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Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open

access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.

It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more

traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and

educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information,

University Hospital

F-86021 Poitiers, France

tel +33 5 49 44 45 46 or +33 5 49 45 47 67

[email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias,

Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain

Zasadzinski.

Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy

Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year

by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French

National Center for Scientific Research (INIST-CNRS) since 2008.

The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

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http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

mailto:[email protected]


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http://www.atlasgeneticsoncology.org/

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)







Editor

Jean-Loup Huret

(Poitiers, France)

Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section

Alessandro Beghini (Milan, Italy) Genes Section

Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections

Judith Bovée (Leiden, The Netherlands) Solid Tumours Section

Vasantha Brito-Babapulle (London, UK) Leukaemia Section

Charles Buys (Groningen, The Netherlands) Deep Insights Section

Anne Marie Capodano (Marseille, France) Solid Tumours Section

Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections

Antonio Cuneo (Ferrara, Italy) Leukaemia Section

Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section

Louis Dallaire (Montreal, Canada) Education Section

Brigitte Debuire (Villejuif, France) Deep Insights Section

François Desangles (Paris, France) Leukaemia / Solid Tumours Sections

Enric Domingo-Villanueva (London, UK) Solid Tumours Section

Ayse Erson (Ankara, Turkey) Solid Tumours Section

Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections

Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section

Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections

Anne Hagemeijer (Leuven, Belgium) Deep Insights Section

Nyla Heerema (Colombus, Ohio) Leukaemia Section

Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections

Sakari Knuutila (Helsinki, Finland) Deep Insights Section

Lidia Larizza (Milano, Italy) Solid Tumours Section

Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section

Edmond Ma (Hong Kong, China) Leukaemia Section

Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections

Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections

Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section

Fredrik Mertens (Lund, Sweden) Solid Tumours Section

Konstantin Miller (Hannover, Germany) Education Section

Felix Mitelman (Lund, Sweden) Deep Insights Section

Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section

Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections

Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections

Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section

Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section

Mariano Rocchi (Bari, Italy) Genes Section

Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section

Albert Schinzel (Schwerzenbach, Switzerland) Education Section

Clelia Storlazzi (Bari, Italy) Genes Section

Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections

Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections

Dan Van Dyke (Rochester, Minnesota) Education Section

Roberta Vanni (Montserrato, Italy) Solid Tumours Section

Franck Viguié (Paris, France) Leukaemia Section

José Luis Vizmanos (Pamplona, Spain) Leukaemia Section

Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 14, Number 8, August 2010

Table of contents

Gene Section

DIRAS3 (DIRAS family, GTP-binding RAS-like 3) 714 Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr

JAK1 (Janus kinase 1) 717 Laurent Knoops, Tekla Hornakova, Jean-Christophe Renauld

PLAUR (plasminogen activator, urokinase receptor) 720 Benedikte Jacobsen, Martin Illemann, Michael Ploug

SHC4 (SHC (Src homology 2 domain containing) family, member 4) 732 Luigi Pasini, Luisa Lanfrancone

TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) 735 Francesca Orso, Daniela Taverna

ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) 739 Kurosh Ameri, Adrian L Harris

CLU (clusterin) 744 Hanna Rauhala, Tapio Visakorpi

ECM1 (Extracellular matrix protein 1) 749 Joseph Merregaert, Wim Van Hul

ESRRG (estrogen-related receptor gamma) 753 Rebecca B Riggins

GAS5 (growth arrest-specific 5 (non-protein coding)) 758 Mirna Mourtada-Maarabouni

GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) 761 Nathalie Britzen-Laurent, Michael Stürzl

GPNMB (glycoprotein (transmembrane) nmb) 765 Shyam A Patel, Philip K Lim, Pranela Rameshwar

MBD2 (methyl CpG binding domain protein 2) 768 Heather Owen

MEF2D (myocyte enhancer factor 2D) 772 Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger

NDRG1 (N-myc downstream regulated 1) 776 Michel Wissing, Nadine Rosmus, Michael Carducci, Sushant Kachhap

SLC5A8 (solute carrier family 5 member 8) 781 Julie Di Bernardo, Kerry J Rhoden

TMPRSS4 (transmembrane protease, serine 4) 785 Youngwoo Park

TSPAN8 (tetraspanin 8) 788 Uwe Matthias Galli

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




TXN (thioredoxin) 790 Zhe Chen, Eiji Yoshihara, Hajime Nakamura, Hiroshi Masutani, Junji Yodoi

Leukaemia Section

t(1;12)(q21;q24) 795 Sang-Guk Lee, Tae Sung Park, Jong Rak Choi

t(1;14)(q21;q32), t(1;22)(q21;q11) 797 Jean-Loup Huret

dic(9;20)(p11-13;q11) 800 Jon C Strefford

Solid Tumour Section

Ovary: inv(10)(q11q11) in ovarian germ cell tumors 804 Douglas S Richardson, Lois M Mulligan

Case Report Section

Dicentric dic(7;9)(p11;p11): a new case in childhood ALL 806 Elvira D Rodrigues Pereira Velloso, Carolina Kassab, Silvia Helena A Figueira, Denise Tiemi Noguchi,

Eliana Carla Armelin Benites, Cristóvão L P Mangueira, Fábio Morato de Oliveira

http://edition.inist.fr/

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 714



DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr

The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 354, Houston, TX

77030, USA (YY, ZL, RZL, RCBJr)

Published in Atlas Database: September 2009

Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRAS3ID702ch1p31.html DOI: 10.4267/2042/44814

This article is an update of : Guénard F, Durocher F. DHX9 (DEAH (Asp-Glu-Ala-His) box polypeptide 9). Atlas Genet Cytogenet Oncol Haematol 2010;14(6):547-549 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Other names: ARHI; NOEY2; RHOI

HGNC (Hugo): DIRAS3

Location: 1p31.3

Local order: Telomeric to GNG12, RMU7-80P and

centromeric to GPR177, RPS7P4.

Note: DIRAS3 is also known as NOEY2 and ARHI

(Ras homologue member I).

DNA/RNA

Description

DIRAS3 encompasses a 7.2-kb region and includes 2.0

kb of the 5'- flanking region, two exons, an intron, and

a 1.2-kb 3'-flanking region.

The first exon contains only the 5'-noncoding

region consisting of 81 nucleotides, whereas the second

exon contains the entire protein-coding region. The two

exons are separated by an intron of 3.2 kb. There are

three CpG island regions. CPG island I (nucleotide (nt)

-1232 to -914) is located about 1 kb upstream of the

transcription initiation site; CpG island II (nt -206 to

+79) is near the transcription initiation region and

adjacent exon 1; CpG island III (nt +3343 to +3691) is

located in the protein-encoding region of exon 2.

Transcription

The entire protein-coding region is located within exon

2 and encodes a 229-residue small GTP-binding

protein.

Pseudogene

No known pseudogenes.

The DIRAS3 gene contains two exons interrupted by a large intron. The red-blocked and opened boxes represent the coding and non-coding regions, respectively. There are three CpG island regions. Blue: CPG island I; green: CpG island II; grey: CpG island III.

DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.


DIRAS3 protein.

Protein

Description

DIRAS3 encodes a 26-kDa GTPase. The DIRAS3 gene

ORF contains three motifs typical of Ras/Rap family

members: (1) a highly conserved GTP binding domain,

(2) a putative effector domain YLPTIENTY, and (3)

the membrane localizing CAAX motif at the COOH

terminus. DIRAS3 contains a unique 34 amino-acid

extension at the N-terminus and differs from other

members of Ras-superfamily.

Expression

DIRAS3 is expressed in brain, heart, liver, lung,

pancreas, breast and ovary.

Localisation

DIRAS is associated at the cell membrane through its

prenylation at the C-terminal cysteine residue.

Mutation of the conserved CAAX box at the C-

terminus led to a loss of its membrane association.

Function

DIRAS3 is a maternally imprinted tumor suppressor

gene that belongs to the Ras superfamily of small G

proteins. DIRAS3 regulates cell cycle, motility,

angiogenesis, autophagy and tumor dormancy.

Introduction of this gene into cancer cells that lack

DIRAS3 expression inhibits proliferation and motility

of cancer cells. DIRAS3 truncates signaling through the

Ras/MAP pathway, induces p21WAF1/CIP1

, down-

regulates cyclin D1, and triggers apoptosis. DIRAS3 is

required for autophagy and that re-expression of

DIRAS3 protein in ovarian cancer cells will induce

autophagic cell death in culture. In xenografts, re-

expression of DIRAS3 also induces autophagy, but can

also promote tumor dormancy in the presence of factors

that promote survival in the cancer microenvironment.

Homology

DIRAS3 shares 56% amino acid homology with

Rap1A, 56% with Rap1B, 58% with Rap 2A, 62% with

Rap2B, 59% with K-Ras, and 54% with H-Ras.

DIRAS3 shares about 40% homology with DIRAS1

and DIRAS2.

Mutations

Note

Mutations have not been detected.

Implicated in

Solid cancers

Disease

Ovarian cancer, breast cancer, pancreatic cancer,

hepatocellular carcinoma, oligodendroglial tumor,

follicular thyroid cancer.

Prognosis

Loss of DIRAS3 expression is associated with tumor

progression in breast cancer and decreased disease-free

survival in ovarian cancer.

Oncogenesis

DIRAS3 is monoallelically expressed and maternally

imprinted, expression from the paternal allele of

DIRAS3 can be lost through LOH, CpG methylation,

and transcriptional regulation. DIRAS3 is

downregulated in 60% of ovarian and breast cancers:

LOH was found in 40% of ovarian and breast cancers.

Mutations have not been detected, but the remaining

allele is silenced in ovarian cancer and breast cancer by

methylation in approximately 10-15% of cases. In the

remaining cancers, DIRAS3 is downregulated by

transcriptional mechanisms that involve E2F1 and

E2F4, as well as by the loss of RNA binding proteins

that decrease the half-life of DIRAS3 mRNA.

References Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):214-9

Peng H, Xu F, Pershad R, Hunt KK, Frazier ML, Berchuck A, Gray JW, Hogg D, Bast RC Jr, Yu Y. ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers. Int J Cancer. 2000 Jun 1;86(5):690-4

Xu F, Xia W, Luo RZ, Peng H, Zhao S, Dai J, Long Y, Zou L, Le W, Liu J, Parlow AF, Hung MC, Bast RC Jr, Yu Y. The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice. Cancer Res. 2000 Sep 1;60(17):4913-20

Luo RZ, Peng H, Xu F, Bao J, Pang Y, Pershad R, Issa JP, Liao WS, Bast RC Jr, Yu Y. Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI. Biochim Biophys Acta. 2001 Jun 28;1519(3):216-22

Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN, LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC Jr. Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. Cancer Res. 2002 Dec 15;62(24):7264-72

DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.


Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR, Kondo Y, Issa JP, Bast RC Jr, Yu Y. Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. Hum Mol Genet. 2003 Aug 1;12(15):1791-800

Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, Bast RC. ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. Oncogene. 2003 May 15;22(19):2897-909

Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, Sahin AA, Lippman SM, Bast RC Jr, Yu Y. Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3660-6

Yu Y, Fujii S, Yuan J, Luo RZ, Wang L, Bao J, Kadota M, Oshimura M, Dent SR, Issa JP, Bast RC Jr. Epigenetic regulation of ARHI in breast and ovarian cancer cells. Ann N Y Acad Sci. 2003 Mar;983:268-77

Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC Jr, Yu Y. Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Res. 2003 Jul 15;63(14):4174-80

Rosen DG, Wang L, Jain AN, Lu KH, Luo RZ, Yu Y, Liu J, Bast RC Jr. Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. Clin Cancer Res. 2004 Oct 1;10(19):6559-66

Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills GB, Liao WS, Chen X, Bast RC Jr, Luo RZ. A Ras homologue member I directly inhibits signal transducers and activators of transcription 3 translocation and activity in human breast and ovarian cancer cells. Cancer Res. 2005 Aug 1;65(15):6701-10

Weber F, Aldred MA, Morrison CD, Plass C, Frilling A, Broelsch CE, Waite KA, Eng C. Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis. J Clin Endocrinol Metab. 2005 Feb;90(2):1149-55

Lu Z, Luo RZ, Peng H, Huang M, Nishmoto A, Hunt KK, Helin K, Liao WS, Yu Y. E2F-HDAC complexes negatively regulate

the tumor suppressor gene ARHI in breast cancer. Oncogene. 2006 Jan 12;25(2):230-9

Lu Z, Luo RZ, Peng H, Rosen DG, Atkinson EN, Warneke C, Huang M, Nishmoto A, Liu J, Liao WS, Yu Y, Bast RC Jr. Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Clin Cancer Res. 2006 Apr 15;12(8):2404-13

Yu Y, Luo R, Lu Z, Wei Feng W, Badgwell D, Issa JP, Rosen DG, Liu J, Bast RC Jr. Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods Enzymol. 2006;407:455-68

Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS, Yu Y. Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. Int J Cancer. 2007 Apr 15;120(8):1664-8

Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC Jr. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest. 2008 Dec;118(12):3917-29

Riemenschneider MJ, Reifenberger J, Reifenberger G. Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss. Int J Cancer. 2008 Jun 1;122(11):2503-10

Huang J, Lin Y, Li L, Qing D, Teng XM, Zhang YL, Hu X, Hu Y, Yang P, Han ZG. ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. Mol Carcinog. 2009 Feb;48(2):130-40

Huang S, Chang IS, Lin W, Ye W, Luo RZ, Lu Z, Lu Y, Zhang K, Liao WS, Tao T, Bast RC Jr, Chen X, Yu Y. ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep. 2009 Dec 15;30(3):159-68

This article should be referenced as such:

Yu Y, Lu Z, Luo RZ, Bast RC Jr. DIRAS3 (DIRAS family, GTP-binding RAS-like 3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):714-716.

Gene Section Review




JAK1 (Janus kinase 1) Laurent Knoops, Tekla Hornakova, Jean-Christophe Renauld

Hematology unit, Cliniques Universitaires Saint-Luc (LK); Ludwig Institute for Cancer Research de Duve

Institute, Université Catholique de Louvain, Avenue Hippocrate 74, B-1200 Brussels, Belgium (LK, TH,

JCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/JAK1ID41031ch1p31.html DOI: 10.4267/2042/44815

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: EC 2.7.10.2; JAK-1; JAK1A; JAK1B;

JTK3

HGNC (Hugo): JAK1

Location: 1p31.3

DNA/RNA

Description

25 exons spanning roughly 135 kb of genomic DNA.

Transcription

5053 bp pre-mRNA; 1 transcript described.

Protein

Description

1154 amino acids; 133,3 kDa; JAK1 contains a N-

terminal FERM domain, responsible of the binding to

the receptor, a central Src homology 2 (SH2) domain,

and two C-terminal domains: a tyrosine kinase domain

JH1 and a pseudokinase domain JH2.

Expression

Ubiquitous.

Localisation

Intracellular, associated to cytokine receptors.

Function

JAK1 is a non-receptor tyrosine kinase that associates

to cytokine receptors without intrinsic kinase activity to

mediate cytokine-induced signal transduction; JAK1

associates with numerous cytokine receptors chains and

is involved in signaling by the majority of cytokines:

the gamma-C family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-

21), the gp130 family (IL-6, OSM, LIF, ...), interferons,

...

Homology

JAK1 belongs to the janus kinase subfamily; four

mammalian JAKs have been identified (JAK1, JAK2,

JAK3 and TYK2); human JAK1 is > 90% identical to

the mouse and the rat JAK1 homologs.

Implicated in

Acute lymphoblastic leukemia T cell type (T-ALL) and Acute lymphoblastic leukemia B cell type (B-ALL)

Prognosis

JAK1 mutations are associated with advanced age, poor

response to therapy and overall prognosis (Flex et al.,

2008).

Oncogenesis

Somatic JAK1 mutations occur in T cell acute

lymphoblastic leukemia (ALL). These mutations seem

to be more frequent among adult T-ALL patients, but

the frequency varies between studies: 8/38 (21.0%;

adult; Flex et al., 2008), 1/49 (2.0%; children; Flex et

al., 2008), 2/11 (27.3%; adult; Jeong et al., 2008),

4/108 (3.7%; adult; Asnafi et al., 2009). These

mutations represent gain of function mutations that

participate in the leukemogenic process by inducing the

constitutive activation of the JAK-STAT pathway.

JAK1 (Janus kinase 1) Knoops L, et al.


Amino acid substitution Proof of hyperactivity domain reference

S512L

SH2 Flex et al., 2008

A634D Yes Pseudokinase Flex et al., 2008

Y652H

Pseudokinase Asnafi et al., 2009

V658F Yes Pseudokinase Jeong et al., 2008

R724H Yes Pseudokinase Flex et al., 2008

R724Q

Pseudokinase Asnafi et al., 2009

T782M

Pseudokinase Jeong et al., 2008

L783F


R879S

Kinase Flex et al., 2008

R879C Yes Kinase Flex et al., 2008

R879H

Kinasee Flex et al., 2008

Table 1: Somatic mutations in JAK1 found in T-ALL patients.


K204M

FERM Flex et al., 2008

L624_R629>W Yes Pseudokinase Mullighan et al., 2009

A634D Yes Pseudokinase Flex et al., 2008

S646F Yes Pseudokinase Mullighan et al., 2009

L653F

Pseudokinase Flex et al., 2008

V658F Yes Pseudokinase Mullighan et al., 2009

R724H Yes Pseudokinase Flex et al., 2008

Table 2: Somatic mutations in JAK1 found in B-ALL patients.


T478S

SH2 Xiang et al., 2008

V623A

Pseudokinase Xiang et al., 2008

V658F Yes Pseudokinase Jeong et al., 2008

Table 3: Somatic mutations in JAK1 found in AML samples.


Q644H;V645F

Pseudokinase Xie et al., 2009

Table 4: Somatic mutations in JAK1 found in hepatocellular carcinomas.


H647Y


Table 5: Somatic mutations in JAK1 found in breast cancer samples.


P782M


Table 6: Somatic mutations in JAK1 found in non-small cell lung cancer samples.

JAK1 (Janus kinase 1) Knoops L, et al.


JAK1 mutations were found in 3 B-cell ALL samples

after the resequencing of 173 B-ALL (Flex et al., 2008)

and in 3 samples after the resequencing of 187 high risk

childhood B-ALL (Mullighan et al., 2009). No

mutations were found after the resequencing of 69 B-

ALL (Jeong et al., 2008).

JAK1 mutants induce the activation of different

cytokine-receptor complexes like the IL-9 receptor or

the IL-2 receptor, that will induce the constitutive

activation of the JAK-STAT pathway.

Acute myeloid leukemia (AML)

Oncogenesis

JAK1 mutaions were found in two AML samples after

the resequencing of 94 AML (Xiang et al., 2008) and in

one AML sample after the resequencing of 105 AML.

Hepatocellular carcinoma

Oncogenesis

JAK1 mutations were found in one hepatocellular

carcinoma sample after the screening of 84

hepatocellular carcinomas.

Breast cancer

Oncogenesis

JAK1 mutation was found in a breast cancer sample

after the resequencing of 90 breast cancers.

Non-small cell lung cancer

Oncogenesis

JAK1 mutation was found in a non-small cell lung

cancer sample after the resequencing of 47 non-small

cell lung cancer samples.

References Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, Martinelli S, Fragale A, Sanchez M, Tavolaro S, Messina M, Cazzaniga G, Camera A, Pizzolo G, Tornesello A, Vignetti M, Battistini A, Cavé H, Gelb BD, Renauld JC, Biondi A, Constantinescu SN, Foà R, Tartaglia M. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med. 2008 Apr 14;205(4):751-8

Jeong EG, Kim MS, Nam HK, Min CK, Lee S, Chung YJ, Yoo NJ, Lee SH. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res. 2008 Jun 15;14(12):3716-21

Knoops L, Hornakova T, Royer Y, Constantinescu SN, Renauld JC. JAK kinases overexpression promotes in vitro cell transformation. Oncogene. 2008 Mar 6;27(11):1511-9

Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008 May 1;111(9):4797-808

Xiang Z, Zhao Y, Mitaksov V, Fremont DH, Kasai Y, Molitoris A, Ries RE, Miner TL, McLellan MD, DiPersio JF, Link DC, Payton JE, Graubert TA, Watson M, Shannon W, Heath SE, Nagarajan R, Mardis ER, Wilson RK, Ley TJ, Tomasson MH. Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. Blood. 2008 May 1;111(9):4809-12

Hornakova T, Staerk J, Royer Y, Flex E, Tartaglia M, Constantinescu SN, Knoops L, Renauld JC. Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. J Biol Chem. 2009 Mar 13;284(11):6773-81

Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, Tasian SK, Loh ML, Su X, Liu W, Devidas M, Atlas SR, Chen IM, Clifford RJ, Gerhard DS, Carroll WL, Reaman GH, Smith M, Downing JR, Hunger SP, Willman CL. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8

Xie HJ, Bae HJ, Noh JH, Eun JW, Kim JK, Jung KH, Ryu JC, Ahn YM, Kim SY, Lee SH, Yoo NJ, Lee JY, Park WS, Nam SW. Mutational analysis of JAK1 gene in human hepatocellular carcinoma. Neoplasma. 2009;56(2):136-40

Asnafi V, Le Noir S, Lhermitte L, Gardin C, Legrand F, Vallantin X, Malfuson JV, Ifrah N, Dombret H, Macintyre E. JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study. Br J Haematol. 2010 Jan;148(1):178-9


Knoops L, Hornakova T, Renauld JC. JAK1 (Janus kinase 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):717-719.

