cancer Genet Cytogenet 2006;171:9-16.

Zamecnikova A. t(3;4)(p21;q34) as a sole anomaly in acute myeloid leukemia patient. Atlas Genet Cytogenet Oncol Haematol 2008;12(4).


Zamecnikova A. t(3;4)(p21;q34). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):347-348.





t(3;18)(q26;q11) Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0318q26q11ID1283.html DOI: 10.4267/2042/38563


Clinics and pathology Disease Myelodysplastic syndrome

Epidemiology Only one case to date, a 73 year old female patient.

Prognosis No data.

Cytogenetics Cytogenetics morphological There was also a del(5q).

Genes involved and Proteins Note: The partner of EVI1 is yet unknown.

EVI1 Location: 3q26.2

Protein Transcription factor; EVI1 targets include: GATA2, ZBTB16/PLZF, ZFPM2/FOG2, JNK and the PI3K/AKT pathway. Role in cell cycle progression, likely to be cell-type dependant; antiapoptotic factor; involved in neuronal development organogenesis; role in hematopoietic differentiation

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

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


Huret JL. t(3;18)(q26;q11). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):349.





t(4;21)(q31;q22) Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0421q31q22ID1448.html DOI: 10.4267/2042/38564


Clinics and pathology Disease Acute myeloid leukaemia (AML)

Epidemiology Only one case to date, a 81 year old male patient with M1 AML.

Prognosis No data.

Genes involved and Proteins SH3D19/Eve1 Location: 4q31

Protein Adaptor protein; may play a role in the positive regulation of the activity of ADAMs (A disintegrin and metalloproteases).

RUNX1 Location: 21q22

Protein Transcription factor (activator) for various hematopoietic-specific genes, which experssion is limited to hematopoetic stem cells, and endothelial cells and mesenchymal cells in the embryo; core

binding factor family member which forms heterodimers with CBFB; binds to the core site 5' PyGPyGGTPy 3' of promotors and enhancers.

Results of the chromosomal anomaly Hybrid gene Description 5' RUNX1 -3' SH3D19

References Shimomura Y, Aoki N, Ito K, Ito M. Gene expression of Sh3d19, a novel adaptor protein with five Src homology 3 domains, in anagen mouse hair follicles. J Dermatol Sci 2003;31:43-51.

Tanaka M, Nanba D, Mori S, Shiba F, Ishiguro H, Yoshino K, Matsuura N, Higashiyama S. ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands. J Biol Chem 2004 ;279:41950-41959.

Nguyen TT, Ma LN, Slovak ML, Bangs CD, Cherry AM, Arber DA. Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia. Genes Chromosomes Cancer 2006;45:918-932.


Huret JL. t(4;21)(q31;q22). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):350.

Case Report Section Paper co-edited with the European LeukemiaNet




A case of chronic lymphocytic leukemia (CLL) with a rare chromosome abnormality: t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32) Alka Dwivedi, Thomas Casey, Siddharth G Adhvaryu

Cinical and Molecular Cytogenetics Laboratory, Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229-3900, USA (AD, SGA); Brooke Army Medical Center, Fort Sam Huston, San Antonio, Texas, USA (TC)


Online updated version is available from: http://AtlasGeneticsOncology.org/Reports/0614AdhvaryuID100033.html DOI: 10.4267/2042/38565


Clinics Age and sex: 57 years old female patient. Previous History : - no preleukemia; - no previous malignant disease; - no inborn condition of note. Organomegaly : - no hepatomegaly; - no splenomegaly; - no central nervous system involvement.

Blood WBC: 34.1 x 109/l; Absolute lymphocyte count = 28,244 x 109/l. The lymphocytes were small and mature in appearance. Rare (less than 1%) prolymphocytes were present. Hb: 13.2 g/dl; platelets: 187x 109/l; blasts: 0%. Bone marrow: Variably cellular, areas of aplasia alternating with areas of residual hematopoiesis with 40% cellularity. The cellular areas show an interstitial lymphoid infiltrate comprised of small mature appearing lymphocytes with rare prolymphocytes. No clusters of large lymphocytes are present. No evidence of large cell or prolymphocytic transformation.

Cytopathology classification Cytology: Chronic lymphocytic leukemia/Small lymphocytic lymphoma. Immunophenotype: Peripheral blood 06/30/05: CD5+, CD19+, CD20+(dim), CD22+, CD23+, CD38+(dim), HLA-DR+, surface lambda+(dim), CD10- (ZAP-70 not

performed). Matutes score = 4 of 5. Bone marrow 05/09/07: CD5+, CD19+, CD20+(dim), CD22+(very dim), CD23+, CD38+, HLA-DR+, surface lambda+(dim), ZAP-70+, CD10-. Matutes score = 4 of 5. Pathology: See bone marrow above. Electron microscopy: Not performed. Precise diagnosis: Chronic lymphocytic leukemia/Small lymphocytic lymphoma.