Gene Section Review




PLAUR (plasminogen activator, urokinase receptor) Benedikte Jacobsen, Martin Illemann, Michael Ploug

Finsen Laboratory 3735, Rigshospitalet, Copenhagen Biocenter, 2200 Copenhagen N, Denmark (BJ, MI,

MP)


Online updated version : http://AtlasGeneticsOncology.org/Genes/PLAURID41741ch19q13.html DOI: 10.4267/2042/44816


Identity

Other names: CD87; MO3; UPAR; URKR

HGNC (Hugo): PLAUR

Location: 19q13

DNA/RNA

Note

The gene for human urokinase-type plasminogen

activator receptor (uPAR) is located on chromosome

19q13 within a 2 Mb cluster harbouring all presently

known glycosylphosphatidylinositol (GPI)-anchored,

multi-domain proteins of the Ly6/uPAR/alpha-

neurotoxin (LU) domain family (Kjaergaard et al.,

2008).

Description

24254 bp; 7 exons (Figure 1).

Transcription

Transcription of the uPAR gene is regulated by a

TATA-less proximal promoter, partly through binding

to SP1 (Soravia et al., 1995).

Protein

Note

uPAR was originally identified on the monocyte-like

human cell line U937 as the membrane receptor for the

serine protease urokinase-type plasminogen activator

(uPA) (Vassalli et al., 1985). It has since been

implicated in a large number of

physiological and pathological conditions, including

cancer invasion and metastasis.

Description

uPAR is a multi-domain member of the

Ly6/uPAR/alpha-neurotoxin (LU) protein family

(Ploug, 2003), containing three of these LU domains

(DI, DII and DIII; Figure 2), each of ~ 90 amino acids,

adopting a "three-fingered" folding topology, and

encompassing 4 consensus disulfide bonds and an

invariant C-terminal asparagine (Figure 2B).

Intriguingly, one of the consensus disulfide bonds,

which is crucial to the proper folding of the single

domain LU proteins, is missing in the N-terminal LU

domain of uPAR. As evident from the crystal structures

solved for human uPAR, the three LU domains

cooperate in creating a deep and hydrophobic ligand-

binding cavity (Figure 2C), in which the growth factor-

like domain (GFD) of the cognate protease ligand uPA

(Huai et al., 2006; Barinka et al., 2006) or synthetic

peptide antagonists (Llinas et al., 2005) are buried

during formation of the corresponding high-affinity

receptor complexes.

The 335 amino acid residue long single polypeptide

chain of human uPAR is processed to a mature protein

of only 283 residues after post-translational excision of

signal peptides at the N- and C-termini, the latter event

being responsible for tethering uPAR to the cell

membrane via a GPI moiety (Figure 2A+C; Ploug et al

1991). Human uPAR contains 5 potential N-

glycosylation sites, of which only four are utilized

(Ploug et al., 1998; Gårdsvoll et al., 2004).

PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.


Figure 1: Location of the uPAR gene in the uPAR-like gene cluster on chromosome 19q13. Each of the three LU domains of uPAR is encoded by separate exon sets, flanked by phase-1 introns (Casey et al., 1994). The introns dividing these 3 exon sets are also phase-1 and are located at a position corresponding to the surface-exposed tip of loop 2 in the three-finger fold of the LU domains (Ploug, 2003). The other known multi LU-domain members of this protein family, which are all present within this gene cluster, are: PRV1/CD177, TEX101, C4.4A, PRO4356 and GPQH2552.

Figure 2: Structure of the uPAR protein. Panel A - Schematic representation of the amino acid sequence of human uPAR showing its three homologous LU domains. Consensus disulfide bonds defining the LU domains are coloured black. The position of the C-terminal glycolipid anchor (GPI) is shown (modified from Ploug and Ellis, 1994, with permission). Insert: The archetypical three-finger fold is illustrated by a ribbon diagram for a single secreted LU-domain protein (snake venom toxin-a) using the PDB coordinates 1NEA and PyMOL

TM (DeLano Scientific).



Panel B - LU domain signatures in the primary sequence of human uPAR. The three LU domains (DI, DII and DIII) of uPAR are aligned with the consensus structures being highlighted (disulfide bonds in yellow and the invariant asparagines in red). The number of residues between the individual cysteines is represented by dots or numbers in brackets (modified from Kjaergaard et al., 2008).

Panel C - The crystal structure solved for uPAR in complex with a peptide antagonist is shown as a ribbon diagram (Llinas et al., 2005). The individual LU domains are colour-coded (DI in yellow, DII in blue and DIII in red), and N-linked carbohydrates are shown as white sticks. The attachment to the cell surface by a glycolipid anchor is modelled in this cartoon. The insert shows uPAR in a surface representation, with the hydrophobic ligand-binding cavity marked with hatched lines; carbon, nitrogen and oxygen atoms are coloured white, blue and red, respectively. These structures are visualized by PyMOL

TM (DeLano Scientific), using the PDB coordinates 1YWH

(reproduced from Kjaergaard et al., 2008).



Expression

Under normal homeostatic conditions, uPAR is

expressed by the following bone marrow-derived blood

cells: monocytes, neutrophils, eosinophils and

macrophages. In the bone marrow itself, uPAR has

been demonstrated in myelocytes, mature myeloid

elements and monocytes. Expression of the receptor is

significantly upregulated upon cytokine stimulation of

various monocyte-derived cell lines in vitro (Plesner et

al., 1994a). Consistent with these observations, uPAR

is classified as a differentiation antigen and is also

denoted CD87. The amount of uPAR in homeostatic

organs is in general low, and when present, usually

associated to quiescent endothelial cells, as

demonstrated in e.g. the lung, kidney, thymus, liver and

heart of normal mice (Solberg et al., 2001). Expression

of uPAR in kidney and thymus has also been

recapitulated in human samples (Wei et al., 2008;

Plesner et al., 1994a).

Whereas uPAR is scarce under normal conditions,

pronounced receptor expression has been observed in

various non-homeostatic tissue remodeling processes.

First, during wound healing, strong uPAR

immunoreactivity is found in migrating keratinocytes at

the leading re-epithelialization edge of the wound,

while non-migrating keratinocytes are negative (Rømer

et al., 1994). In addition, uPAR is located in infiltrating

granulocytes located underneath the wound crush, and

in endothelial cells in the wound area (Solberg et al.,

2001). In squamous cell carcinoma of the skin, uPAR

mRNA and protein is seen in well-differentiated cancer

cells at the invasive front of the tumour lesion (Rømer

et al., 2001; Ferrier et al., 2002).

In view of the localization of uPAR in the leading-edge

keratinocytes in regenerating epidermis during mouse

skin wound healing, it has been proposed that

similarities exist between the mechanisms of generation

and regulation of extracellular proteolysis during skin

re-epithelialization and squamous cell carcinoma

invasion (Rømer et al., 2001). As a second example of

tissue remodeling, late pregnancy in mouse shows

uPAR expression in spongiotrophoblasts and

endothelial cells in the placenta (Solberg et al., 2001).

In the human counterpart, uPAR was encountered in

endothelial cells and macrophages in association with

fibrinoid deposits, suggesting a participation of uPAR

in placental development and fibrin surveillance

(Pierleoni et al., 1998 and 2003). Third, uPAR is

present in the regression of mammary glands in post-

lactational involution in mice (Solberg et al., 2001).

These three processes mimic some of the

characteristics of cancer invasion and can accordingly

be used as model systems for the elucidation of the role

of uPAR in malignant transformation. Indeed, the

receptor is upregulated in several cancer types,

expression often being confined to stromal cells

associated with the

tumour, as detailed later for gastro-intestinal, breast and

squamous cell cancers (Figure 3). Other examples

conforming to this pattern include hepatocellular

carcinoma, where uPAR has been found in

macrophages and fibroblasts, as well as in a

subpopulation of rare CK7-positive tumoural

hepatocytes (Akahane et al., 1998; Dubuisson et al.,

2000). In invasive lesions of human prostate

adenocarcinoma, uPAR mRNA and protein is also

expressed by macrophages, located throughout the

interstitial tissue of tumours (Figure 3D), whereas in

benign lesions, it is confined to intraluminal

macrophages (Usher et al., 2005). A summary of uPAR

expression patterns in various cancer forms can be

found in Table below.

Cancer type Cancer

cells

Macrop

hages

Fibroblast-like

cells

Neutrop

hils

Endothelial

cells Nerves References

Breast + + + + Pyke et al., 1993; Nielsen et

al., 2007

Colon + + + + Pyke et al., 1994; Illemann et

al., 2009

Gastric + + + +

Migita et al., 1999; Zhang et

al., 2006; Alpízar-Alpízar et

al., 2009

Glioblastoma + + Yamamoto et al., 1994

Liver + + Dubuisson et al., 2000

Lung + + + Pappot et al., 1997; Morita et

al., 1998

Oral + + + + Lindberg et al., 2006

Prostate + + Usher et al., 2005

Skin + + Rømer et al., 2001; Ferrier et

al., 2002



Figure 3: Expression of uPAR in cancer tissue. Peroxidase stainings with the same batch of a polyclonal antibody against uPAR produced at the Finsen Laboratory (Copenhagen, Denmark), showing reactivity in stromal cells associated with the tumour. Panel A - Primary colorectal adenocarcinoma (1) and a corresponding liver metastasis (2) (reproduced from Illemann et al., 2009). Panel B - Ductal carcinoma in situ lesion of the breast with microinvasion (1) and normal breast (2) (reproduced from Nielsen et al., 2007). Panel C - Gastric cancer, intestinal subtype (courtesy of W. Alpízar-Alpízar, Finsen Laboratory, Copenhagen, Denmark). Panel D - Prostate carcinoma (reproduced from Usher et al., 2005, Copyright (2004, Wiley-Liss, Inc.), with permission of John Wiley Sons, Inc.).

Localisation

The cell membrane attachment of uPAR via GPI

implicates a differential partitioning of the receptor into

detergent-resistant microdomain lipid rafts that are

enriched in cholesterol and sphingolipids. In complex

with uPA and the plasminogen activator inhibitor type

1, uPAR can also be internalized (Cubellis et al., 1990),

and later recycled back to the membrane (Nykjær et al.,

1997). Interestingly, upon stimulation of resting

neutrophils, uPAR is rapidly translocated from

secretory vesicles to the cell surface (Plesner et al.,

1994b). Proteolytic cleavage of the receptor either in

the linker region between DI and DII, e.g. by its own

ligand uPA (Høyer-Hansen et al., 1992), or between

domain III and the GPI-anchor, yield various soluble

uPAR fragments that are detectable in body fluids such

as plasma and urine, the levels of which have been

shown to correlate to overall survival in several human

cancers (Høyer-Hansen and Lund, 2007).

Function

Through its high-affinity interaction with the serine

protease urokinase-type plasminogen activator (uPA),

uPAR plays a central role in cell surface-associated

plasminogen activation, entailing proteolytic

degradation of the extracellular matrix surrounding the

cells (Ellis et al., 1989; Stephens et al., 1989). This

cascade, mediated by the broad-spectrum serine

protease plasmin, is involved in several tissue

remodeling processes such as wound healing and

mammary gland involution (Ploug,

2003; Danø et al., 2005). The proteolytic role of uPAR

in tumour invasion and metastasis is reflected by the

frequently encountered expression of uPAR at the

invasive front of cancer tissue, and by the impact of

uPAR status in malignant cells disseminated to the

bone marrow on the prognosis of gastric cancer patients

(Heiss et al., 2002).

Other ligands with which uPAR allegedly also interacts

include the matrix component vitronectin (Waltz and

Chapman, 1994; Wei et al., 1994; Gårdsvoll and Ploug,

2007; Huai et al., 2008), various integrins (Wei et al.,

1996; Aguirre Ghiso et al., 1999) and the G-protein

coupled receptor FPRL1 (Resnati et al., 1996),

affecting cell adhesion and migration, as well as signal

transduction (Figure 4; for reviews, see Ossowski and

Aguirre-Ghiso, 2000; Blasi and Carmeliet, 2002;

Kjøller, 2002; Kugler et al., 2003; Ragno, 2006; Tang

and Wei, 2008).

Homology

uPAR is homologous to the other multi-domain

proteins of the Ly6/uPAR/alpha-neurotoxin protein

domain family (C4.4A, PRV-1/CD177, TEX101,

PRO4356, GPQH2552), of which C4.4A is the best-

studied until now (Jacobsen and Ploug, 2008), and to a

vast number of single LU-domain proteins such as the

Ly-6 antigens, CD59, SLURP 1 and SLURP 2, the

extracellular ligand-binding domains of the TGF-

receptor family and the snake venom alpha-neurotoxins

(Ploug and Ellis, 1994; Ploug, 2003).



Figure 4: uPAR ligands. Schematic representation of the functions of uPAR via its interaction with uPA, integrins, and vitronectin (modified from Kjaergaard et al., 2008).

Mutations

Note

An mRNA splice variant of uPAR, lacking exons 4 and

5, which encode domain II of the receptor, has recently

been shown to have prognostic relevance in breast

cancer (Kotzsch et al., 2008). Restriction fragment

length polymorphisms of the uPAR gene have been

identified by EcoRI and PstI (Børglum et al., 1991 and

1992), and a highly polymorphic CA/GT repeat is

present in intron 3 (Kohonen-Corish et al., 1996). In a

comparison of the latter in colon cancer patients and

controls, however, there were no significant differences

in the frequencies of alleles (Przybylowska et al., 2008;

Kohonen-Corish et al., 1998). Genetic linkage and

association analyses on 587 families with high

incidences of asthma have revealed a correlation

between asthma/lung function decline and certain SNP

in the uPAR gene (Barton et al., 2009).

Implicated in

Colon cancer

Note

The first study on uPAR expression was performed by

in situ hybridization on samples of human colon cancer

(Pyke et al., 1991), which revealed the presence of

uPAR mRNA both in stromal cells and some cancer

cells located at the invasive foci. Using

immunohistochemistry and antibodies raised against

recombinant human uPAR protein, this finding was

substantiated, and demonstrated that uPAR is expressed

primarily by macrophages, some a-smooth-muscle-

actin (a-SMA)-positive

myofibroblasts, a few endothelial cells located at the

front of the cancer, as well as by some so-called

budding cancer cells (Figure 3A1; Pyke et al., 1994;

Ohtani et al., 1995; Illemann et al., 2009). Interestingly,

these uPAR-positive budding cancer cells also produce

the 2-chain of laminin 5 (LN5.2), which has been

shown to correlate with poor prognosis in colon cancer,

in addition to being a marker of early invasion of cervix

cancers (Pyke et al., 1995; Lenander et al., 2001;

Skyldberg et al., 1999). Furthermore, by combining

immunohistochemistry and in situ hybridization, it

became clear that these uPAR- and LN5.2-positive

budding cancer cells produce uPA mRNA, thus linking

uPA and its receptor to cancer cells with high invasive

potential (Illemann et al., 2009). uPAR is also found in

neutrophils scattered throughout colon cancer tissue

and in nerve bundles located in muscularis propia

(Pyke et al., 1994; Illemann et al., 2009). In fact,

immunohistochemical staining in neutrophils represents

a valuable internal positive control, as uPAR is

synthesized in these cells during differentiation in the

bone marrow and is present in all circulating

neutrophils (Plesner et al., 1994a). In colon cancer liver

metastasis with encapsulation of the secondary tumour,

uPAR expression is in general very similar to that

found in the primary tumour (Figure 3A2; Illemann et

al., 2009).

Prognosis

The high expression of uPAR encountered in malignant

tissue can be furthered into its potential as a prognostic

marker in several cancer forms, including colon cancer.

Preoperative levels of soluble uPAR is an independent

predictor of survival in patients with colorectal cancer,

as observed in a study encompassing 591 patients



(Stephens et al., 1999), with highest clinical utility in

early stage disease (Dukes' stage B).

Gastro-intestinal cancer

Note

In adenocarcinomas of the lower

esophagus/gastroesophageal junction, the pattern of

uPAR is reminiscent of that described in colon cancer

(Laerum et al., 2009), which is also the case for

adenocarcinomas of the lower stomach (Figure 3C;

Heiss et al., 1995; Migita et al., 1999; Alpízar-Alpízar

et al., 2009), i.e. expression by invasive cancer cells,

macrophages, a-SMA-positive myofibroblasts, and

some endothelial cells, as well as scattered neutrophils

and nerves bundles in the muscularis propia.

Interestingly, in these two cancer types, a much higher

number of invasive cancer cells are found to contain

uPAR as compared to colon cancer, which, in view of

the poorer prognosis of these patients, points to an

association of uPAR cancer cell expression with a

higher invasive potential (Alpízar-Alpízar et al., 2009).

In the lower esophagus and gastroesophageal junction,

uPAR expression is confined to invasive foci (Laerum

et al., 2009), whereas in the lower stomach, uPAR is

also present in benign lesions (Alpízar-Alpízar et al.,

2009). Cancer in the latter region is believed to be

caused by infection of Helicobacter pylori (Suzuki et

al., 2007). As non-neoplastic mucosa infected with H.

pylori has been shown to be positive for uPAR, in both

the epithelial cells and macrophages, the receptor

appears to be present in the tissue already at the onset

of tumourigenesis (Alpízar-Alpízar et al., 2009; Kenny

et al., 2008).

Prognosis

Importantly, in metastatic disease, uPAR positivity in

tumour cells that have disseminated to the bone marrow

is a strong negative prognostic indicator for disease-

free and overall survival in curatively resected gastric

cancer patients (Heiss et al., 2002).

Breast cancer

Note

In human ductal breast carcinomas, uPAR is primarily

expressed by tumour-associated macrophages and a-

SMA-positive myofibroblasts (Pyke et al., 1993;

Nielsen et al., 2007), whereas normal breast tissue is

devoid of reactivity (Figure 3B2). In some biopsies,

uPAR has in addition been found in invasive tumour

cells and a few endothelial cells. As for other solid

cancer forms, neutrophils also display uPAR

immunoreactivity in the breast. In early invasive ductal

carcinoma in situ (DCIS) lesions without

microinvasion, the receptor is confined to ductal

macrophages and few neoplastic cells within the

epithelial lesion. The advent of microinvasion is

accompanied by a strong uPAR signal in several layers

of tumour-associated macrophages and a-SMA-positive

myofibroblasts surrounding the DCIS lesions (Figure

3B1). These results indicate that restricted expression

of uPAR in myofibroblasts and macrophages is an early

event in breast carcinogenesis, which is strongly

amplified after transition to invasive ductal carcinoma.

Furthermore, uPAR and uPA co-localize in both

macrophages and myofibroblasts located at the front of

collapsed ducts in DCIS lesions with microinvasion

(Nielsen et al., 2007).

Prognosis

uPAR has shown potential as a prognostic marker in

breast cancer, with high levels of uPAR in cytosolic

extracts from primary breast tumours significantly

correlating with a shorter overall survival (Grøndahl-

Hansen et al., 1995). Similarly, there was a significant

association between age-adjusted levels of the receptor

in preoperative serum from breast cancer patients and

their relapse-free and overall survival, independent of

lymph node status, tumour size, and estrogen receptor

status (Riisbro et al., 2002).

Oral cancer

Note

In squamous cell carcinoma (SCC) of the oral cavity,

uPAR is strongly upregulated in areas with incipient

and invasive SCC compared to areas with dysplastic

and normal epithelium. The receptor is predominantly

observed in stromal cells, primarily macrophages, but

also in fibroblasts as well as neutrophils. uPAR-

positive neoplastic cells found in areas with incipient

and invasive SCC are also reported to express LN5.2

(Lindberg et al., 2006), which as mentioned above is a

marker for invasiveness.

Glioblastoma

Note

Presence of uPAR at the invasive edge of the cancer, as

seen in colon, breast and skin cancer, is recapitulated in

human glioblastomas, but with the notable difference

that the mRNA for uPAR in this particular case is

predominantly expressed by tumour cells, as well as in

some endothelial cells, indicating that uPAR is related

to tumour cell invasiveness and endothelial cell

migration (Yamamoto et al., 1994).

Lung cancer

Prognosis

The prognostic significance of uPAR in non-small cell

lung cancer is apparent for patients with the histologic

subtype of squamous cell carcinoma, where high levels

of uPAR is an independent marker of prognosis, as

evaluated in tumour extracts (Pedersen et al., 1994).

Measuring the levels of uPAR domain I alone in these

same extracts similarly predicted overall survival

(Almasi et al., 2005).

Ovarian cancer

Prognosis

Like in non-small cell lung cancer, uPAR domain I

present in high concentrations in preoperative plasma



independently predicts poor survival of patients with

ovarian cancer. Furthermore, soluble full-length uPAR

+ the soluble fragment of uPAR domains II+III can,

together with CA125 in plasma collected

preoperatively, serve as a diagnostic tool,

discriminating between malignant and benign ovarian

tumours (Henic et al., 2008).

Prostate cancer

Prognosis

As described for breast, colon and lung cancer, uPAR

also correlates with shorter survival of patients with

prostate cancer, where serum levels of the receptor are

elevated as compared to healthy controls (Miyake et al.,

1999).

Haematological malignancies

Note

In line with its expression in normal hematopoietic

cells, uPAR is also observed in various hematopoietic

disorders, most importantly acute leukemia and

multiple myeloma, and its level could have diagnostic

and prognostic implications for these diseases (Béné et

al., 2004).

Paroxysmal nocturnal haemoglobinuria

Note

As a consequence of being a GPI-anchored protein,

membranous uPAR is absent from blood cells derived

from clonally expanded bone marrow cells affected by

point mutations causing the haematological disease

paroxysmal nocturnal haemoglobinuria, PNH (Ploug et

al., 1992).

Figure 5: Inhibition of the uPA-uPAR interaction. Two different peptide-based strategies for pharmacological inhibition of uPAR take advantage of either mimicking the binding of the GFD-portion of uPA (Panel A) or that of a peptide antagonist (Panel B), to the hydrophobic ligand-binding cavity in the receptor (made with PyMOL

TM (DeLano Scientific), using PDB coordinates 2FD6 and 1YWH, respectively) (reproduced from Jacobsen and Ploug, 2008, with

permission). Panel C - In vivo imaging showing uptake of the uPAR peptide antagonist AE105 coupled to

64Cu-DOTA in xenotransplanted uPAR-

positive human glioblastoma tumours (white arrow; reproduced from Li et al., 2008).



Inflammatory conditions

Note

In inflammatory conditions such as Crohn's disease and

chronic ulcerative colitis, uPAR immunoreactivity is

seen in numerous macrophages, including granulomas

and granulocytes located throughout the whole

intestinal wall, as well as in nerve bundles (Laerum et

al., 2008), providing a possible link between uPAR and

inflammation.

To be noted

Note

As a result of the well-established correlation of uPAR

to tumour invasion and metastasis, several targeting

strategies with therapeutic potential have been devised

to interfere with the receptor (Mazar, 2008):

A series of small molecule antagonists of the uPA-

uPAR interaction have been identified by screening in

chemical libraries (Tyndall et al., 2008).

Synthetic peptide antagonists have also been

developed, either on the basis of the receptor-binding

region of human uPA (Figure 5A), or by combinatorial

chemistry of lead compounds selected by random

phage-display technology (Figure 5B) (Reuning et al.,

2003; Rømer et al., 2004; Jacobsen and Ploug, 2008).

The most potent of the latter group (the AE105 peptide)

has already shown its applicability in vivo. Conjugation

of modified versions of this peptide with the metal

chelator DOTA enabled its use in the non-invasive

molecular bioimaging of uPAR expression in

xenotransplanted human glioblastomas in nude mice by

PET scanning using the positron emitter 64

Cu (Figure

5C; Li et al., 2008). The biodistributions of 111

In- and 213

Bi-labelled peptide derivatives of AE105 were also

explored (Liu et al., 2009; Knör et al., 2008), the latter

with a view to subsequent studies on uPAR-targeted

radiotherapy.

Monoclonal antibodies are being developed aiming at

inhibiting the uPA-uPAR interaction and thereby

providing a means of cancer patient treatment (Bauer et

al., 2005; Jögi et al 2007; Pass et al., 2007).

Anti-tumour toxins targeting uPAR include engineered

anthrax toxins that rely on activation by receptor-bound

uPA to unleash their cytotoxicity (Liu et al., 2001), and

fusion proteins encompassing the uPAR-binding part of

uPA linked to e.g. diphtheria toxins (Rustamzadeh et

al., 2003).

In the field of gene therapy, downregulation of uPAR

gene expression has been done by anti-sense or siRNA

technology (Pillay et al., 2007).

New strategies are constantly unfolding regarding the

intervention of the uPA-uPAR interaction, as illustrated

by the recent reports of synthetic self-assembly

nanoparticles taken up by uPAR-expressing cells via

receptor-mediated endocytosis (Wang et al., 2009),

molecular imaging of pancreatic cancer using dual-

modality nanoparticles (Yang et al., 2009), and an

oncolytic measles virus retargeted against the receptor

with potent anti-tumour effect in a breast cancer

xenograft model (Jing et al., 2009).

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Pyke C, Graem N, Ralfkiaer E, Rønne E, Høyer-Hansen G, Brünner N, Danø K. Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. Cancer Res. 1993 Apr 15;53(8):1911-5

Casey JR, Petranka JG, Kottra J, Fleenor DE, Rosse WF. The structure of the urokinase-type plasminogen activator receptor gene. Blood. 1994 Aug 15;84(4):1151-6

Pedersen H, Brünner N, Francis D, Osterlind K, Rønne E, Hansen HH, Danø K, Grøndahl-Hansen J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 1994 Sep 1;54(17):4671-5

Plesner T, Ploug M, Ellis V, Rønne E, Høyer-Hansen G, Wittrup M, Pedersen TL, Tscherning T, Danø K, Hansen NE. The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. Blood. 1994 Feb 1;83(3):808-15



Plesner T, Ralfkiaer E, Wittrup M, Johnsen H, Pyke C, Pedersen TL, Hansen NE, Danø K. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol. 1994 Dec;102(6):835-41

Ploug M, Ellis V. Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins. FEBS Lett. 1994 Aug 1;349(2):163-8

Pyke C, Ralfkiaer E, Rønne E, Høyer-Hansen G, Kirkeby L, Danø K. Immunohistochemical detection of the receptor for urokinase plasminogen activator in human colon cancer. Histopathology. 1994 Feb;24(2):131-8

Rømer J, Lund LR, Eriksen J, Pyke C, Kristensen P, Danø K. The receptor for urokinase-type plasminogen activator is expressed by keratinocytes at the leading edge during re-epithelialization of mouse skin wounds. J Invest Dermatol. 1994 Apr;102(4):519-22

Waltz DA, Chapman HA. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J Biol Chem. 1994 May 20;269(20):14746-50

Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem. 1994 Dec 23;269(51):32380-8

Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicolson GL, Rao JS. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res. 1994 Sep 15;54(18):5016-20

Grøndahl-Hansen J, Peters HA, van Putten WL, Look MP, Pappot H, Rønne E, Dano K, Klijn JG, Brünner N, Foekens JA. Prognostic significance of the receptor for urokinase plasminogen activator in breast cancer. Clin Cancer Res. 1995 Oct;1(10):1079-87

Heiss MM, Babic R, Allgayer H, Gruetzner KU, Jauch KW, Loehrs U, Schildberg FW. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J Clin Oncol. 1995 Aug;13(8):2084-93

Ohtani H, Pyke C, Danø K, Nagura H. Expression of urokinase receptor in various stromal-cell populations in human colon cancer: immunoelectron microscopical analysis. Int J Cancer. 1995 Sep 15;62(6):691-6

Pyke C, Salo S, Ralfkiaer E, Rømer J, Danø K, Tryggvason K. Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res. 1995 Sep 15;55(18):4132-9

Soravia E, Grebe A, De Luca P, Helin K, Suh TT, Degen JL, Blasi F. A conserved TATA-less proximal promoter drives basal transcription from the urokinase-type plasminogen activator receptor gene. Blood. 1995 Jul 15;86(2):624-35

Kohonen-Corish MR, Wang Y, Doe WF. A highly polymorphic CA/GT repeat in intron 3 of the human urokinase receptor gene (PLAUR). Hum Genet. 1996 Jan;97(1):124-5

Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J. 1996 Apr 1;15(7):1572-82

Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA. Regulation of integrin function by the urokinase receptor. Science. 1996 Sep 13;273(5281):1551-5

Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, Blasi F. Recycling of the urokinase receptor upon

internalization of the uPA:serpin complexes. EMBO J. 1997 May 15;16(10):2610-20

Pappot H, Skov BG, Pyke C, Grøndahl-Hansen J. Levels of plasminogen activator inhibitor type 1 and urokinase plasminogen activator receptor in non-small cell lung cancer as measured by quantitative ELISA and semiquantitative immunohistochemistry. Lung Cancer. 1997 Jul;17(2-3):197-209

Akahane T, Ishii M, Ohtani H, Nagura H, Toyota T. Stromal expression of urokinase-type plasminogen activator receptor (uPAR) is associated with invasive growth in primary liver cancer. Liver. 1998 Dec;18(6):414-9

Kohonen-Corish M, Young J, Chenevix-Trench G, Doe WF. Urokinase receptor genotypes in colorectal cancer. Carcinogenesis. 1998 Jun;19(6):1149-51

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Pierleoni C, Samuelsen GB, Graem N, Rønne E, Nielsen BS, Kaufmann P, Castellucci M. Immunohistochemical identification of the receptor for urokinase plasminogen activator associated with fibrin deposition in normal and ectopic human placenta. Placenta. 1998 Sep;19(7):501-8

Ploug M, Rahbek-Nielsen H, Nielsen PF, Roepstorff P, Dano K. Glycosylation profile of a recombinant urokinase-type plasminogen activator receptor expressed in Chinese hamster ovary cells. J Biol Chem. 1998 May 29;273(22):13933-43

Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol. 1999 Oct 4;147(1):89-104

Migita T, Sato E, Saito K, Mizoi T, Shiiba K, Matsuno S, Nagura H, Ohtani H. Differing expression of MMPs-1 and -9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma. Int J Cancer. 1999 Feb 19;84(1):74-9

Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate. 1999 May;39(2):123-9

Skyldberg B, Salo S, Eriksson E, Aspenblad U, Moberger B, Tryggvason K, Auer G. Laminin-5 as a marker of invasiveness in cervical lesions. J Natl Cancer Inst. 1999 Nov 3;91(21):1882-7

Stephens RW, Nielsen HJ, Christensen IJ, Thorlacius-Ussing O, Sørensen S, Danø K, Brünner N. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst. 1999 May 19;91(10):869-74

Dubuisson L, Monvoisin A, Nielsen BS, Le Bail B, Bioulac-Sage P, Rosenbaum J. Expression and cellular localization of the urokinase-type plasminogen activator and its receptor in human hepatocellular carcinoma. J Pathol. 2000 Feb;190(2):190-5

Ossowski L, Aguirre-Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol. 2000 Oct;12(5):613-20

Lenander C, Habermann JK, Ost A, Nilsson B, Schimmelpenning H, Tryggvason K, Auer G. Laminin-5 gamma 2 chain expression correlates with unfavorable prognosis in colon carcinomas. Anal Cell Pathol. 2001;22(4):201-9



Liu S, Bugge TH, Leppla SH. Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem. 2001 May 25;276(21):17976-84

Rømer J, Pyke C, Lund LR, Ralfkiaer E, Danø K. Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin. J Invest Dermatol. 2001 Mar;116(3):353-8

Solberg H, Ploug M, Høyer-Hansen G, Nielsen BS, Lund LR. The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J Histochem Cytochem. 2001 Feb;49(2):237-46

Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43

Ferrier CM, Van Geloof WL, Straatman H, Van De Molengraft FJ, Van Muijen GN, Ruiter DJ. Spitz naevi may express components of the plasminogen activation system. J Pathol. 2002 Sep;198(1):92-9

Heiss MM, et al. Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J Clin Oncol. 2002 Apr 15;20(8):2005-16

Kjøller L. The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biol Chem. 2002 Jan;383(1):5-19

Riisbro R, Christensen IJ, Piironen T, Greenall M, Larsen B, Stephens RW, Han C, Høyer-Hansen G, Smith K, Brünner N, Harris AL. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res. 2002 May;8(5):1132-41

Kugler MC, Wei Y, Chapman HA. Urokinase receptor and integrin interactions. Curr Pharm Des. 2003;9(19):1565-74

Pierleoni C, Castellucci M, Kaufmann P, Lund LR, Schnack Nielsen B. Urokinase receptor is up-regulated in endothelial cells and macrophages associated with fibrinoid deposits in the human placenta. Placenta. 2003 Jul;24(6):677-85

Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr Pharm Des. 2003;9(19):1499-528

Reuning U, Sperl S, Kopitz C, Kessler H, Krüger A, Schmitt M, Magdolen V. Urokinase-type plasminogen activator (uPA) and its receptor (uPAR): development of antagonists of uPA/uPAR interaction and their effects in vitro and in vivo. Curr Pharm Des. 2003;9(19):1529-43

Rustamzadeh E, Li C, Doumbia S, Hall WA, Vallera DA. Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme. J Neurooncol. 2003 Oct;65(1):63-75

Béné MC, Castoldi G, Knapp W, Rigolin GM, Escribano L, Lemez P, Ludwig WD, Matutes E, Orfao A, Lanza F, van't Veer M. CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: a review. Leukemia. 2004 Mar;18(3):394-400

Gårdsvoll H, Werner F, Søndergaard L, Danø K, Ploug M. Characterization of low-glycosylated forms of soluble human urokinase receptor expressed in Drosophila Schneider 2 cells after deletion of glycosylation-sites. Protein Expr Purif. 2004 Apr;34(2):284-95

Romer J, Nielsen BS, Ploug M. The urokinase receptor as a potential target in cancer therapy. Curr Pharm Des. 2004;10(19):2359-76

Almasi CE, Høyer-Hansen G, Christensen IJ, Danø K, Pappot H. Prognostic impact of liberated domain I of the urokinase

plasminogen activator receptor in squamous cell lung cancer tissue. Lung Cancer. 2005 Jun;48(3):349-55

Bauer TW, Liu W, Fan F, Camp ER, Yang A, Somcio RJ, Bucana CD, Callahan J, Parry GC, Evans DB, Boyd DD, Mazar AP, Ellis LM. Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res. 2005 Sep 1;65(17):7775-81

Danø K, Behrendt N, Høyer-Hansen G, Johnsen M, Lund LR, Ploug M, Rømer J. Plasminogen activation and cancer. Thromb Haemost. 2005 Apr;93(4):676-81

Llinas P, Le Du MH, Gårdsvoll H, Danø K, Ploug M, Gilquin B, Stura EA, Ménez A. Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. EMBO J. 2005 May 4;24(9):1655-63

Usher PA, Thomsen OF, Iversen P, Johnsen M, Brünner N, Høyer-Hansen G, Andreasen P, Danø K, Nielsen BS. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int J Cancer. 2005 Mar 1;113(6):870-80

Barinka C, Parry G, Callahan J, Shaw DE, Kuo A, Bdeir K, Cines DB, Mazar A, Lubkowski J. Structural basis of interaction between urokinase-type plasminogen activator and its receptor. J Mol Biol. 2006 Oct 20;363(2):482-95

Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, Li Y, Yuan C, Bian C, Chen L, Furie B, Furie BC, Cines DB, Huang M. Structure of human urokinase plasminogen activator in complex with its receptor. Science. 2006 Feb 3;311(5761):656-9

Lindberg P, Larsson A, Nielsen BS. Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer. 2006 Jun 15;118(12):2948-56

Ragno P. The urokinase receptor: a ligand or a receptor? Story of a sociable molecule. Cell Mol Life Sci. 2006 May;63(9):1028-37

Zhang L, Zhao ZS, Ru GQ, Ma J. Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol. 2006 Jul 7;12(25):3970-6

Gårdsvoll H, Ploug M. Mapping of the vitronectin-binding site on the urokinase receptor: involvement of a coherent receptor interface consisting of residues from both domain I and the flanking interdomain linker region. J Biol Chem. 2007 May 4;282(18):13561-72

Høyer-Hansen G, Lund IK. Urokinase receptor variants in tissue and body fluids. Adv Clin Chem. 2007;44:65-102

Jögi A, et al. Systemic administration of anti-urokinase plasminogen activator receptor monoclonal antibodies induces hepatic fibrin deposition in tissue-type plasminogen activator deficient mice. J Thromb Haemost. 2007 Sep;5(9):1936-44

Nielsen BS, Rank F, Illemann M, Lund LR, Danø K. Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor. Int J Cancer. 2007 May 15;120(10):2086-95

Pass J, Jögi A, Lund IK, Rønø B, Rasch MG, Gårdsvoll H, Lund LR, Ploug M, Rømer J, Danø K, Høyer-Hansen G. Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: inhibitory effects on receptor-mediated uPA activity in vitro and in vivo. Thromb Haemost. 2007 Jun;97(6):1013-22



Pillay V, Dass CR, Choong PF. The urokinase plasminogen activator receptor as a gene therapy target for cancer. Trends Biotechnol. 2007 Jan;25(1):33-9

Suzuki H, Hibi T, Marshall BJ. Helicobacter pylori: present status and future prospects in Japan. J Gastroenterol. 2007 Jan;42(1):1-15

Henic E, Borgfeldt C, Christensen IJ, Casslén B, Høyer-Hansen G. Cleaved forms of the urokinase plasminogen activator receptor in plasma have diagnostic potential and predict postoperative survival in patients with ovarian cancer. Clin Cancer Res. 2008 Sep 15;14(18):5785-93

Huai Q, Zhou A, Lin L, Mazar AP, Parry GC, Callahan J, Shaw DE, Furie B, Furie BC, Huang M. Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes. Nat Struct Mol Biol. 2008 Apr;15(4):422-3

Jacobsen B, Ploug M. The urokinase receptor and its structural homologue C4.4A in human cancer: expression, prognosis and pharmacological inhibition. Curr Med Chem. 2008;15(25):2559-73

Kenny S, Duval C, Sammut SJ, Steele I, Pritchard DM, Atherton JC, Argent RH, Dimaline R, Dockray GJ, Varro A. Increased expression of the urokinase plasminogen activator system by Helicobacter pylori in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2008 Sep;295(3):G431-41

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Li ZB, Niu G, Wang H, He L, Yang L, Ploug M, Chen X. Imaging of urokinase-type plasminogen activator receptor expression using a 64Cu-labeled linear peptide antagonist by microPET. Clin Cancer Res. 2008 Aug 1;14(15):4758-66

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Jacobsen B, Illemann M, Ploug M. PLAUR (plasminogen activator, urokinase receptor). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):720-731.

Gene Section Mini Review




SHC4 (SHC (Src homology 2 domain containing) family, member 4) Luigi Pasini, Luisa Lanfrancone

IEO, European Institute of Oncology, Department of Experimental Oncology, IFOM-IEO Campus, Via

Adamello 16, 20139 Milano, Italy (LP, LL)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SHC4ID44503ch15q21.html DOI: 10.4267/2042/44817


Identity

Other names: MGC34023; RaLP; SHCD; hShcD

HGNC (Hugo): SHC4

Location: 15q21.1

Note: The mammalian Src homology and collagen

(SHC) gene family comprises four distinct loci that

encode proteins sharing a unique structural

organization. SHC proteins function as

phosphotyrosine-binding docking molecule mediating

the signaling transduction of cell-membrane receptors,

including receptor tyrosine kinases (RTKs). SHC

proteins display mutually exclusive tissue localization.

SHC1 is ubiquitously expressed except than in the

nervous system, while SHC2 and SHC3 are specifically

found in the brain. SHC4 is the latest member being

identified and its expression is restricted to brain and

skeletal muscle

of adult mice, whereas in human it appears primarily

expressed in melanoma tissues and cell lines of

melanocytic origin.

DNA/RNA

Description

Human SHC4 locus spans 139,707 bases on

chromosome 15, starting at position 46,903,227 bp and

ending at position 47,042,933 from pter (according to

hg18-Mar-2006).

The same locus that codifies for SHC4 transcript also

produces the small and unrelated protein EP300

interacting inhibitor of differentiation 1 (EID1) that has

been found only in the mammalian genome.

Orthologs of SHC4 are present in other metazoan. The

corresponding mouse gene is located on chromosome

2F1.

Genomic position of the human SHC4 locus, situated on the long arm (q21.1-q21.2) of chromosome 15. The DNA sequence containing the SHC4 gene also codifies for the short unrelated transcript EID1.

SHC4 (SHC (Src homology 2 domain containing) family, member 4) Pasini L, Lanfrancone L


SHC4 shares the same genomic architecture and protein organization typical of the SHC family. Evolutionarily conserved phosphotyrosine sites in the collagen homology 1 (CH1) region are marked in blue. Green boxes identify exons; bent arrow highlights the first ATG codon.

Transcription

Both human and mouse SHC4 open reading frame

consist of twelve exons, producing nucleotide

sequences of 1893 nt and 1881 nt respectively that

encode for putative polypeptides of 630 amino acids in

human and 626 amino acids in mouse. No clear

evidence of alternative splicing isoforms of the main

mRNA transcript has been found so far.

Pseudogene

None identified.