Survival Date of diagnosis: 06-2005; Original diagnosis made by flow cytometric analysis of peripheral blood on 06/2005. First bone marrow with cytogenetic analysis performed on 05/2007. Treatment: None to date. Complete remission: N/A. Treatment related death: - Relapse: N/A. Status: Alive 04-2007.

Karyotype Sample: Bone marrow; Culture time: 24, 48 and 72 hours; Banding: GTW (G-banding by Trypsin treatment followed by Wright stain). Results: 46,XX,t(8;10)(p21;q22)c[16]/46, idem,t(1;14;6)(q21;q32;p21),-6,-12,+1-2mar [4] Karyotype at relapse: N/A. Other molecular cytogenetic technics: Fluorescence In Situ Hybridization (FISH) using Vysis LSI IGH break apart (Cat # 32-191019) on the mataphases, CLL I probe set (LSI ATM/p53) and CLL II probe sets (CEP

A case of chronic lymphocytic leukemia (CLL) with a rare chromosome abnormality: Dwivedi A, et al. t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32)


12/CEP13q14.3/CEP13q34 probes) (Cat # 32-191025) on interphase nuclei. Other molecular cytogenetics results: 2. FISH analysis (Fig. 4) of IGH break-apart probe on G-banded metaphases (Fig. 1) showed the complex translocation, t(1;14;6)(q21;q32;p21). The LSI IgH 3’ flanking region (250 kb) is labeled with Spectrum Orange and LSI IgH V 5’ region (900 kb) is labeled with Spectrum Green. A normal fusion signal is seen on chromosome 14. A translocation between 14q32 and 6p21 led to the IgH signal being split with der(14) retaining the IgH 3’ flanking region (red) and translocation of 5’ IgH V region (green) to der(6). Subsequent complex translocations involving chromosomes 1, 14 and 6 are evident by der(14) and der(1) harboring the 1q and 6p regions, respectively.

Other molecular studies Technics: FISH studies on metaphases using LSI IGH break apart probes. Results: FISH analysis confirmed the t(1;14;6)(q21;q32;p21).

Other findings results : N/A

Comments CLL is primarily a B-cell disease represented with the following anomalies; +12, del(11q) and del(17p). Cases of CLL with 14q32 (IGH) rearrangements have been reported. We present here a unique case of CLL showing a variant CCND3:IGH rearrangement in the form of t(1;14;6)(q21;q32;p21). The loss of 6q (indicated by -6) has been reported in CLL. Exact significance of monosomy 12 is not known. Interphase FISH showed del(13)(q34) in 10% cells, the significance of which is not known (Fig. 3). Metaphase FISH performed with the LSI IGH break apart probe confirmed the t(1;14;6) (Fig. 4).This case does not show the common deletions (6q, 13q14.3, 11q22-23 or 17p13) or amplification (trisomy 12).

A representative metaphase showing t(1;14;6)(q21;q32;p21) and other anomalies.



A representative metaphase of PHA stimulated blood culture showing t(8;10)(p12;q22) as the constitutional abnormality.

A representative FISH result confirming the variant t(1;14;6)(q21;q32;p21) using the IGH break apart probe (entire IGH variable region (900 kb) labeled with Spectrum Green and IGH 3' flanking region (250 kb) labeled with Spectrum Orange). A normal fusion signal (yellow) is seen on chromosome 14. Abnormal signal pattern for this probe is seen on der (14) retaining the 3'IgH flanking region and translocation of 5'IGH V region to der (6).



A: A representative FISH result showing a normal signal pattern of ATM and p53 loci (ATM loci labeled with Spectrum Green and p53 loci labeled with Spectrum Orange). B: A representative FISH result showing a deletion of 13(q34) (CEP 12, 13(q14.3) and 13(q34) labeled with Spectrums Orange, Green and Aqua, respectively).

References Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Eng J Med 2000 Dec 28;343(26):1910-1916.

Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Eng J Med 2005 Feb 24;352(8):804-815. (Review).

Reddy KS. Chronic Lymphocytic Leukemia (CLL). Atlas Genet Cytogenet Oncol Haematol 2005;9(3).

Adhvaryu SG, Dwivedi A, Stoll P. A novel chromosomal translocation (6;14) (p22;q32) in a case of precursor B-cell Acute Lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol 2007;11(2).