Protein

Description

The amino-terminal positioning of the

phosphotyrosine-binding (PTB) domain and the

carbossi-terminal positioning of the Src homology 2

(SH2) domain is a hallmark of the SHC family. These

two domains are divided by the CH1 region, which

contains three highly conserved tyrosine residues. A

second collagen homology (CH2) region is present in

the longest isoforms of the Shc family members and in

SHC4. The human SHC4 protein consists of 630 amino

acids with a total estimated molecular weight of 69

kDa. Although no splicing isoform are known, it is

postulated that two other polypeptides may be

produced by the usage of alternate initiator codons,

corresponding to predicted products of 59 kDa and 49

kDa.

Expression

Human SHC4 shows a specific expression in advanced-

stage melanomas and in no other human normal and

tumoral adult tissues. SHC4 protein product is detected

in primary cultures and cell lines of metastatic

melanoma, while its expression decreases in non-

invasive melanoma cell lines and in primary

melanocytes. In adult mouse tissues

SHC4 is primarily detected in brain and skeletal

muscle.

Localisation

In humans, SHC4 protein is mostly localized in the

cytosol of melanocytes and melanoma cells and partly

to cell membranes. The murine SHC4 protein was

demonstrated to co-localize with muscle-specific

kinase (MuSK) at the postsynaptic neuromuscular

junction (NMJ).

Function

SHC4 is a substrate of several receptor tyrosine kinases

(RTK) and G protein-coupled receptors (GPCR). When

ectopically expressed in non-metastatic melanoma cell

lines SHC4 becomes phosphorylated upon growth

factor stimulation and associates with the growth factor

receptor-bound protein 2 (Grb2). Tyrosine-

phosphorylated SHC4 induces Ras GTPase and

mitogen activated protein kinase (MAPK) activation,

resulting in enhanced cell migration. Conversely,

silencing of SHC4 expression in metastatic melanoma

cells reduces migration without affecting MAPK

pathway, suggesting that SHC4 may participate in both

Ras - dependent and - independent pathways in human

melanoma. SHC4 appears to be important for the

regulation of postsynaptic signals of motoneurons

through association with MuSK and activation of

acetylcholine receptors (AChR), as indicated by

biochemical studies of the mouse protein.

Homology

Among all the human paralogous genes, SHC4 shares

an overall identity at protein level of 45%, 37% and

41% with SHC1, SHC2, and SHC3 respectively. The

highest conservation is detected in the PTB and SH2

regions. Human and murine SHC4 display 75%

sequence identity in both the PTB and SH2 domains.

SHC4 (SHC (Src homology 2 domain containing) family, member 4) Pasini L, Lanfrancone L


Phylogenetic relationship of SHC proteins based on the comparison of their aminoacidic sequences. SHC4 is most likely derived by gene duplication of the SHC1 locus.

Implicated in

Melanoma

Disease

Melanoma is an extremely aggressive cancer of the

skin and of the internal mucosa that is capable of

metastasizing in almost every site of the body. Patients

with an advanced-stage melanoma are at greater risk of

dying of their melanoma.

Prognosis

The more reliable prognostic parameters in melanoma

are the Breslow measurement and the Clark level. The

Breslow index measures the thickness of the

melanoma: the thinner the melanoma, the better the

prognosis. In general, melanomas less than 1 millimeter

(mm) in depth have a very small chance of spreading

and then invading. The Clark level describes how far a

melanoma has penetrated into the skin, using a scale of

I to V (with higher numbers indicating a deeper

melanoma). According to Clark's model, cutaneous

melanoma initially develops from an in situ growth to a

radial growth phase (RGP) and evolves into the vertical

growth phase (VGP), which is associated to an

increased risk of metastatization.

Oncogenesis

The RGP melanoma expands radially into the

epidermis and proceeds to the VGP phase invading the

dermis, before becoming metastatic. Analysis of a

cohort of human melanoma lesions at various stages of

the disease revealed that SHC4 expression is found in

around 50% of the VGP and metastatic melanomas and

not in nevi and RGP melanomas, thus suggesting a

putative role for SHC4 as a prognostic marker. When

SHC4 is ectopically overexpressed in RGP melanoma

cells it can stimulate migration in vitro, without

perturbing proliferation. Conversely, SHC4 silencing in

metastatic melanoma cell lines inhibits migration and

delays tumor formation in vivo, suggesting that SHC4

is important for the invasive potential of melanoma

cells.

References Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L. RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas. Cancer Res. 2007 Apr 1;67(7):3064-73

Jones N, Hardy WR, Friese MB, Jorgensen C, Smith MJ, Woody NM, Burden SJ, Pawson T. Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase. Mol Cell Biol. 2007 Jul;27(13):4759-73

Pasini L, Turco MY, Luzi L, Aladowicz E, Fagiani E, Lanfrancone L. Melanoma: targeting signaling pathways and RaLP. Expert Opin Ther Targets. 2009 Jan;13(1):93-104


Pasini L, Lanfrancone L. SHC4 (SHC (Src homology 2 domain containing) family, member 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):732-734.





TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Francesca Orso, Daniela Taverna

Molecular Biotechnology Center (MBC) and Department of Oncological Sciences, University of Torino, Via

Nizza, 52, 10126 Torino, Italy (FO, DT); Center for Complex Systems in Molecular Biology and Medicine,

University of Torino, Via Acc Albertina, 13, 10023 Torino, Italy (FO, DT)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TFAP2AID42526ch6p24.html DOI: 10.4267/2042/44818


Identity Other names: AP-2; AP-2alpha; AP2-alpha; AP2TF;

BOFS; FLJ51761; TFAP2

HGNC (Hugo): TFAP2A

Location: 6p24.3

DNA/RNA

Description

The gene encompasses 22.882 kb of DNA; 7 exons.

Transcription

mRNA, NM_001042425; NM_003220;

NM_001032280.

Figure 1 : TFAP2A human gene including promoter, 7 exons and 6 introns. Modified from Entrez Gene (Genomic DNA).

Figure 2 : Three main transcripts are shown. Exons: red and green. Red: protein-coding sequences; Green: 5' and 3' Untranslated (UTR) regions. Black lines: introns. Modified from Entrez Gene (Transcripts).

TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Orso F, Taverna D


Figure 3. Modified from Williams and Tjian, 1991.

Protein

Description

The main TFAP2A isoform consists of 437 amino acids

and has a molecular weight of 52 kDa. TFAP2A

proteins contain a unique, highly conserved helix-span-

helix dimerization motif at the C-terminal half of the

protein, a central basic region and a less conserved

proline- and glutamine-rich domain at the amino

terminus. The helix-span-helix motif and the basic

region mediate DNA binding and dimerization while

the proline- and glutamine-rich region is responsible

for transcriptional transactivation (see figure 3).

Expression

Ubiquitous. Abnormal expression is found in a variety

of human tumours.

Localisation

Located predominantly in the nucleus.

Function

The TFAP2A proteins are able to form hetero- as well

as homo-dimers and bind to GC-rich DNA sequences

within regulatory regions of their target genes,

mediating both activation and repression of gene

transcription. Functional TFAP2 binding sites, such as

5'-GCCN3GGC-3' or 5'-GCCN4GGC-3' or 5'-

GCCN3/4GGG-3' or 5'-CCCCAGGC-3' have been

identified and regulate genes involved in physiological

or pathological processes such as development, cell

growth, differentiation, apoptosis and tumorigenesis.

Examples of activated genes are CDKN1A, TGFA,

estrogen receptor, keratinocyte-specific genes, KIT,

ERBB2 and IGFBP5 while MCAM/MUC18, C/EBPA,

MYC and DCBLD2/ESDN/CLCP1 are repressed by

TFAP2A. TFAP2A protein expression is highly cell-

type specific, showing different spatial and temporal

expression during development and in various tissues.

The TFAP2A proteins are essential during

embryogenesis as demonstrated by mouse genetic

studies. Loss of TFAP2A impairs cranial closure and

leads to severe dismorphogenesis of different organs

and death at birth. Loss of TFAP2A activity in general

alters proliferation and induces premature

differentiation and/or apoptosis in various cell types as

demonstrated by in vivo and in vitro studies. Because

of their involvement in these fundamental cellular

processes TFAP2A proteins are essential for

maintaining cellular homeostasis. Deregulation of

TFAP2A protein

levels alter the cell functions in such a drastic way that

it can eventually lead to cancer formation and/or

progression. In fact, several studies have associated

aberrant TFAP2A activity with tumorigenesis (see

below).

Homology

With the other members of the TFAP2 family:

TFAP2B, TFAP2C, TFAP2D, TFAP2E.

Mutations

Note

Found in branchio-oculo-facial syndrome (BOFS).

A de novo 10529A-G transition in exon 4 of the

TFAP2A human gene was found in an 18-year-old man

with branchio-oculo-facial syndrome (BOFS), a rare

autosomal-dominant cleft palate-craniofacial disorder

with variable expressivity. The mutation leads to

arg255-to-gly (R255G) substitution in a highly

conserved residue in the basic region of the DNA-

binding domain, a change that replaces a charged polar

side chain with a nonpolar side chain with a predicted

conformational space change. Four additional BOFS

patients were found to have de novo missense

mutations in the highly conserved exons 4 and 5. No

mutations were found in more than 300 controls

(Milunsky et al., 2008).

A de novo deletion of 18 and insertion of 6 nucleotides,

resulting in LPGARR deletion and RI insertion

between amino acids 276 and 281, was found within

the basic DNA binding and dimerization domains of

TFAP2A in a 4-year-old girl with congenital

sensorineural deafness associated with inner ear

malformation. The girl also had pseudocleft lips, skin

defects, auricle abnormalities, and unilateral

multicystic dysplastic kidney, leading to the diagnosis

of branchio-oculo-facial (BOF) syndrome (Tekin et al.,

2009).

Implicated in

Various cancers

Note

TFAP2A has been implicated in various cancers, first

of all in melanoma and breast tumors. However several

evidences link deregulation of TFAP2A to prostate and

ovarian carcinomas as well as gliomas.

Melanoma

Note

Malignant melanoma follows the transformation



and proliferation of melanocytes, normally present in

the basal cell layer of the epidermis. Tumor growth

consists of a horizontal or radial initial growth phase

(RGP) followed by a subsequent vertical growth phase

(VGP) corresponding to the infiltration of the dermis

and hypodermis (biphasic growth). Alternatively the

growth pattern can be only vertical (monophasic

growth). When the lesion enters the vertical growth

phase, the expression of adhesion molecules changes as

the tumor enters the dermis and acquires the capacity to

metastasize. Deregulated expression or activity of a

number of transcription factors and their downstream

target genes (including those involved in invasion and

motility) has been found and TFAP2A is one of them.

In fact, in cutaneous malignant melanoma, reduced

nuclear TFAP2A expression has been associated with

aggressive clinicopathological outcomes. Moreover

low TFAP2A levels predict shorter recurrence-free

survival. In melanoma cell lines, loss of TFAP2A

associates with enhanced invasion, metastasis

formation as well as angiogenesis as tested in mouse

models, due to events such as overexpression of the cell

adhesion molecule MCAM/MUC18, protease protease-

activated receptor 1 (F2R/PAR1), MMP2 as well as

downregulation of the tyrosine kinase receptor KIT. On

the other hand TFAP2A re-expression in melanoma

cells suppresses tumorigenicity and metastatic

potential.

Breast cancer

Note

TFAP2A nuclear or total expression is significantly

reduced in invasive carcinomas compared to benign

breast epithelium (BBE) or ductal carcinoma in situ

(DCIS) and associates with adverse clinicopathological

parameters suggesting a tumor suppressor function for

this transcription factor. However, there are reports

showing increased TFAP2A expression in breast

tumors. Discrepancies could be related to the low

specificity of the tools (mostly antibodies) used to

analyze TFAP2A expression. In fact, other TFAP2-

family members with biological or pathological

functions, could have been identified in those

experiments. One possible mechanism by which

TFAP2A could function as a tumor suppressor is by

inducing growth arrest and apoptosis via induction of

p21WAF1

expression, inhibition of MYC-related

transactivation and BCL2 expression. TFAP2A

expression in breast cancer has also been related to

high sensitiveness to chemotherapeutic drugs due to

massive induction of apoptosis in TFAP2A highly

expressing cells.

Prostate cancer

Note

TFAP2A expression is associated with luminal

differentiation of normal prostate tissues but its

expression is lost early when prostate adenocarcinomas

develop. Increase cell proliferation has been observed

in prostate tumors with low cytoplasmic TFAP2A

expression. In TFAP2A-negative prostate cancer cells,

TFAP2A expression inhibits tumorigenicity and leads

to deregulation of relevant genes such as VEGF.

Ovarian cancer

Note

Reduced cytoplasmic TFAP2A expression predicts

poor overall survival of epithelial ovarian tumors and in

ovarian cancer cells this transcription factor suppresses

cell proliferation and invasion parallel to decreased

phosphorylation of HER2, AKT and ERK pathways,

reduced pro-MMP2 levels and increased CDH1/ECAD

expression.

Gliomas

Note

High nuclear levels of TFAP2A associate with better

differentiation of human gliomas, absence of MMP2

and VEGF expression and offer some survival

advantage to the patients.

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

Bosher JM, Williams T, Hurst HC. The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):744-7

Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M. Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J. 1995 Apr 3;14(7):1508-19

Bosher JM, Totty NF, Hsuan JJ, Williams T, Hurst HC. A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene. 1996 Oct 17;13(8):1701-7

Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996 May 16;381(6579):235-8

Wang D, Shin TH, Kudlow JE. Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene. J Biol Chem. 1997 May 30;272(22):14244-50

Zeng YX, Somasundaram K, el-Deiry WS. AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression. Nat Genet. 1997 Jan;15(1):78-82

Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M. Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J. 1998 Aug 3;17(15):4358-69

Karjalainen JM, Kellokoski JK, Eskelinen MJ, Alhava EM, Kosma VM. Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma. J Clin Oncol. 1998 Nov;16(11):3584-91

Gee JM, Robertson JF, Ellis IO, Nicholson RI, Hurst HC. Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer. J Pathol. 1999 Dec;189(4):514-20

Hilger-Eversheim K, Moser M, Schorle H, Buettner R. Regulatory roles of AP-2 transcription factors in vertebrate



development, apoptosis and cell-cycle control. Gene. 2000 Dec 30;260(1-2):1-12

Perissi V, Menini N, Cottone E, Capello D, Sacco M, Montaldo F, De Bortoli M. AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen. Oncogene. 2000 Jan 13;19(2):280-8

Pellikainen J, Kataja V, Ropponen K, Kellokoski J, Pietiläinen T, Böhm J, Eskelinen M, Kosma VM. Reduced nuclear expression of transcription factor AP-2 associates with aggressive breast cancer. Clin Cancer Res. 2002 Nov;8(11):3487-95

Nyormoi O, Bar-Eli M. Transcriptional regulation of metastasis-related genes in human melanoma. Clin Exp Metastasis. 2003;20(3):251-63

Eckert D, Buhl S, Weber S, Jäger R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 2005;6(13):246

Wajapeyee N, Raut CG, Somasundaram K. Activator protein 2alpha status determines the chemosensitivity of cancer cells: implications in cancer chemotherapy. Cancer Res. 2005 Oct 1;65(19):8628-34

Wajapeyee N, Britto R, Ravishankar HM, Somasundaram K. Apoptosis induction by activator protein 2alpha involves transcriptional repression of Bcl-2. J Biol Chem. 2006 Jun 16;281(24):16207-19

Pellikainen JM, Kosma VM. Activator protein-2 in carcinogenesis with a special reference to breast cancer--a mini review. Int J Cancer. 2007 May 15;120(10):2061-7

Juriloff DM, Harris MJ. Mouse genetic models of cleft lip with or without cleft palate. Birth Defects Res A Clin Mol Teratol. 2008 Feb;82(2):63-77

Melnikova VO, Bar-Eli M. Transcriptional control of the melanoma malignant phenotype. Cancer Biol Ther. 2008 Jul;7(7):997-1003

Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet. 2008 May;82(5):1171-7

Orso F, Penna E, Cimino D, Astanina E, Maione F, Valdembri D, Giraudo E, Serini G, Sismondi P, De Bortoli M, Taverna D. AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs. FASEB J. 2008 Aug;22(8):2702-14

Tekin M, Sirmaci A, Yüksel-Konuk B, Fitoz S, Sennaroğlu L. A complex TFAP2A allele is associated with branchio-oculo-facial syndrome and inner ear malformation in a deaf child. Am J Med Genet A. 2009 Mar;149A(3):427-30


Orso F, Taverna D. TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):735-738.

Gene Section Review




ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Kurosh Ameri, Adrian L Harris

Stanford University School of Medicine, Department of Surgery, Medical School Lab Surge Building 1201

Welch Road, Stanford, CA 94305, USA (KA); University of Oxford, Cancer Research UK, Weatherall

Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK (ALH)

Published in Atlas Database: October 2009

Online updated version : http://AtlasGeneticsOncology.org/Genes/ATF4ID44413ch22q13.html DOI: 10.4267/2042/44819


Identity Other names: CREB-2; CREB2; TAXREB67;

TXREB

HGNC (Hugo): ATF4

Location: 22q13.1

Note: ATF4 has a genomic size of 2122 bp.

The mouse ATFx has been classified as a member of

the ATF4 subgroup due to 55% identity to mATF4.

DNA/RNA

Note

ATF4 gene is transcribed at very high levels (according

to ACEview). Several stress conditions such as

hypoxia, anoxia, and glucose deprivation result in

endoplasmic reticulum stress (ER stress), initiating the

unfolded protein response pathway (UPR pathway) that

increases the synthesis (increased mRNA translation)

of ATF4.

Description

The mouse ATF4 mRNA contains two upstream

open reading frames, uORF1 and uORF2, and the

human ATF4 contains three open reading frames,

uORF1 (uO1), uORF2 (uO2), and uORF3 (uO3) that

are located 5' to the ATF4 coding sequence. These

uORFs are translated in non-stressed conditions, which

result in exclusion of ATF4 translation. In mouse,

uORF2, or in humans, uORF3 overlap ATF4 ORF in

an out of frame manner. After translation of uORF1,

sufficient eIF2-GTP makes it possible to reinitiate

translation from the uORF2 in mouse, and uORF3 in

human, and therefore ATF4 synthesis is minimized.

During ER stress, PERK phosphorylates eIF2alpha

resulting in a decrease of functional eIF2 complex.

Stress-induced p-elF2alpha leads to limited eIF2-GTP

and prolongs the duration for the scanning ribosome to

reinitiate following uORF1, 2, and 3. Consequently

ribosome scanning bypasses the mouse uORF2 or

human uORF3, and translation re-initiation occurs at

the ATF4 ORF (initiation at the ATF4 coding region is

increased). Therefore, translation of ATF4 is increased

in response to stress including hypoxia, anoxia,

nutrition deprivation, including amino acid limitation

and glucose deprivation.

ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Ameri K, Harris AL


Protein

Note

ATF4 protein consists of 351 amino acids and is 38,590

Da. The protein is structured into several

domains/motifs.

Description

ATF4 protein consists of 351 amino acids. The protein

is unstable and structured into several domains/motifs

that are essential for ATF4 homo/heterodimerization,

DNA binding, and the regulation of ATF4 at the

protein stability level. The organization of the motifs

modulating ATF4 protein stability is potentially

essential for the regulation of ATF4 stability in

response to stress, including hypoxic and anoxic insult.

ATF4 has an oxygen dependent degradation domain

(ODDD) motif which is recognized by the orthologs of

C. elegans Egl-9, designated as PH (prolyl

hydroxylase) domain containing enzymes (PHD) [also

called HIF Prolyl Hydroxylase, HPH], specifically

PHD3. The betaTrCP recognition motif is another

degradation motif, which when phosphorylated, is

recognized by betaTrCP and targeted for proteasomal

degradation.

Expression

ATF4 mRNA is transcribed ubiquitously, but protein

expression and level is increased in cells that are

exposed to various stress factors such as hypoxia,

anoxia, lack of nutrition, as well as during

development.

Localisation

ATF4 protein is targeted to the nucleus. Single point

mutations of basic amino acids within the basic region

of ATF4 identified the sequence KKLKK (amino acids

280 to 284) as important for nuclear targeting.

Function

ATF4 protein can function as a transcriptional

activator, as well as a repressor. It is also a protective

gene regulating the adaptation of cells to stress factors

such as anoxic insult, endoplasmic

reticulum stress and oxidative stress. ATF4 plays an

essential role in development, and is particularly

required for proper skeletal and eye development as

well as haematopoiesis. ATF4 is also involved in

proper function of memory. Furthermore, ATF4 is also

a major factor in nutrition sensing, and has also been

recently implicated in extreme hypoxia/anoxia

mediated metastasis.