Dwivedi A, Casey T, Adhvaryu SG. A case of chronic lymphocytic leukemia (CLL) with a rare chromosome abnormality: t(1;14;6)(q21;q32;p21), a variant of t(6;14)(p21;q32). Atlas Genet Cytogenet Oncol Haematol.2008;12(4):351-354.

Case Report Section Paper co-edited with the European LeukemiaNet




Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage Marta Susana Gallego, Mariela Coccé, Andrea Bernasconi, Maria Felice, Cristina Alonso, Myriam Guitter

Laboratorio de Citogenetica - Servicio de Genetica- Servicio de Inmunologia - Servicio de Hemato-Oncologia, Hospital de Pediatria SAMIC 'Prof. Dr. J. P. Garrahan', Buenos Aires, Argentina


Online updated version is available from: http://AtlasGeneticsOncology.org/Reports/0812GallegoID100029.html DOI: 10.4267/2042/38566


Clinics Age and sex: 2 years old female patient. Previous History : - no preleukemia; - no previous malignant disease; - no inborn condition of note. Organomegaly : - no hepatomegal; - no splenomegaly; - no central nervous system involvement.

Blood WBC: 254,4 x 109/l; Hb:6,8 g/dl; platelets: 86x 109/l; blasts: L2 morphology%. Bone marrow: 89% of infiltration by L2 lymphoblasts.

Cytopathology classification Cytology: Ambiguous lineage acute leucemia. Immunophenotype: Blast cells were positive for T linage antigens: CD2, CD7, cCD3; B linage antigens: CD19 and cCD79a and myeloid antigens: CD13 and CD33. A minor (10%) myeloid blast population was also detected among the leukemic cells expressing MPO and CD117. Other positive markers were CD45, CD34, HLA-DR whereas CD10 and TdT were negative. Rearranged Ig or Tcr: -

Pathology: - Electron microscopy: - Precise diagnosis: acute leukemia of ambiguous lineage.

Survival Date of diagnosis: 04-2006. Treatment: 12-ALLIC/BFM-PROTOCOL. Complete remission was obtained. Treatment related death: - Relapse: - Status: alive 07-2007. Survival: 14 months

Karyotype Sample: Bone marrow; Culture time: 24; Banding: G banding. Results: 46,XX,t(8;12)(q13;p13)[16]/46,XX[4]. Karyotype at relapse: - Other molecular cytogenetic technics: Fluorescence in situ hybridization (FISH) with painting probes (WCP 8, WCP 12) and LSI ES Dual Color Translocation Probes (TEL/AML1 and AML1/ETO) (Vysis, Inc.). Other molecular cytogenetics results : ish t(8;12)(q13;p13) (WCP8+,WCP12+,TEL+,ETO-;WCP8+,WCP12+,ETO+,TEL-). FISH analysis with TEL/AML1 probe revealed that the gene ETV6 is in the derivate 8 and it is not involved in the translocation.

Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage Gallego MS, et al.


Partial GTG banded karyotype showing t(8;12)(q13;p13).

FISH with painting probes for chromosomes 8 (green) y 12 (red).

Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage Gallego MS, et al.


FISH with TEL/AML1 and AML1/ETO probes.

Comments To our knowledge four cases of t(8;12)(q13;p13) have been reported in the literature. Three of them were described in childhood acute leukemia. The fourth case was described during disease progression in acute myelomonocytic leukemia with t(11;19). It was suggested that t(8;12) might play an important role in the relapse and lead to a poor prognosis. Our patient presented a bad response to prednisone and was considered of high risk group. At present she remains in complete remission.

References Pui CH, Williams DL, Raimondi SC, Rivera GK, Look AT, Dodge RK, George SL, Behm FG, Crist WM, Murphy SB.

Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Blood 1987;70(1):247-253.

Schneider NR, Carroll AJ, Shuster JJ, Pullen DJ, Link MP, Borowitz MJ, Camitta BM, Katz JA, Amylon MD. New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases. Blood 2000;96(7):2543-2549.

Yamamoto K, Nagata K, Tsurukubo Y, Inagaki K, Ono R, Taki T, Hayashi Y, Hamaguchi H. Translocation (8;12)(q13;p13) during disease progression in acute myelomonocytic leukemia with t(11;19)(q23;p13.1). Cancer Genetics and Cytogenetics 2002;137:64-67.


Gallego MS, Coccé M, Bernasconi A, Felice M, Alonso C, Guitter M. Translocation t(8;12)(q13;p13) in a case with acute leukemia of ambiguous lineage. Atlas Genet Cytogenet Oncol Haematol.2008;12(4):355-357.



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