Metabolism: ATF4 is a conserved regulator of

metabolism and carbohydrate homeostasis, and

provides a mechanistic link between nutrients, insulin

resistance, and diabetes, and has been described as a

major mediator of nutrition-sensing response pathway,

regulating the expression of asparagine synthetase

(ASNS). In addition to regulating the expression of

ASNS during lack of nutrition, ATF4 also regulates

several aspects of mammalian metabolism, such as fat

storage, energy expenditure, and glycemic control. The

TOR pathway regulates invertebrate and vertebrate

metabolism, and ATF4 mutant mice have reduced TOR

signaling, and consequently reduced expression of

genes important in the intracellular concentration of

amino acids. Therefore, lack of ATF4 results in

reduced concentration of amino acids, attributed to

reduced TOR input. Thus, there is a close relationship

between ATF4 function, the TOR pathway, and

metabolism. This function of ATF4 also explains why

type I collagen synthesis is specifically reduced in

primary osteoblast cultures lacking ATF4, which can

be rescued by adding nonessential amino acids to the

culture. Thus, ATF4 is required for efficient amino acid

import into osteoblasts.

Bone metabolism: ATF4 is being considered as a

global regulator of osteoblast biology and bone

metabolism and formation. ATF4 supports bone

formation through two mechanisms, which depend on

its phosphorylation by RSK2. ATF4 regulates

osteoblast-specific gene transcription and the synthesis

of type I collagen, the main component of the bone



extracellular matrix (ECM). ATF4 does this by

favoring amino acid import, and therefore is a critical

determinant of the synthesis of proteins in osteoblasts.

Type I collagen is the most abundant protein of the

bone ECM, and therefore, ATF4 is a major regulator of

bone formation and of bone ECM mineralization.

Consequently, ATF4-deficient mice are runted and

harbor low bone mass, reduced osteoblast activity,

decreased type I collagen synthesis, and inhibited

osteocalcin and bone sialoprotein gene transcription.

Skeletogenesis: ATF4 plays an important role in

assuring that osteoblasts fulfill their function. Rsk2-

deficient mice display decreased bone mass due to

impaired bone formation. ATF4 is more strongly

phosphorylated by Rsk2 than any other proposed

substrate. ATF4-deficient mice have revealed that this

transcription factor plays several crucial roles in

osteoblast differentiation and function. ATF4-deficient

mice display a delayed skeletal development and result

in a severe low-bone-mass phenotype caused by

decreased bone formation.

Osteoclast differentiation: ATF4 regulates osteoclast

differentiation and ultimately bone resorption through

its expression in osteoblasts. ATF4 binds to the

promoter of the receptor activator of nuclear factor-

KappaB ligand (RankL) gene, which encodes a factor

secreted by osteoblasts that promotes osteoclast

differentiation. Accordingly, ATF4-deficient mice have

decreased osteoclast numbers owing to reduced RankL

expression.

Fetal liver hematopoiesis: A knockout mutation of

ATF4 has demonstrated severe fetal anemia in mice.

ATF4-/-

Fetal livers are pale and hypoplastic, and the

number of hematopoietic progenitors of multiple

lineages is decreased more than 2 fold. Therefore,

ATF4 is essential for the normal, high-level

proliferation required for fetal-liver hematopoiesis.

Memory: ATF4 is a memory repressor that blocks the

new expression of genes needed for memories, which

appears to be a conserved mechanism. Decreasing the

activity of ATF4 in mice or ApCREB2 (the ortholog of

ATF4) in the sea slug Aplysia lowers the threshold for

long-lasting changes and memory.

Homology

Drosophila: Cryptocephal (CRC) gene.

C. elegans: According to WormBase, the C. elegans

homologue of the human ATF4 gene is atf-5

(T04C10.4). The binding site of C. elegans ATF-5 is

uncharacterized.

Mutations

Note

A frameshift mutation is present in one allele of the

ATF4 gene in F9 embryonal carcinoma stem cells. The

mutation gives rise to the fusion of a short 5' open

reading frame to the coding sequence of ATF4.

Overexpression of mutant ATF4 suppresses ras-

induced transformation.

Implicated in

Note

Implication of ATF4 in disease comes mainly from

transgenic and in vitro studies. Studies in transgenic

animals have indicated that ATF4 is required for

skeletal and eye development, cellular proliferation,

hematopoiesis, and neurological disorders, including

memory. ATF4 has also been observed in greater levels

in tumors than in normal tissue, suggesting that ATF4

signaling in hypoxic and anoxic areas of tumors might

regulate processes relevant to cancer progression.

Various cancers

Note

ATF4 is a major factor induced by tumor hypoxia and

anoxia, as well as lack of nutrition including low

glucose levels. The expression of ATF4 has been noted

to be greater in patient cancer compared to paired

normal tissue. ATF4 is important for cellular survival

under conditions of extreme hypoxia, including anoxia.

Recently it has been shown that antiangiogenic

treatment with avastin results in induction of ATF4 in

vivo.

ATF4 renders cells resistant to multiple anti-cancer

drugs and it has been implicated to be a multidrug

resistant gene in cancer, and is involved in metastasis,

by regulating the expression of the metastasis

associated gene LAMP3.

Oncogenesis

ATF4 is a major factor in regulating the expression of

asparagine synthetase (ASNS) during hypoxia and

nutritional deprivation (lack of amino acids and

glucose). ASNS is associated with drug resistance in

leukemia and oncogenesis triggered by mutated p53.

Skeletal abnormalities of neurofibromatosis

Note

There has been a link between increased Rsk2-

dependent phosphorylation of ATF4 and the

development of the skeletal abnormalities in human

patients suffering from neurofibromatosis. This disease

of tumor development in the nervous system, is caused

by inactivating mutations of the neurofibromatosis 1

(NF 1), which plays a major physiological role in bone

remodeling. The Nf1ob-/-

(NF knockout specifically in

osteoblasts) mice display a high bone mass phenotype.

NF1 induces an increased production of type I

collagen, attributed to Rsk2-dependent activation of

ATF4. Thus, transgenic mice overexpressing ATF4 in

osteoblasts display a phenotype similar to the Nf1ob-/-

mice.



Alzheimer's

Note

In human brains, ATF4 and phospho-eIF2alpha levels

are tightly correlated and up-regulated in Alzheimer

disease, most probably representing an adaptive

response against disease-related cellular stress rather

than a correlate of neurodegeneration.

Coffin-lowry syndrome

Note

Coffin-Lowry Syndrome (CLS) is an X-linked mental

retardation condition associated with skeletal

abnormalities. ATF4 has been identified as a critical

regulator of osteoblast differentiation and function, and

lack of ATF4 phosphorylation by RSK2 may contribute

to the skeletal phenotype of CLS.

Vascular disease

Note

ATF4 can be induced by both vascular injury and

fibroblast growth factor-2 (FGF-2) and can serves as a

conduit for the inducible expression of one growth

factor by another during the process of intimal

thickening.

Joubert syndrome

Note

The centrosomal protein, nephrocystin-6 (NPHP6), is

disrupted in Joubert syndrome. NPHP6 interacts

physically with and activates ATF4 as a signaling

component on the level of transcriptional regulation in

this disease group.

Microphthalmia

Note

Lack of ATF4 results in severe microphthalmia due to

complete aphakia (absence of the eye lens). The affects

of lack of ATF4 is attributed to p53 mediated apoptosis

of anterior lens epithelial cells.

References Bartsch D, Ghirardi M, Skehel PA, Karl KA, Herder SP, Chen M, Bailey CH, Kandel ER. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell. 1995 Dec 15;83(6):979-92

Mielnicki LM, Hughes RG, Chevray PM, Pruitt SC. Mutated Atf4 suppresses c-Ha-ras oncogene transcript levels and cellular transformation in NIH3T3 fibroblasts. Biochem Biophys Res Commun. 1996 Nov 12;228(2):586-95

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lacking the CREB-2 transcription factor. Dev Biol. 2000 Jun 1;222(1):110-23

Hewes RS, Schaefer AM, Taghert PH. The cryptocephal gene (ATF4) encodes multiple basic-leucine zipper proteins controlling molting and metamorphosis in Drosophila. Genetics. 2000 Aug;155(4):1711-23

Lassot I, Ségéral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol. 2001 Mar;21(6):2192-202

Masuoka HC, Townes TM. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood. 2002 Feb 1;99(3):736-45

Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem. 2002 Jul 5;277(27):24120-7

Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003 Aug 14;39(4):655-69

Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003 Mar;11(3):619-33

Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL. Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood. 2004 Mar 1;103(5):1876-82

Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das A, Valerie K, Deb SP, Deb S. Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene. 2004 May 27;23(25):4430-43

Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11269-74

Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004 Apr 30;117(3):387-98

Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005 Oct 5;24(19):3470-81

Lassot I, Estrabaud E, Emiliani S, Benkirane M, Benarous R, Margottin-Goguet F. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. J Biol Chem. 2005 Dec 16;280(50):41537-45

Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006 Dec;4(6):441-51

Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert



A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006 Jun;38(6):674-81

Igarashi T, Izumi H, Uchiumi T, Nishio K, Arao T, Tanabe M, Uramoto H, Sugio K, Yasumoto K, Sasaguri Y, Wang KY, Otsuji Y, Kohno K. Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Oncogene. 2007 Jul 19;26(33):4749-60

Köditz J, Nesper J, Wottawa M, Stiehl DP, Camenisch G, Franke C, Myllyharju J, Wenger RH, Katschinski DM. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood. 2007 Nov 15;110(10):3610-7

Ameri K, Harris AL. Activating transcription factor 4. Int J Biochem Cell Biol. 2008;40(1):14-21

Deng ZL, Sharff KA, Tang N, Song WX, Luo J, Luo X, Chen J, Bennett E, Reid R, Manning D, Xue A, Montag AG, Luu HH, Haydon RC, He TC. Regulation of osteogenic differentiation during skeletal development. Front Biosci. 2008 Jan 1;13:2001-21

Malabanan KP, Kanellakis P, Bobik A, Khachigian LM. Activation transcription factor-4 induced by fibroblast growth factor-2 regulates vascular endothelial growth factor-A transcription in vascular smooth muscle cells and mediates

intimal thickening in rat arteries following balloon injury. Circ Res. 2008 Aug 15;103(4):378-87

Lewerenz J, Maher P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. J Biol Chem. 2009 Jan 9;284(2):1106-15

Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, Harris AL. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res. 2009 May 15;69(10):4415-23

Mujcic H, Rzymski T, Rouschop KM, Koritzinsky M, Milani M, Harris AL, Wouters BG. Hypoxic activation of the unfolded protein response (UPR) induces expression of the metastasis-associated gene LAMP3. Radiother Oncol. 2009 Sep;92(3):450-9

Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes. 2009 Nov;58(11):2565-73


Ameri K, Harris AL. ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):739-743.

Gene Section Review




CLU (clusterin) Hanna Rauhala, Tapio Visakorpi

Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

(HR, TV)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CLUID40107ch8p21.html DOI: 10.4267/2042/44820


Identity Other names: AAG4; APOJ; Apo-J; CLI; KUB1;

MGC24903; NA1/NA2; SGP-2; SGP2; SP-40; TRPM-

2; TRPM2

HGNC (Hugo): CLU

Location: 8p21.1

DNA/RNA

Description

Clusterin gene is 17876 bp long and contains 10 exons

in total. First two exons are alternative (designated 1

and 1') used by two different transcript isoforms.

A) Clusterin gene genomic location at chromosome 8p21-p12 (minus strand) and annotated transcripts. B) Exons are numbered and presented by boxes. Shaded areas represent untranslated regions (UTR). Endoplastic reticulum (ER)-targeting signal in exon 2 and nuclear localization signal (NLS) in exon 3 are marked. Three in-frame translation start sites in exons 1, 2 and 3 are marked (ATG).

CLU (clusterin) Rauhala H, Visakorpi T


Other exons (2-9) are shared with both isoforms. CLU

gene resides in minus strand and is transcribed in

reverse orientation (from centromere to p-telomere).

Transcription

Clusterin gene is transcribed into 2 mRNA isoforms

(NM-001831, 2859 bp; and NM-203339, 2979 bp).

They result from the use of alternative first exons (1

and 1') and shared exons 2 to 9.

Protein

Description

Secreted clusterin is produced from the transcript

isoform 2. The initial protein precursor, presecretory

psCLU (~60 kDa), becomes heavily glycosylated and

cleaved in the ER, and the resulting alpha and beta

peptide chains are held together by 5 disulfide bonds in

the mature secreted heterodimer protein form, sCLU

(~75-80 kDa).

Also the nuclear clusterin is first translated as a non-

glycosylated protein precursor, pnCLU (~49 kDa), that

is then translocated into nucleus. There is evidence of

two distinct sized nuclear clusterin proteins (~50 kDa

and ~60 kDa, Pajak et al., 2007), that could results

from translation started either at ATG present in exon 3

or in exon 1, respectively.

Clusterin proteins have never been crystallized, so

the suggested protein structures are based on

computational modeling.

Expression

Ubiquitous expression in various tissue types.

Localisation

The different clusterin protein isoforms localize to

different cellular compartments. The nuclear clusterin

translocated to nucleus after translation and

glycosylation. The secreted clusterin is initially

targeted to ER, and the glycosylated protein is

eventually secreted. There is also evidence of stress-

caused retention of sCLU in the cytosol instead of

secretion (Nizard et al., 2007).

Function

The functions of clusterin in cells are not fully known.

The controversiality of clusterin functions mainly

results from the not well-established role of the two

different protein isoforms with distinct subcellular

localization and somewhat opposing functionalities.

Some known functions include involvement in

apoptosis through complexing with Ku70 autoantigen

(nCLU, proapoptotic) or interfering with Bax-

activation (sCLU, antiapoptotic) (Yang et al., 2000;

Leskov et al., 2003; Zhang et al., 2005; Zhang et al.,

2006).

Clusterin transcripts contain 3 different translation start sites (ATG), all in-frame. The best characterized protein isoform is produced from transcript isoform 2, where translation starts at the second ATG present in exon 2, right before ER-targeting signal. This protein (NP-976084) consists of 449 amino acids. The mechanism by which the protein products are translated from isoform 1 is not as well understood. There is evidence suggesting that two nuclear protein isoforms can be produced from this transcript isoform, one in which translation starts at ATG in exon 3 (417 aa), and another with translation starting from ATG in exon 1 (459 aa).



Clusterin has also been linked to spermatogenesis

(Roberts et al., 1991), lipid transport (Jenne et al.,

1991; Calero et al., 1994; Gelissen et al., 1998),

epithelial cell differentiation (French et al., 1993;

Schedin et al., 2000; Kim et al., 2007), TGF-beta

signaling through Smad2/Smad3 (Lee et al., 2008),

complement activation (Kirszbaum et al., 1992) and

tumorigenesis (see below).

Homology

Homolog to murine Clu (75%),

Homolog to rat Clu (77%),

Low level homology to human clusterin-like 1 (retinal)

(25%).

Mutations

Somatic

6316delT, an insertion (I)/deletion (D) polymorphism,

has been studied in Japanese population (Miwa et al.,

2005). D/D genotype was shown to associate with

significantly higher total cholesterol levels and low-

density lipoprotein (LDL) levels in hypertensive

females, and the D allele was an independent predictor

of plaque prevalence.

Several SNPs have also been found in CLU-gene, both

at coding regions and at UTRs and introns. See SNP

database at NCBI.

Implicated in

Prostate cancer

Note

Several studies have shown decreased clusterin levels

in prostate cancer (Bettuzzi et al., 2000; Scaltriti et al.,

2004; Rauhala et al., 2008). On the other hand, there

are also reports on increased expression of clusterin in

prostate cancer, specifically after androgen ablation

therapy (July et al., 2002). These opposing results have

been explained by the different isoforms of clusterin,

i.e. proapoptotic nCLU being decreased, while

antiapoptotic, pro-survival sCLU could be increased.

Antisense oligonucleotide (ASO) therapy against

clusterin is currently tested in clinical trials to evaluate

its efficacy in improving androgen deprivation therapy,

as well as to prevent chemoresistance (reviewed in

Gleave and Miyake, 2005; Sowery et al., 2008). Data

supporting the tumor suppressive role for clusterin

include reports on epigenetic regulation of clusterin

expression in prostate cancer cell lines (Rauhala et al.,

2008) and a recently developed TRAMP/cluKO mouse

clusterin knock-out model that develops more poorly

differentiated and metastatic tumors (Bettuzzi et al.,

2008).

Breast cancer

Note

Clusterin expression has been shown to increase in

breast cancer (Redondo et al., 2000; Kruger et al.,

2007). Similarly to prostate cancer, clusterin ASO

therapy is being tested also for breast cancer. Recent

results from phase II trial did not support show

significant increase in treatment response when

docetaxel was combined with anti-clusterin therapy

(Chia et al., 2009).

Ovarian cancer

Note

Cytoplasmic clusterin expression has been shown to

increase in ovarian cancer in stage-specific manner and

in response to chemotherapy as a cell-survival

promoter (Xie et al., 2007; Wei et al., 2009).

Colorectal cancer

Note

Increased cytoplasmic clusterin expression has also

been found in colorectal cancers (Xie et al., 2005), and

the increased clusterin levels were shown to associate

with poor prognosis of stage II colon cancers (Kevans

et al., 2009). Clusterin has also been suggested to be a

potential stool biomarker for colon cancer screening

(Pucci et al., 2009).

Pancreatic cancer

Note

In pancreatic cancer the reports of clusterin expression

are controversial, with both high and low expression

reported for cancers (Xie et al., 2002; Jhala et al.,

2006). Lack of clusterin expression was also suggested

as a potential discriminator factor for distinguishing

pancreatic adenocarcinomas from pancreatic patients

from fine-needle aspirations (Jhala et al., 2006). In

pancreatic cancers, clusterin expression was associated

with longer survival, supporting the idea of clusterin

down-regulation in tumor progression (Xie et al.,

2002).

Alzheimer's disease

Note

Increased clusterin levels are shown in Alzheimer's

disease, mostly in astrocytes. Clusterin can bind to

amyloid-beta peptides stabilizing them leading to their

clearance from the brain. Fibrillized amyloid deposits

can be masked by clusterin so that they are not

recognized by the host defense system, thus preventing

excessive inflammation reaction. Additional protection

of neural cells is achieved by inhibiting the

complement activation. Furthermore, clusterin can

http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=1191



function antiapoptotically through Bax-interference and

potentiate survival mediated through TGF-beta

signalling (reviewed in Nuutinen et al., 2009).

Nephrotic syndrome

Note

Clusterin expression is decreased in glomerular

diseases causing nephrotic syndrome, with

hypercholesterolemia appearing as the unifying feature

(Ghiggeri et al., 2002).

References Jenne DE, Lowin B, Peitsch MC, Böttcher A, Schmitz G, Tschopp J. Clusterin (complement lysis inhibitor) forms a high density lipoprotein complex with apolipoprotein A-I in human plasma. J Biol Chem. 1991 Jun 15;266(17):11030-6

Roberts KP, Awoniyi CA, Santulli R, Zirkin BR. Regulation of Sertoli cell transferrin and sulfated glycoprotein-2 messenger ribonucleic acid levels during the restoration of spermatogenesis in the adult hypophysectomized rat. Endocrinology. 1991 Dec;129(6):3417-23

Kirszbaum L, Bozas SE, Walker ID. SP-40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges. FEBS Lett. 1992 Feb 3;297(1-2):70-6

French LE, Chonn A, Ducrest D, Baumann B, Belin D, Wohlwend A, Kiss JZ, Sappino AP, Tschopp J, Schifferli JA. Murine clusterin: molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis. J Cell Biol. 1993 Sep;122(5):1119-30

Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, Brown AJ. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function? Biochem J. 1998 Apr 1;331 ( Pt 1):231-7

Calero M, Tokuda T, Rostagno A, Kumar A, Zlokovic B, Frangione B, Ghiso J. Functional and structural properties of lipid-associated apolipoprotein J (clusterin). Biochem J. 1999 Dec 1;344 Pt 2:375-83

Bettuzzi S, Davalli P, Astancolle S, Carani C, Madeo B, Tampieri A, Corti A. Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res. 2000 Jan 1;60(1):28-34

Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M, Petito CK. Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000 Aug;157(2):393-9

Schedin P, Mitrenga T, Kaeck M. Estrous cycle regulation of mammary epithelial cell proliferation, differentiation, and death in the Sprague-Dawley rat: a model for investigating the role of estrous cycling in mammary carcinogenesis. J Mammary Gland Biol Neoplasia. 2000 Apr;5(2):211-25

Ghiggeri GM, Bruschi M, Candiano G, Rastaldi MP, Scolari F, Passerini P, Musante L, Pertica N, Caridi G, Ferrario F, Perfumo F, Ponticelli C. Depletion of clusterin in renal diseases causing nephrotic syndrome. Kidney Int. 2002 Dec;62(6):2184-94

July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002 Feb 15;50(3):179-88

Xie MJ, Motoo Y, Su SB, Mouri H, Ohtsubo K, Matsubara F, Sawabu N. Expression of clusterin in human pancreatic cancer. Pancreas. 2002 Oct;25(3):234-8

Scaltriti M, Brausi M, Amorosi A, Caporali A, D'Arca D, Astancolle S, Corti A, Bettuzzi S. Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer. Int J Cancer. 2004 Jan 1;108(1):23-30

Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol. 2005 Feb;23(1):38-46

Miwa Y, Takiuchi S, Kamide K, Yoshii M, Horio T, Tanaka C, Banno M, Miyata T, Sasaguri T, Kawano Y. Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females. Biochem Biophys Res Commun. 2005 Jun 17;331(4):1587-93

Xie D, Lau SH, Sham JS, Wu QL, Fang Y, Liang LZ, Che LH, Zeng YX, Guan XY. Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma. Cancer. 2005 Jan 15;103(2):277-83

Xie D, Sham JS, Zeng WF, Che LH, Zhang M, Wu HX, Lin HL, Wen JM, Lau SH, Hu L, Guan XY. Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression. World J Gastroenterol. 2005 Jun 7;11(21):3285-9

Jhala N, Jhala D, Vickers SM, Eltoum I, Batra SK, Manne U, Eloubeidi M, Jones JJ, Grizzle WE. Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates. Am J Clin Pathol. 2006 Oct;126(4):572-9

Kim SY, Lee S, Min BH, Park IS. Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation. Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S122-6

Krüger S, Ola V, Fischer D, Feller AC, Friedrich M. Prognostic significance of clusterin immunoreactivity in breast cancer. Neoplasma. 2007;54(1):46-50

Bettuzzi S, Davalli P, Davoli S, Rizzi F, Belloni L, Pellacani D, Astancolle S, Corti A.. The tumor-suppressor activity of Clusterin (CLU) is fully displayed in a novel transgenic model of prostate cancer: the TRAMP/CluKO mice model. 18th Meeting of the European Society for Urological Research (ESUR) 2008.

Lee KB, Jeon JH, Choi I, Kwon OY, Yu K, You KH. Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability. Biochem Biophys Res Commun. 2008 Feb 22;366(4):905-9

Rauhala HE, Porkka KP, Saramäki OR, Tammela TL, Visakorpi T. Clusterin is epigenetically regulated in prostate cancer. Int J Cancer. 2008 Oct 1;123(7):1601-9

Sowery RD, Hadaschik BA, So AI, Zoubeidi A, Fazli L, Hurtado-Coll A, Gleave ME. Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 2008 Aug;102(3):389-97

Chia S, Dent S, Ellard S, Ellis PM, Vandenberg T, Gelmon K, Powers J, Walsh W, Seymour L, Eisenhauer EA. Phase II trial of OGX-011 in combination with docetaxel in metastatic breast cancer. Clin Cancer Res. 2009 Jan 15;15(2):708-13

Kevans D, Foley J, Tenniswood M, Sheahan K, Hyland J, O'Donoghue D, Mulcahy H, O'Sullivan J. High clusterin expression correlates with a poor outcome in stage II colorectal cancers. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):393-9



Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer's disease. Brain Res Rev. 2009 Oct;61(2):89-104

Pucci S, Bonanno E, Sesti F, Mazzarelli P, Mauriello A, Ricci F, Zoccai GB, Rulli F, Galatà G, Spagnoli LG. Clusterin in stool: a new biomarker for colon cancer screening? Am J Gastroenterol. 2009 Nov;104(11):2807-15

Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X. Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer. Int J Cancer. 2009 Aug 15;125(4):791-806


Rauhala H, Visakorpi T. CLU (clusterin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):744-748.





ECM1 (Extracellular matrix protein 1) Joseph Merregaert, Wim Van Hul

Laboratory of Molecular Biotechnology, Department of Biomedical Sciences, University of Antwerp,

Universiteitsplein 1, 2610 Wilrijk/Antwerp, Belgium (JM, WVH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ECM1ID40398ch1q21.html DOI: 10.4267/2042/44821


Identity

Other names: p85 protein

HGNC (Hugo): ECM1

Location: 1q21.2

DNA/RNA

Description

The gene was initially described as having 10 exons.

Afterwards an alternative spliced exon 5a was detected.

Transcription

Four transcripts are described of which three transcripts

have been identified by Northern blot analysis and 1 by

PCR.

ECM1a (lacks exon 5a, 1.8 kb);

ECM1b (exon 5a and exon 7 are missing, 1.4 kb);

ECM1c (contains exon 5a, 1.85 kb);

ECM1d (splice variant in which 71 bp of the 3' end of

intron 1 are transcribed, resulting in a truncated 57 aa

protein, only dedected by PCR, DQ010946).

A. ECM1 DNA. B. ECM1 transcripts.

ECM1 (Extracellular matrix protein 1) Merregaert J, Van Hul W


Protein

Expression

ECM1a is widely expressed in liver, small testines,

lung, ovary, prostate, testis, skeletal muscle, pancreas,

kidney, placenta, heart, basal keratinocytes, dermal

blood vessels, and adnexal epithelia including hair

follicles and sweat glands.

ECM1b is dedectable in tonsils and the spinous and

granular layers of the epidermis.

ECM1c is expressed in the basal layer of the epidermis.

Important remark: ECM1 antibodies available to detect

ECM1 protein are not able to discriminate between

ECM1a and ECM1c.

ECM1d: expression pattern is not known yet.

Localisation

Ultrastructurally, ECM1a/c is a basement membrane

protein in human skin and is part of network-like

suprastructures containing perlecan, collagen type IV

and laminin 332 as constituents.

Function

The exact biological function of ECM1 is not

elucidated yet, but evidence for its involvement in

important biophysiological processes, like skin

differentiation, endochondral bone formation and

angiogenesis have now emerged. In the broader context

of skin biology, ECM1 appears to have many functions

and particular a 'biological super-glue' action has been

hypothesized.

Homology

A computationally predicted three-dimensional

structure of ECM1a is depicted below. Based on the

third serum albumin domain ECM1a protein can be

divided into four domains. The first domain containing

alpha-helices (alphaD1) and three serum albumin

subdomain-like domains (SASDL 2-4), each of three

sequences comparable with a complete subdomain of

the third serum albumin domain. AlphaD1 exits only of

Alpha-helices, whereas SASDL2 and -3 are capable of

binding most of the extracellular matrix proteins

identified so far (collagen type IV, laminin 332,

fibronectin, perlecan, fibulin 1C/D, fibulin-3 and MPP-

9).

Schematic representation of ECM1 and its four splice variants: ECM1 protein is divided in a signal sequence (19 aa) (black box) and four different domains based on the presence or absence of cysteines: an N-terminal cysteine-free domain (white box), two tandem repeats (green and gray box), and a C-terminal region (blue box). ECM1c differs from ECM1a containing 19 aa encoded by exon 5a, ECM1b results from an alternative trancript caused by splicing out exon 7(shaded black). ECM1d encodes a truncated protein composed of 57 aa containing exon 1, exon 2 and a part of exon 3.

Computationally predicted three-dimensional structure of ECM1a.



Mutation in ECM1. The homozygous mutations in LiP patients are indicated with double arrows. Missense or nonsense mutations are indicated in red and frameshift mutations in black.

Mutations

Note

Mutations were described in lipoid proteinosis (LiP;

OMIN#247100), also known as hyalinosis cutis et

mucosae or Urbach-Wiethe disease. This is a rare,

autosomal recessive disorder characterized by

generalized thickening of skin, mucosae, and certain

viscera. Histologically, there is widespread deposition

of hyaline (glycoprotein) material and

disruption/reduplication of basement membrane.

Classic features include beaded eyelid papules and

laryngeal infiltration leading to hoarseness. More than

40 distinct missenses, nonsenses, splice sites, small and

large deletions and insertions have been reported.

Approximately 50% of the mutations cluster to exon 6

and 7 of the gene.

Implicated in

Lipoid proteinosis

Disease

Lipoid proteinosis, also known as hyalinosis cutis et

mucosae or Urbach-Wiethe disease.

Lipoid proteinosis is a rare autosomal recessive

genodermatosis characterized by the deposition of an

amorphous hyaline material in the skin, mucosa, and

viscera. Papular infiltration of the margin of the lids

producing 'itchy eyes', and infiltration in the tongue and

its frenulum, in the larynx leading to hoarseness, and in

the skin (e.g., elbows and axilla) are characteristic.

Lichen sclerosus et atrophicus

Disease

Lichen sclerosus (LS) is a chronic inflammatory skin

disorder of unknown aethiology that results in white

plaques with epidermal atrophy. It has both genital and

extragenital presentations. HLA-subtype susceptibility

and high rates of other autoimmune disorders suggest

that autoantibodies to specific mucocutaneous antigens

may be involved in the aetiology of lichen sclerosus.

The similarities with lipoid proteinosis, which results

from mutations in the ECM1 gene, suggested that this

protein may be an autoantigen in lichen sclerosus.

Indeed, circulating auto-antibodies to ECM1 were

found in the sera of 67% of lichen sclerosus patients.

In conclusion lipoid proteinosis and lichen sclerosus

are immunogenetic counterparts targeting ECM1.

Ulcerative colitis

Note

A nonsynonymous SNP (rs11205387) has been

associated with ulcerative colitis. ECM1 variation was

not associated with Crohn's disease.

Cancer

Note

A survey of ECM1 expression in different tumors

indicated that ECM1, although not tumor specific, is

significantly elevated in many malignant epithelial

tumors that gave rise to metastases. Together with the

observation that human recombinant ECM1 stimulates

proliferation of cultured endothelial cells and promotes

blood vessel formation in the chorioallantoic membrane

of chicken embryos suggest that ECM1 is a possible

trigger for angiogenesis, tumor progression and

malignancies.

References Johnson MR, Wilkin DJ, Vos HL, Ortiz de Luna RI, Dehejia AM, Polymeropoulos MH, Francomano CA. Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21. Matrix Biol. 1997 Nov;16(5):289-92

Smits P, Ni J, Feng P, Wauters J, Van Hul W, Boutaibi ME, Dillon PJ, Merregaert J. The human extracellular matrix gene 1 (ECM1): genomic structure, cDNA cloning, expression pattern, and chromosomal localization. Genomics. 1997 Nov 1;45(3):487-95

Smits P, Poumay Y, Karperien M, Tylzanowski P, Wauters J, Huylebroeck D, Ponec M, Merregaert J. Differentiation-dependent alternative splicing and expression of the extracellular matrix protein 1 gene in human keratinocytes. J Invest Dermatol. 2000 Apr;114(4):718-24

Han Z, Ni J, Smits P, Underhill CB, Xie B, Chen Y, Liu N, Tylzanowski P, Parmelee D, Feng P, Ding I, Gao F, Gentz R, Huylebroeck D, Merregaert J, Zhang L. Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells. FASEB J. 2001 Apr;15(6):988-94

Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, Edelstein I, South AP, Bleck O, Wessagowit V,



Mallipeddi R, Orchard GE, Wan H, Dopping-Hepenstal PJ, Mellerio JE, Whittock NV, Munro CS, van Steensel MA, Steijlen PM, Ni J, Zhang L, Hashimoto T, Eady RA, McGrath JA. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet. 2002 Apr 1;11(7):833-40

Hamada T, Wessagowit V, South AP, Ashton GH, Chan I, Oyama N, Siriwattana A, Jewhasuchin P, Charuwichitratana S, Thappa DM, Jeevankumar B, Lenane P, Krafchik B, Kulthanan K, Shimizu H, Kaya TI, Erdal ME, Paradisi M, Paller AS, Seishima M, Hashimoto T, McGrath JA. Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation. J Invest Dermatol. 2003 Mar;120(3):345-50

Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV. Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem. 2003 May 9;278(19):17491-9

Oyama N, Chan I, Neill SM, Hamada T, South AP, Wessagowit V, Wojnarowska F, D'Cruz D, Hughes GJ, Black MM, McGrath JA. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet. 2003 Jul 12;362(9378):118-23

Wang L, Yu J, Ni J, Xu XM, Wang J, Ning H, Pei XF, Chen J, Yang S, Underhill CB, Liu L, Liekens J, Merregaert J, Zhang L. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors. Cancer Lett. 2003 Oct 8;200(1):57-67

Oyama N, Chan I, Neill SM, South AP, Wojnarowska F, Kawakami Y, D'Cruz D, Mepani K, Hughes GJ, Bhogal BS, Kaneko F, Black MM, McGrath JA. Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus. J Clin Invest. 2004 Jun;113(11):1550-9

Horev L, Potikha T, Ayalon S, Molho-Pessach V, Ingber A, Gany MA, Edin BS, Glaser B, Zlotogorski A. A novel splice-site mutation in ECM-1 gene in a consanguineous family with lipoid proteinosis. Exp Dermatol. 2005 Dec;14(12):891-7

Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Ann Surg. 2005 Sep;242(3):353-61; discussion 361-3

Sercu S, Poumay Y, Herphelin F, Liekens J, Beek L, Zwijsen A, Wessagowit V, Huylebroeck D, McGrath JA, Merregaert J. Functional redundancy of extracellular matrix protein 1 in epidermal differentiation. Br J Dermatol. 2007 Oct;157(4):771-5

Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008 Jun;40(6):710-2

Sercu S, Zhang L, Merregaert J. The extracellular matrix protein 1: its molecular interaction and implication in tumor progression. Cancer Invest. 2008 May;26(4):375-84

Sercu S, Zhang M, Oyama N, Hansen U, Ghalbzouri AE, Jun G, Geentjens K, Zhang L, Merregaert JH. Interaction of extracellular matrix protein 1 with extracellular matrix components: ECM1 is a basement membrane protein of the skin. J Invest Dermatol. 2008 Jun;128(6):1397-408

Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology. 2009 Feb;136(2):523-9.e3

Lal G, Hashimi S, Smith BJ, Lynch CF, Zhang L, Robinson RA, Weigel RJ. Extracellular matrix 1 (ECM1) expression is a novel prognostic marker for poor long-term survival in breast cancer: a Hospital-based Cohort Study in Iowa. Ann Surg Oncol. 2009 Aug;16(8):2280-7

Sercu S, Lambeir AM, Steenackers E, El Ghalbzouri A, Geentjens K, Sasaki T, Oyama N, Merregaert J. ECM1 interacts with fibulin-3 and the beta 3 chain of laminin 332 through its serum albumin subdomain-like 2 domain. Matrix Biol. 2009 Apr;28(3):160-9

Sercu S, Oyama N, Merregaert J. Importance of extracellular matrix protein 1 (ECM1) in maintaining the functional integrity of the human skin. The Open Dermatology. 2009, 3, 44-51. (REVIEW)


Merregaert J, Van Hul W. ECM1 (Extracellular matrix protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):749-752.

Gene Section Review




ESRRG (estrogen-related receptor gamma) Rebecca B Riggins

Department of Oncology, Georgetown University, 3970 Reservoir Road NW, E407 Research Bldg,

Washington, DC 20057, USA (RBR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ESRRGID45840ch1q41.html DOI: 10.4267/2042/44822


Identity

Other names: ERR3; ERRG2; FLJ16023; KIAA0832;

NR3B3; DKFZp781L1617

HGNC (Hugo): ESRRG

Location: 1q41

DNA/RNA

Description

The ESRRG gene encompasses 587 kb of sequence on

the minus strand. ERRgamma transcript variant 1

contains 7 exons, while variants 2, 3, and 4 contain 6

exons.

Transcription

ERRgamma has 4 coding and 1 (presumed) non-coding

transcript variants. ERRgamma transcript variant 1

(NCBI, NM_001438) is the longest isoform, while

ERRgamma transcript variant 2 (NM_206594) utilizes

an alternate 5' UTR and lacks the first 23 amino acids

of the coding sequence of variant 1 (Heard et al., 2000).

In 2006, a third splice variant (ERRgamma3,

NM_206595) was identified (Kojo et al., 2006). This

isoform has 3 novel amino-terminal exons and lacks

Exon F, which contains the second zinc-finger binding

motif within the DNA binding domain of the receptor.

Consequently ERRgamma3 cannot stimulate

transcription from an estrogen response element (ERE)-

driven reporter construct, although it can modulate the

activity of other nuclear receptors, such as estrogen

receptors alpha and beta (ERalpha, ERbeta), thyroid

hormone receptor (TR), and glucocorticoid receptor

(GR) (Kojo et al., 2006). ERRgamma4

(NM_001134285), similar to variant 2, uses an

alternate 5' UTR and also encodes a shorter protein

isoform than variant 1. ERRgamma5 (NR_024099) is

transcribed but presumed to be non-coding.

Protein

Note

The domain structure of ERRgamma is typical for a

member of the nuclear receptor superfamily.

ERRgamma and its family members (ERRalpha and

ERRbeta) are most similar to the classical estrogen

receptors alpha and beta (ERalpha, ERbeta).

Description

AF1: Like most nuclear receptors, the activation

function -1 (AF1) domain of ERRgamma participates

in the regulation of transcription by the receptor. It is

the region to which several coactivators can bind (see

below), as well as the site of post-translational

modification.

Schematic of ERRgamma domain structure. aa = amino acid, and numbers correspond to the ERRgamma1 isoform; AF1 = activation function-1 ; DBD = DNA binding domain ; LBD = ligand binding domain; (%) denotes amino acid identity to estrogen receptor alpha (ERalpha).

ESRRG (estrogen-related receptor gamma) Riggins RB


Phosphorylation of the family member ERRalpha at

serine 19 has recently been shown to direct subsequent

SUMOylation at a nearby lysine (residue 14), and that

this series of post-translational modifications is in fact

inhibitory for receptor transcriptional activity (Vu et

al., 2007). While ERRgamma lacks a serine residue in

this position, in March of 2008 Tremblay et al.

confirmed ERRalpha phosphorylation at serine 19 and

reported that ERRgamma transcriptional activity can

also be inhibited by SUMOylation of lysine 40 that is

directed by phosphorylation of serine 45 (Tremblay et

al., 2008). The authors went on to identify protein

inhibitor of activated signal transducer and activator of

transcription gamma (PIAS4) as a functional E3 ligase

for the family member ERRalpha, and hypothesized

that PIAS4 and the SUMO-conjugating enzyme Ubc9

are responsible for the modification of ERRgamma as

well.

DBD: The greater than 60% identity between the DNA

binding domains (DBDs) of ERRgamma and ERalpha

(see figure) results in ERRgamma being able to bind

the estrogen response element (ERE:

AGGTCA...TGACCT). However, ERRgamma also

binds to what was originally identified as the consensus

sequence for steroidogenic factor 1 (SF1, SFRE:

TCAAGGTCA) (Horard and Vanacker, 2003).

LBD: A key difference between ERRgamma and most

members of the nuclear receptor superfamily is the

regulation of its transcriptional activity. There is only

about 23% sequence identity between classical

ERalpha and ERRgamma in the ligand binding domain

(LBD) (see figure). Therefore, while ERalpha (like

most nuclear receptors) is dependent upon ligand for

full activation, ERRgamma and the other members of

the ERR family exhibit constitutive transcriptional

activity. None of the ERR family members are affected

by estradiol (E2) stimulation because their LBDs

cannot accommodate E2 binding (discussed in Ariazi

and Jordan, 2006). However, ERRgamma

transcriptional activity at EREs and SFREs can be

inhibited by 4-hydroxytamoxifen (4HT) and the

synthetic estrogen diethylstilbestrol (Greschik et al.,

2002; Greschik et al., 2004; Yu and Forman, 2005). In

contrast, 4HT-bound ERRgamma acquires the ability to

positively regulate transcription at activator protein-1

(AP1) sites (Huppunen et al., 2004), but the mechanism

by which this occurs is not clear. ERRgamma

constitutive activity can be enhanced or stabilized by

the synthetic agonist GSK4716 (Yu and Forman, 2005;

Zuercher et al., 2005), the endocrine disruptor

Bisphenol A (BPA) (Matsushima et al., 2007;

Takayanagi et al., 2006), and a variant of this

compound (4-alpha-cumylphenol) (Matsushima et al.,

2008). ERRgamma constitutive activity has also

recently been shown to be inhibited by kaempferol, a

dietary flavonoid (Wang et al., 2009).

Coactivators/Corepressors: Like other nuclear

receptors, ERRgamma transcriptional activity is

modulated by binding to other proteins that can serve

as coactivators or corepressors. Coactivators and

corepressors bind directly to nuclear receptors, most

often within the carboxyl-terminal activation function-2

(AF2) domain that participates in ligand-binding but

some can exert their effects by binding to the amino-

terminal AF1 domain or the flexible hinge region of the

receptor (Hall and McDonnell, 2005). Among the

coactivators that have been demonstrated to bind and

activate ERRgamma are PPARGC1A (also known as

PGC-1alpha), TLE1, NCOA1, NCOA2 and, under

certain circumstances, NRIP1 (Gowda et al., 2006;

Sanyal et al., 2004). PPARGC1A is best known as a

coactivator for peroxisome proliferator-activated

receptor gamma, but it is also able to enhance

ERRgamma activity in an AF1-dependent manner

(Hentschke et al., 2002). TLE1 can also enhance

ERRgamma activity by binding to its AF1 domain, and

the coactivator function of TLE1 in this context is

unique because this protein typically functions as a

repressor for Drosophila and mammalian high mobility

group (HMG) box transcription factors. TLE1 also has

no known interactions with classical ERalpha or any

other nuclear receptor (Hentschke and Borgmeyer,

2003). In contrast, NCOA1 and NCOA2 are well-

known AF2-dependent coactivators of ERalpha and

other nuclear receptors, including ERRgamma

(reviewed in Hall and McDonnell, 2005).

Expression

In fetal and adult human tissues, ERRgamma1 and

ERRgamma2 are most highly expressed in the heart,

brain, kidney, and skeletal muscle (Heard et al., 2000),

while ERRgamma3 expression appears to be restricted

to the prostate and adipose tissue (Kojo et al., 2006).

Interestingly, in the mouse ERRgamma is also

expressed in these tissues but is even more abundant in

the brain stem and spinal cord

(http://www.nursa.org/10.1621/datasets.02001).

Localisation

Endogenous ERRgamma is localized to the nucleus in

human breast cancer (Park et al., 2005) and prostate

tissue (Yu et al., 2007), and transfected, exogenous

ERRgamma is also found in the nucleus of tissue

culture cells (Yasumoto et al., 2007).

Function

Molecular function: transcription factor activity, steroid

hormone receptor activity, steroid binding, protein

binding, zinc ion binding.

Biological processes: transcription, positive regulation

of transcription (DNA-dependent).

As a member of the nuclear receptor superfamily,

ERRgamma is a transcription factor. In the mouse,

homozygous knockout of ERR results in death on or

about postnatal day 1 caused by severe cardiac defects

(Alaynick et al., 2007). This is due to a key metabolic

defect whereby the animals are unable to switch from

deriving energy from carbohydrates in utero to lipids as

a neonate because ERRgamma controls the

http://www.nursa.org/10.1621/datasets.02001



transcription of essential genes that regulate oxidative

metabolic processes (Giguere, 2008).

Homology

ERRgamma is highly conserved among several species.

At the amino acid level, human ERRgamma is 100%

identical to rat, mouse, and cow ERRgamma, and

99.78% identical to dog and chimpanzee ERRgamma.

Mutations

Germinal

Two recent studies have identified single nucleotide

polymorphisms (SNPs) in ERRgamma. In a genome-

wide association study searching for genes linked to

Type 2 diabetes in an Amish population, Rampersaud

et al. identified the non-coding rs2818781, which is

present in an intron of ERRgamma2 and ERRgamma3

(Rampersaud et al., 2007). The T vs. C allele confers an

increased risk for Type 2 diabetes (O.R. 1.61, p=0.003),

and is also significantly associated with elevated

glucose area under the curve (GAUC), a measure of

impaired glucose tolerance collected during the oral

glucose tolerance test (OGTT).

Two different SNPs in ERRgamma have been linked to

breast cancer risk in a population of Thai women

(Sangrajrang et al., 2009). The non-coding rs1857407

is located in an intron of ERRgamma1, ERRgamma2,

and ERRgamma3, and heterozygotes for the G vs. A

allele have a reduced breast cancer risk (O.R. 0.72,

p=0.022). This risk reduction is even more pronounced

in post-menopausal women (O.R. 0.69, p=0.043). In

contrast, homozygote carriers of the CC (vs. TT) allele

of rs945453 have an elevated breast cancer risk (O.R.

1.66, p=0.034), though this shows no significant

association with pre- vs. post-menopausal status. This

SNP leads to a synonymous change (serine-to-serine) at

position 318 for ERRgamma1, and 295 for

ERRgamma2, ERRgamma3, and ERRgamma4.

Implicated in

Breast cancer

Note

In 2002 Ariazi et al. published a study of ERRgamma

family expression in 38 breast tumors as compared to

normal mammary epithelial cells (MECs) (Ariazi et al.,

2002). ERRgamma mRNA expression is nearly 4-fold

higher in these tumors than in the MECs and is

positively associated with ERalpha and progesterone

receptor (PR) expression. It was therefore concluded

that the correlation of ERRgamma with ERalpha and

PR in breast tumors suggests that ERRgamma

expression is an indicator of good prognosis in breast

cancer (Ariazi et al., 2002), given that women with

ER+/PR+ breast tumors are excellent candidates for

adjuvant endocrine therapy with aromatase inhibitors or

antiestrogens such as Tamoxifen (TAM).

However, TAM therapy is ineffective in approximately

30% of patients with ER+/PR+ breast tumors, and the

majority of women who initially respond to TAM but

go on to acquire resistance to this and other endocrine

agents do so without complete loss of ERalpha

expression (Clarke et al., 2001). Moreover, 4-

hydroxytamoxifen (4HT)-bound ERRgamma is known

to activate transcription at AP1 sites, and elevated AP1

activity has been linked to TAM resistance in multiple

in vitro (Dumont et al., 1996; Zhou et al., 2007) and in

vivo (Johnston et al., 1999; Schiff et al., 2000) studies.

In light of this, we were intrigued to find that that

endogenous expression of ERRgamma is upregulated

during the acquisition of TAM resistance by the

ER+/PR+ SUM44 breast cancer cell line (Riggins et

al., 2008). We subsequently demonstrated that

overexpression of ERRgamma confers Tamoxifen

(TAM) resistance to this and another ERalpha+ breast

cancer cell line, and that ERRgamma-driven AP1

activation plays a dominant role in the resistance

phenotype.

Ovarian cancer

Note

In a study of ovarian cancer specimens, normal ovaries,

and ovarian cancer cell lines, Sun et al. showed that

ERRgamma expression is significantly greater in

ovarian cancer relative to normal tissue (Sun et al.,

2005). However, patients whose tumors were positive

for ERRgamma had significantly improved disease-free

survival, and ERRgamma expression was not

correlated with serum levels of CA-125, a tumor

marker used to monitor ovarian cancer recurrence.

Endometrial cancer

Note

In 2006, Gao et al. reported that ERRgamma mRNA

expression was significantly higher in ERalpha-positive

endometrial carcinoma than normal endometrial

tissues, although patients with ERRgamma-positive

tumors had a reduced occurrence of lymph node

metastases (Gao et al., 2005).

Prostate cancer

Note

In cell culture models of prostate cancer, stable

overexpression of ERRgamma has been shown to

inhibit cell proliferation and survival in vitro and in in

vivo xenograft tumor models (Yu et al., 2007). This

occurs via cell cycle arrest at the G1/S phase transition,

which is induced by upregulation of the cell cycle

inhibitors p21 and p27. ERRgamma activates

transcription at both the p21 and p27 promoters, which

may suggest that ERRgamma has tumor suppressor

activities in prostate cancer.

References Dumont JA, Bitonti AJ, Wallace CD, Baumann RJ, Cashman EA, Cross-Doersen DE. Progression of MCF-7 breast cancer



cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity. Cell Growth Differ. 1996 Mar;7(3):351-9

Johnston SR, Lu B, Scott GK, Kushner PJ, Smith IE, Dowsett M, Benz CC. Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance. Clin Cancer Res. 1999 Feb;5(2):251-6

Heard DJ, Norby PL, Holloway J, Vissing H. Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. Mol Endocrinol. 2000 Mar;14(3):382-92

Schiff R, Reddy P, Ahotupa M, Coronado-Heinsohn E, Grim M, Hilsenbeck SG, Lawrence R, Deneke S, Herrera R, Chamness GC, Fuqua SA, Brown PH, Osborne CK. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst. 2000 Dec 6;92(23):1926-34

Clarke R, Skaar TC, Bouker KB, Davis N, Lee YR, Welch JN, Leonessa F. Molecular and pharmacological aspects of antiestrogen resistance. J Steroid Biochem Mol Biol. 2001 Jan-Mar;76(1-5):71-84

Ariazi EA, Clark GM, Mertz JE. Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res. 2002 Nov 15;62(22):6510-8

Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell. 2002 Feb;9(2):303-13

Hentschke M, Süsens U, Borgmeyer U. PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma. Biochem Biophys Res Commun. 2002 Dec 20;299(5):872-9

Hentschke M, Borgmeyer U. Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma. Biochem Biophys Res Commun. 2003 Dec 26;312(4):975-82

Horard B, Vanacker JM. Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. J Mol Endocrinol. 2003 Dec;31(3):349-57

Greschik H, Flaig R, Renaud JP, Moras D. Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity. J Biol Chem. 2004 Aug 6;279(32):33639-46

Huppunen J, Wohlfahrt G, Aarnisalo P. Requirements for transcriptional regulation by the orphan nuclear receptor ERRgamma. Mol Cell Endocrinol. 2004 Apr 30;219(1-2):151-60

Sanyal S, Matthews J, Bouton D, Kim HJ, Choi HS, Treuter E, Gustafsson JA. Deoxyribonucleic acid response element-dependent regulation of transcription by orphan nuclear receptor estrogen receptor-related receptor gamma. Mol Endocrinol. 2004 Feb;18(2):312-25

Gao M, Wei LH, Sun PM, Zhao D, Wang JL, Wang ZQ, Zhao C. [Expression of estrogen receptor-related receptor isoforms in endometrial carcinoma tissues and its clinical significance]. Zhonghua Fu Chan Ke Za Zhi. 2005 Nov;40(11):756-60

Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv. 2005 Dec;5(6):343-57

Sun P, Sehouli J, Denkert C, Mustea A, Könsgen D, Koch I, Wei L, Lichtenegger W. Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells. J Mol Med. 2005 Jun;83(6):457-67

Yu DD, Forman BM. Identification of an agonist ligand for estrogen-related receptors ERRbeta/gamma. Bioorg Med Chem Lett. 2005 Mar 1;15(5):1311-3

Zuercher WJ, Gaillard S, Orband-Miller LA, Chao EY, Shearer BG, Jones DG, Miller AB, Collins JL, McDonnell DP, Willson TM. Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma. J Med Chem. 2005 May 5;48(9):3107-9

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Gowda K, Marks BD, Zielinski TK, Ozers MS. Development of a coactivator displacement assay for the orphan receptor estrogen-related receptor-gamma using time-resolved fluorescence resonance energy transfer. Anal Biochem. 2006 Oct 1;357(1):105-15

Kojo H, Tajima K, Fukagawa M, Isogai T, Nishimura S. A novel estrogen receptor-related protein gamma splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors. J Steroid Biochem Mol Biol. 2006 Mar;98(4-5):181-92

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GAS5 (growth arrest-specific 5 (non-protein coding)) Mirna Mourtada-Maarabouni

Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, Staffordshire

ST5 5BG, UK (MMM)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GAS5ID50217ch1q25.html DOI: 10.4267/2042/44823


Identity

Other names: NCRNA00030; SNHG2

HGNC (Hugo): GAS5

Location: 1q25.1

Note: GAS5 is also designed as small nucleolar RNA

host gene (non-protein coding) 2 and non-protein

coding RNA 30.

1q25 locus displays abnormalities in a number of

cancers, melanoma, prostate, breast and several types

of leukaemia and lymphoma. The GAS5 gene was

isolated from NIH 3T3 cells using subtraction

hybridisation, in a screen intended to isolate potential

tumor suppressor genes. The functions of GAS5 is not

well known as yet, however, emerging evidence

implicates this gene in apoptosis, autoimmune disease,

leukemias and lymphomas, and other cancers.

DNA/RNA

Description

The gene spans about 4.98 kb. Orientation minus

strand. Number of exons: 12. GenBank: AF141346.1.

GAS5 gene hosts multiple small

Representation of five of GAS5 splice variants. Boxes numbered 2 to12 represent exons. U79, U80, U47, U81 and U74 represent the box C/D small nucleolar RNAs (snoRNAs). Horizontal lines represent the intronic sequences. Exons, introns and snoRNAs are not drawn to scale (IMAGE clone 6194071, 1249 bp; IMAGE clone 2598129, 1270 bp; IMAGE clone 3585621, 1396 bp; Gas5 3A, 1802 bp; IMAGE clone 5739605, 1802 bp; IMAGE clone 2761825, 1802 bp).

GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M


nucleolar RNA (snoRNA) host gene similar to UHG

(U22 host gene) which encode, within the 11 introns of

the human GAS5 gene, ten box C/D snoRNAs

predicted to play a role in the 2'-O-methylation of

rRNA. Its 5' end sequence contains an oligopyrimidine

tract characteristic of the 5'-TOP class of genes.

Transcription

The length of GAS5 transcript is 651 bp (NR_002578

in GenBank). The 5' end sequence of the GAS5

transcript contains an oligopyrimidine tract

characteristic of the 5'-TOP class of genes. GAS5

transcripts display several patterns of alternate splicing.

The initial GAS5 transcript is subject to complex post-

transcriptional processing resulting in several splice

variants. However its putative open reading frame is

small and poorly conserved during even relatively short

periods of evolution, as demonstrated by a number of

disruptions caused by frameshift mutations in several

mouse strains, and by an interruption by a stop codon

after the first 13 amino acids in rat GAS5. The diagram

above shows some of GAS5 splice variants which are

reported to affect cell fate in different ways.

Protein

Note

GAS5 exons do not encode a polypeptide product.

Mutations

Note

Chromosomal rearrangements involving GAS5 have

been identified in a human B-cell lymphoma where

GAS5 gene becomes fused to the BCL6 gene. GAS5 is

also involved in a chromosomal rearrangement with

Notch1 in radiation-induced murine thymic lymphoma.

Implicated in

Regulation of cell growth

Note

The GAS5 gene was isolated from NIH 3T3 cells using

subtraction hybridisation, in a screen intended to isolate

potential tumor suppressor genes. GAS5 is reported to

be ubiquitously expressed during mouse development

and adult life, and also to be expressed only at low

levels in actively growing Friend leukemia and NIH

3T3 cells, with substantially increased abundance in

cells grown to saturation density. The RNA levels of

GAS5 appear to be regulated primarily through

changes in its rate of degradation rather than through

changes in its transcription rate. GAS5 RNA abundance

was also found to be increased by amino acid

deprivation. Studies also have shown that GAS5 is

necessary and sufficient for growth arrest in both

untransformed and leukaemic lymphocytes.

Systemic lupus erythematosus

Note

The GAS5 gene is located in the disease susceptibility

locus in mouse BXSB strain, which develops

glomerulonephritis associated with systemic lupus

erythematosus (SLE). Subsequent studies involving

genetic analysis of a mouse model of SLE have

indicated that GAS5 may well be involved in its

pathology. Besides, the human chromosomal locus

1q25 at which the GAS5 gene is encoded has been

associated with SLE in genetic studies in humans.

Apoptosis/cell cycle regulation

Note

A fragment of GAS5 cDNA has been isolated from a

retroviral cDNA expression library by using an

unbiased functional screen for genes that control

apoptosis in lymphocytes. Further studies have shown

that GAS5 plays an essential role in normal growth

arrest in both T-cell lines and non-transformed

lymphocytes. Overexpression of GAS5 causes both an

enhancement in apoptosis and a decrease in the rate of

progression through the cell cycle in leukeamic T cell

lines and primary lymphocytes. Consistent with this,

downregulation of endogenous GAS5 inhibits

apoptosis and maintains a more rapid cell cycle,

indicating that GAS5 expression is both essential and

sufficient for normal growth arrest in T-cell lines as

well as human peripheral blood T-cells.

Overexpression of certain GAS5 transcripts is reported

to induce growth arrest and apoptosis in several

mammalian cell lines.

Oncogenesis

Note

GAS5 is encoded at 1q25, a locus displaying

abnormalities in a number of cancers, e.g. melanoma,

prostate, breast, and several types of leukaemia and

lymphoma. Gene expression analysis has shown that

GAS5 is up-regulated 3.3-fold (the greatest up-

regulation for any gene in the whole-genome array) by

oncogenic kinases associated with myeloproliferative

disorders. Chromosomal rearrangements involving

GAS5 have also been identified in a human B-cell

lymphoma. GAS5 expression levels are reported to

regulate both the induction of apoptosis and cell cycle

arrest in T-cell lines and non-transformed lymphocytes,

suggesting that it may be very significant in the

development of leukaemia and lymphoma.

Overexpression of certain GAS5 transcripts is reported

to induce growth arrest and apoptosis in several human

cell lines, including human breast cancer cell lines.

GAS5 expression is significantly downregulated in

breast cancer tissue compared with those found in

untransformed breast epithelial tissue from the same

patients, a clear reduction of more than 65% was

GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M


observed in this study, suggesting that the reduction in

GAS5 expression is an early event in oncogenesis.

References Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988 Sep 9;54(6):787-93

Coccia EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L, Sorrentino V. Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol. 1992 Aug;12(8):3514-21

Vacha SJ, Bennett GD, Mackler SA, Koebbe MJ, Finnell RH. Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice. Dev Genet. 1997;21(3):212-22

Fleming JV, Hay SM, Harries DN, Rees WD. Effects of nutrient deprivation and differentiation on the expression of growth-arrest genes (gas and gadd) in F9 embryonal carcinoma cells. Biochem J. 1998 Feb 15;330 ( Pt 1):573-9

Muller AJ, Chatterjee S, Teresky A, Levine AJ. The gas5 gene is disrupted by a frameshift mutation within its longest open reading frame in several inbred mouse strains and maps to murine chromosome 1. Mamm Genome. 1998 Sep;9(9):773-4

Smith CM, Steitz JA. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5'-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998 Dec;18(12):6897-909

Raho G, Barone V, Rossi D, Philipson L, Sorrentino V. The gas 5 gene shows four alternative splicing patterns without coding for a protein. Gene. 2000 Oct 3;256(1-2):13-7

Smedley D, Sidhar S, Birdsall S, Bennett D, Herlyn M, Cooper C, Shipley J. Characterization of chromosome 1 abnormalities in malignant melanomas. Genes Chromosomes Cancer. 2000 May;28(1):121-5

Fontanier-Razzaq N, Harries DN, Hay SM, Rees WD. Amino acid deficiency up-regulates specific mRNAs in murine embryonic cells. J Nutr. 2002 Aug;132(8):2137-42

Johanneson B, Lima G, von Salomé J, Alarcón-Segovia D, Alarcón-Riquelme ME. A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet. 2002 Nov;71(5):1060-71

Tsuji H, Ishii-Ohba H, Ukai H, Katsube T, Ogiu T. Radiation-induced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Carcinogenesis. 2003 Jul;24(7):1257-68

Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004 Sep;16(5):513-21

Williams GT, Farzaneh F. The use of gene function to identify the rate-limiting steps controlling cell fate. Cancer Immunol Immunother. 2004 Mar;53(3):160-5

Haywood ME, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ, Morley BJ. Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun. 2006 Apr;7(3):250-63

Lelièvre H, Cervera N, Finetti P, Delhommeau F, Vainchenker W, Bertucci F, Birnbaum D. Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators. Leukemia. 2006 Oct;20(10):1885-8

Stange DE, Radlwimmer B, Schubert F, Traub F, Pich A, Toedt G, Mendrzyk F, Lehmann U, Eils R, Kreipe H, Lichter P. High-resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer. Clin Cancer Res. 2006 Jan 15;12(2):345-52

Williams GT, Hughes JP, Stoneman V, Anderson CL, McCarthy NJ, Mourtada-Maarabouni M, Pickard M, Hedge VL, Trayner I, Farzaneh F. Isolation of genes controlling apoptosis through their effects on cell survival. Gene Ther Mol Biol. 2006 Dec 12;10(B):255-262

Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 2008 Apr 1;121(Pt 7):939-46

Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, Niitsu N, Jinnai I, Bessho M. The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 2008 Apr 15;182(2):144-9

Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009 Jan 15;28(2):195-208


Mourtada-Maarabouni M. GAS5 (growth arrest-specific 5 (non-protein coding)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):758-760.

Gene Section Review




GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Nathalie Britzen-Laurent, Michael Stürzl

Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander University,

Schwabachanlage 10, 91054 Erlangen, Germany (NBL, MS)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GBP1ID50147ch1p22.html DOI: 10.4267/2042/44824


Identity

Other names: GBP-1; HuGBP-1

HGNC (Hugo): GBP1

Location: 1p22.2

Local order: Chromosome 1; starts at 89,290,575 bp

from pter and ends 89,303,631 bp from pter;

size= 13,056 base pairs;

orientation: minus strand (according to hg18-

Mar_2006).

The family of guanylate binding proteins (GBP)

consists of 7 members.

All seven genes are located in 1p22.2.

The human GBP1 gene is telomeric to GBP2 and

centromeric to GBP3.

A schematic representation of the domain structure and the three-dimensional structure of GBP-1. GBP-1 consists of a globular domain (residues 1 to 278), which contains the GTP binding and hydrolysis domains, and of a helical domain (residues 279 to 593) terminated by a polybasic sequence and an isoprenylation motif (CAAX). C= Cysteine, A= aliphatic acid, X= any amino-acid (here a serine, specifically recognized by a farnesyl-transferase).

GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Britzen-Laurent N, Stürzl M


DNA/RNA

Description The GBP1 gene consists of 11 exons (ranging from 102

to 1164 bp) and 10 introns. The coding sequence starts

in the second exon.

Transcription Only one variant mRNA has been described for GBP-1

(Accession Number: NM_002053). This mRNA is

3050 bp long with a coding sequence of 1779 bp. Four

polymorphisms have been described for GBP-1:

c.232A>G (codon 78 Ile>Val), c.498G>C (codon 166

Glu>Asp), c.1046C>G (codon 349 Thr>Ser),

c.1226C>G (codon 409 Ala>Gly).

Pseudogene A pseudogene has been identified for GBP1

(LOC400759 alias FLJ17004) on chromosome 1

(1p22.2, chro 1: 89645826-89663081, according to

hg18-Mar_2006). Two pseudogenes have also been

described in the mouse (pseudomGbp1 and

pseudomGbp2).

Protein

Description GBP-1 belongs to the class of large GTPases that

contains, in addition to the GBPs, three further groups

of proteins, which share structural and biochemical

properties: the dynamins, the Mx proteins and the

atlastins. GBP-1 has a molecular weight of 67 kDa and

its crystal structure has revealed the presence of two

domains: (1) a N-terminal globular alpha/beta domain

harbouring the GTPase activity and (2) a long C-

terminal part organized in an index finger-like domain

composed exclusively of seven alpha-helices (alpha7 -

alpha13). The domains are connected by a short

intermediate region consisting of one alpha-helix and a

short two-stranded beta-sheet. In addition, GBP-1

harbours a C-terminal CAAX isoprenylation motif.

GTPases typically harbour three classical GTP-binding

domains: the phosphate-binding P-loop

GXXXXGK(S/T), the phosphate- and Mg2+

-binding

DXXG motif (G, glycine; K, lysine; S, serine; D,

aspartic acid; T, threonine; and X, any amino acid) and

the guanine nucleotide-specificity providing (N/T)KXD

motif (N, asparagine). In GBP-1 the classical

(N/T)KXD motif is substituted by a conserved

arginine-aspartic acid (RD)-motif (TLRD, with L,

leucine and R, arginine).

Expression GBP-1 was initially shown to be among the most

highly induced proteins in human fibroblasts exposed

to interferon (IFN)-gamma. Subsequently, it was

reported that in vitro hGBP-1 expression can be

induced by IFN-gamma in many different cell types

including endothelial cells, fibroblasts, keratinocytes,

B-cells, T-cells or peripheral blood mononuclear cells.

In vivo expression of hGBP-1 has been predominantly

detected in inflammatory tissues and has been found to

be associated almost exclusively with endothelial cells

and monocytes. It has been shown subsequently that

hGBP-1 expression in endothelial cells is also induced

by other pro-inflammatory cytokines such as IFNalpha,

TNFalpha and IL1alpha/IL1beta. Many other cytokines

(IL-4, IL-6, IL-10, IL-18), chemokines (MCP-1, PF4)

or growth factors (angiopoietin-2, PDGF B/B) tested

did not affect GBP-1 expression in these cells.

Interestingly, the two major angiogenic growth factors

(AGF: bFGF, VEGF) are able to inhibit the expression

of GBP-1 induced by inflammatory cytokines.

Localisation The localization of GBP-1 is primarily cytosolic and its

distribution is granular. Plasma membrane association

at the level of tight junctions has also been described.

In addition, GBP-1 has been shown to be secreted from

IFN-gamma-stimulated endothelial cells through a non-

classical secretion pathway.

Function GTPase activity.

GBP-1 can bind the three nucleotides GTP, GDP and

GMP with a relative low affinity (Kd mant-GMP=0,53 μM,

Kd mant-GDP=2,4 μM, Kdmant-GppNHp=1,1 μM). GBP-1 has

however the ability to hydrolyse GTP to both GDP and

GMP with a high hydrolysis rate (max 95 min-1

). At

physiological temperature GMP is the major product

(90%) of hGBP1. On the contrary to small GTPases

like Ras, GBP-1 does not require the presence of GEF

(GTP exchange factor) or GAP (GTPase activating

protein) proteins for its GTPase activity. In the case of

GBP-1, the GTP hydrolysis is self-stimulated by

oligomerization of the protein.

GBP-1 is involved in IFN-gamma response, either in

infection or in inflammation.

Homology The human GBP family comprises 7 highly

homologous members, all located on the chromosome

1. GBP-1 is to 77% similar to GBP-2, 88% to GBP-3,

56% to GBP-4, 68% to GBP-5, 54% to GBP-6 and

56% to GBP-7. Homologues have been found in

various species like zebrafish, chimpanzee (99%

homology), rat, dog or mouse. GBP-1 shares 59% of

homology with murine GBP-1 and murine GBP-2.

Mutations Note

No somatic or germline mutations have yet been

reported for human GBP-1.

Implicated in

Infection Note

GBP-1 exhibits antiviral activity against vesicular

stomatitis virus and encephalomyocarditis virus. The



expression of GBP-1 is also elevated in the blood of

patients with a chronic active Epstein-Barr virus

infection. Furthermore GBP-1 and GBP-2 can

potentiate the inhibitory effects of IFN-gamma on

Chlamydia trachomatis growth. Finally, elevated

concentrations of GBP-1 have been detected in the

cerebrospinal fluid of patients with bacterial

meningitis.

Inflammation

Note

As GBP-1 is mainly expressed in endothelial cells in

vivo in a context of inflammation, its effects have been

extensively studied in these cells. It has been showed in

endothelial cells that GBP-1 mediates the effects of

inflammatory cytokines and inhibits proliferation,

spreading, migration or invasion. GBP-1 is also

involved in the regulation of apoptosis and senescence

in endothelial cells stimulated with IFN-alpha.

Evidence for an implication in cancer has been found

for GBP-1 (see below).

Colorectal carcinomas

Note

GBP-1 protein is strongly expressed in the stroma of

about one third of colorectal carcinomas in association

with an IFN-gamma dominated Th-1-like angiostatic

immune response.

Prognosis

This expression correlates with an increased cancer-

related 5-year survival.

References Cheng YS, Colonno RJ, Yin FH. Interferon induction of fibroblast proteins with guanylate binding activity. J Biol Chem. 1983 Jun 25;258(12):7746-50

Cheng YS, Becker-Manley MF, Chow TP, Horan DC. Affinity purification of an interferon-induced human guanylate-binding protein and its characterization. J Biol Chem. 1985 Dec 15;260(29):15834-9

Schwemmle M, Staeheli P. The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP. J Biol Chem. 1994 Apr 15;269(15):11299-305

Nantais DE, Schwemmle M, Stickney JT, Vestal DJ, Buss JE. Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1. J Leukoc Biol. 1996 Sep;60(3):423-31

Anderson SL, Carton JM, Lou J, Xing L, Rubin BY. Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology. 1999 Mar 30;256(1):8-14

Praefcke GJ, Geyer M, Schwemmle M, Robert Kalbitzer H, Herrmann C. Nucleotide-binding characteristics of human guanylate-binding protein 1 (hGBP1) and identification of the third GTP-binding motif. J Mol Biol. 1999 Sep 17;292(2):321-32

Prakash B, Praefcke GJ, Renault L, Wittinghofer A, Herrmann C. Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins. Nature. 2000 Feb 3;403(6769):567-71

Prakash B, Renault L, Praefcke GJ, Herrmann C, Wittinghofer A. Triphosphate structure of guanylate-binding protein 1 and implications for nucleotide binding and GTPase mechanism. EMBO J. 2000 Sep 1;19(17):4555-64

Guenzi E, Töpolt K, Cornali E, Lubeseder-Martellato C, Jörg A, Matzen K, Zietz C, Kremmer E, Nappi F, Schwemmle M, Hohenadl C, Barillari G, Tschachler E, Monini P, Ensoli B, Stürzl M. The helical domain of GBP-1 mediates the inhibition of endothelial cell proliferation by inflammatory cytokines. EMBO J. 2001 Oct 15;20(20):5568-77

Lubeseder-Martellato C, Guenzi E, Jörg A, Töpolt K, Naschberger E, Kremmer E, Zietz C, Tschachler E, Hutzler P, Schwemmle M, Matzen K, Grimm T, Ensoli B, Stürzl M. Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases. Am J Pathol. 2002 Nov;161(5):1749-59

Guenzi E, Töpolt K, Lubeseder-Martellato C, Jörg A, Naschberger E, Benelli R, Albini A, Stürzl M. The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression. EMBO J. 2003 Aug 1;22(15):3772-82

Naschberger E, Werner T, Vicente AB, Guenzi E, Töpolt K, Leubert R, Lubeseder-Martellato C, Nelson PJ, Stürzl M. Nuclear factor-kappaB motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells. Biochem J. 2004 Apr 15;379(Pt 2):409-20

Praefcke GJ, Kloep S, Benscheid U, Lilie H, Prakash B, Herrmann C. Identification of residues in the human guanylate-binding protein 1 critical for nucleotide binding and cooperative GTP hydrolysis. J Mol Biol. 2004 Nov 12;344(1):257-69

Modiano N, Lu YE, Cresswell P. Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8680-5

Vestal DJ. The guanylate-binding proteins (GBPs): proinflammatory cytokine-induced members of the dynamin superfamily with unique GTPase activity. J Interferon Cytokine Res. 2005 Aug;25(8):435-43

Ghosh A, Praefcke GJ, Renault L, Wittinghofer A, Herrmann C. How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP. Nature. 2006 Mar 2;440(7080):101-4

Naschberger E, Lubeseder-Martellato C, Meyer N, Gessner R, Kremmer E, Gessner A, Stürzl M. Human guanylate binding protein-1 is a secreted GTPase present in increased concentrations in the cerebrospinal fluid of patients with bacterial meningitis. Am J Pathol. 2006 Sep;169(3):1088-99

Olszewski MA, Gray J, Vestal DJ. In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res. 2006 May;26(5):328-52

Pammer J, Reinisch C, Birner P, Pogoda K, Sturzl M, Tschachler E. Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation. Lab Invest. 2006 Oct;86(10):997-1007

Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Würthner J, Kurig S, Beer S, Pfeffer K. Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. J Immunol. 2007 Dec 1;179(11):7729-40

Tripal P, Bauer M, Naschberger E, Mörtinger T, Hohenadl C, Cornali E, Thurau M, Stürzl M. Unique features of different



members of the human guanylate-binding protein family. J Interferon Cytokine Res. 2007 Jan;27(1):44-52

Ito Y, Shibata-Watanabe Y, Ushijima Y, Kawada J, Nishiyama Y, Kojima S, Kimura H. Oligonucleotide microarray analysis of gene expression profiles followed by real-time reverse-transcriptase polymerase chain reaction assay in chronic active Epstein-Barr virus infection. J Infect Dis. 2008 Mar 1;197(5):663-6

Naschberger E, Croner RS, Merkel S, Dimmler A, Tripal P, Amann KU, Kremmer E, Brueckl WM, Papadopoulos T,

Hohenadl C, Hohenberger W, Stürzl M. Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer. 2008 Nov 1;123(9):2120-9

Weinländer K, Naschberger E, Lehmann MH, Tripal P, Paster W, Stockinger H, Hohenadl C, Stürzl M. Guanylate binding

protein-1 inhibits spreading and migration of endothelial cells through induction of integrin alpha4 expression. FASEB J. 2008 Dec;22(12):4168-78

Schnoor M, Betanzos A, Weber DA, Parkos CA. Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-gamma and regulates barrier function through effects on apoptosis. Mucosal Immunol. 2009 Jan;2(1):33-42

Tietzel I, El-Haibi C, Carabeo RA. Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-gamma. PLoS One. 2009 Aug 4;4(8):e6499


Britzen-Laurent N, Stürzl M. GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):761-764.





GPNMB (glycoprotein (transmembrane) nmb) Shyam A Patel, Philip K Lim, Pranela Rameshwar

University of Medicine and Dentistry of New Jersey - New Jersey Medical School,Newark, New Jersey,

USA (SAP, PKL, PR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/GPNMBID40739ch7p15.html DOI: 10.4267/2042/44825


Identity

Other names: HGFIN; NMB; osteoactivin

HGNC (Hugo): GPNMB

Location: 7p15.3

DNA/RNA

Description

The GPNMB gene maps (Homo sapiens) on the plus

strand of chromosome 7p15 between 23,252,841 and

23,281,254 bp from the promoter and spans 28,414 bp.

Transcription

2 transcript variants:

Variant 1:

- 2775bp, accession #: NM_001005340.1

- the longer transcript

- encodes the longer isoform (isoform a)

- open reading frame from bp 162 to 1880

- 11 exons.

Variant 2:

- accession #: NM_002510.2

- undergoes alternative splicing and uses an in-frame

splice site

- conserved N- and C-terminals compared to isoform a,

but decreased in length.

Protein

Note

The GPNMB gene, which is the human homolog of

murine osteoactivin, encodes a type I transmembrane

glycoprotein. It has homology to the melanocyte

specific protein precursor pMEL17. GPNMB

expression is inversely correlated with

aggressiveness of melanoma cell lines. GPNMB is

thought to be inversely correlated with metastatic

potential, although limited data is available.

Description

Two protein isoforms exist: isoform a: 572 aa; isoform

b: 560 aa.

Expression

GPNMB is expressed in osteoclasts, dendritic cells,

macrophages, and breast epithelia. Its expression is

nearly undetectable in monocytes but increases upon

conversion of monocytes to macrophages.

Localisation

GPNMB localizes to the plasma membrane, as it is a

type I transmembrane glycoprotein. It is also found in

melanosomes and membrane-bound vesicles in the

cytoplasm.

Function

GPNMB is involved in binding to heparin sulfate and

integrins. It functions in mineralization of bone and

differentiation of osteoblasts. It also functions in

cellular adhesion. It is thought to reduce inflammation

involving macrophages.

Homology

Homo sapiens GPNMB shares sequence homology

with mouse and rat sequences. GPNMB shares

structural homology with neurokinin 1 (NK1) and can

interact with the NK ligand substance P.

Implicated in

Breast cancer

Note

It is unclear to date whether GPNMB plays a tumor

GPNMB (glycoprotein (transmembrane) nmb) Patel SA, et al.


suppressive role or oncogenic role in breast cancer.

Disease

In a murine model, osteoactivin (OA) has been

associated with enhanced invasiveness of breast cancer

cells in vivo, and forced overexpression of OA in

weakly bone metastatic cells lines resulted in increased

migratory and invasive characteristics in vitro (Rose et

al., 2007). Furthermore, analysis of 51 breast cancer

cell lines revealed higher osteoactivin expression than

normal breast MCF-12A cells and in estrogen receptor

negative breast tumors (Rose and Siegel, 2007).

However, other studies with non-tumorigenic human

breast cancer cells have shown that there was increased

migration and evidence of transformation and loss of

contact dependency in the absence of GPNMB/HGFIN

(Metz et al., 2007).

Glioblastoma multiforme (GBM)

Note

In immunocompromised mice, glioma cells expressing

osteoactivin and osteonectin (two strucurally bone-

related genes) developed a highly invasive phenotype

and invaded the brain along blood vessels when

implanted intracranially (Rich et al., 2003).

Disease

Evaluation of 50 GBM patient tumor samples revealed

that 35 out of 50 samples (70%) were positive for

GPNMB wild-type and splice variant transcripts while

the remaining 30% were positive for wild-type only

(Kuan et al., 2006). This is in contrast to normal brain

samples that expressed little or no GPNMB mRNA

(Kuan et al., 2006).

Prognosis

Detection of GPNMB mRNA and surface membrane

protein in glioma cells may potentially be used as a

tumor-associated antigen for targeting by therapeutic

treatment (Kuan et al., 2006).

Melanoma

Note

Analysis of a cDNA library between lowly and highly

metastatic human melanoma showed the preferential

expresion of GPNMB in low-metastatic cell lines

(Weterman et al., 1995). Additionally, transfection of

partial GPNMB cDNA into highly-metastatic

melanoma cell line resulted in slower subcutaneous

tumor growth in nude mice (Weterman et al., 1995).

Disease

A potential therapeutic agent in the treatment of

malignant melanomas is an antibody-drug conjugate

tartgeting GPNMB (Pollack et al., 2007). Intravenous

administration of the immunoconjugate in athymic

mice with human melanoma xenografts showed

inhibition of tumor growth and complete regression of

the tumor (Pollack et al., 2007).

End-stage kidney disease

Note

Macrophages involved in uremia have elevated levels

of GPNMB expression. Its role in end-stage kidney

disease may relate to its role in soft tissue calcification

and arteriosclerosis (Pahl et al., 2009).

Acute liver injury

Note

In normal rat livers, OA was found to be expressed in

high levels in Kupffer cells and peritoneal macrophages

(Haralanova-Ilieva et al., 2005). Upon induction of

acute liver injury after carbon tetrachloride

administration, OA expression was upregulated after 2

days and returned to normal levels after 7 days

(Haralanova-Ilieva et al., 2005). In normal human liver,

OA RNA was not detected while fulminant hepatitis B

and C infections, paracetamol intoxication, and liver

cirrhosis all resulted in positive OA RNA levels

(Haralanova-Ilieva et al., 2005).

Osteopetrosis

Note

OA cDNA was found to be overexpressed 3- to 4-fold

in rats with osteopetrotic bones when compared to

normal rat long bones (Safadi et al., 2001).

Furthermore, OA mRNA was primarily localized in

cuboidal osteoblasts lining bone surfaces (Safadi et al.,

2001).

Disease

Osteopetrosis, also known as marble bone disease, is a

rare hereditary disease which results in thickening and

hardening of bones due to deficient osteoclast activity

(Kumar et al., 2003). OA is expressed at highest levels

in primary osteoblasts and thus, may account for the

imbalance in activity of osteoblasts and osteoclasts in

osteopetrosis (Sadafai et al., 2001).

References Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, Bloemers HP. nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer. 1995 Jan 3;60(1):73-81

Safadi FF, Xu J, Smock SL, Rico MC, Owen TA, Popoff SN. Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts. J Cell Biochem. 2001;84(1):12-26

Kumar V, Cotran RS, Robbins SL.. Diseases of Bone - Osteopetrosis. Robbins Basic Pathology (7th Edition). 2003:757.

Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan CT, Bigner DD, Counter CM, Wang XF. Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem. 2003 May 2;278(18):15951-7

Haralanova-Ilieva B, Ramadori G, Armbrust T. Expression of osteoactivin in rat and human liver and isolated rat liver cells. J Hepatol. 2005 Apr;42(4):565-72

GPNMB (glycoprotein (transmembrane) nmb) Patel SA, et al.


Kuan CT, Wakiya K, Dowell JM, Herndon JE 2nd, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):1970-82

Metz RL, Patel PS, Hameed M, Bryan M, Rameshwar P. Role of human HGFIN/nmb in breast cancer. Breast Cancer Res. 2007;9(5):R58

Pollack VA, Alvarez E, Tse KF, Torgov MY, Xie S, Shenoy SG, MacDougall JR, Arrol S, Zhong H, Gerwien RW, Hahne WF, Senter PD, Jeffers ME, Lichenstein HS, LaRochelle WJ. Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol. 2007 Aug;60(3):423-35

Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM. Osteoactivin promotes breast cancer metastasis to bone. Mol Cancer Res. 2007 Oct;5(10):1001-14

Rose AA, Siegel PM. Osteoactivin/HGFIN: is it a tumor suppressor or mediator of metastasis in breast cancer? Breast Cancer Res. 2007;9(6):403

Pahl MV, Vaziri ND, Yuan J, Adler SG. Upregulation of monocyte/macrophage HGFIN (Gpnmb/Osteoactivin) expression in end-stage renal disease. Clin J Am Soc Nephrol. 2010 Jan;5(1):56-61


Patel SA, Lim PK, Rameshwar P. GPNMB (glycoprotein (transmembrane) nmb). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):765-767.





MBD2 (methyl CpG binding domain protein 2) Heather Owen

Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King's

Buildings, Mayfield Road, Edinburgh EH9 3JR, UK (HO)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MBD2ID41309ch18q21.html DOI: 10.4267/2042/44826


Identity

Other names: DKFZp586O0821; DMTase;

Demethylase; NY-CO-41

HGNC (Hugo): MBD2

Location: 18q21.2

Note: Homologous to MBD3 gene.

DNA/RNA

Description

MBD2 (NM_003927.3) is a gene of 70,583 bp coded

by 7 exons from 33,240,260 to 33,169,677 according to

NCBI reference sequence NT_010966.14 or

51,751,158 to 51,680,575 according to Genome

reference consortium human build 37 GRCh37. There

is an alternative transcript for MBD2 (NM_015832.3)

of 22,111 bp from 33,240,260 to 33,218,149 on NCBI

reference sequence NT_010966.14. This transcript

shares the first 2 exons (coding for the methyl binding

domain) but differs in the 3rd exon, resulting in a

shorter truncated protein.

Transcription

The longer transcript encoded by NM_003927.3,

mRNA length of 2584 bp, is expressed ubiquitiously

(according to symatlas).

The shorter transcript NM_015832.3, mRNA length of

1357 bp is expressed in germ cells (according to

symatlas).

Protein

Description

In somatic tissues MBD2 is expressed from a single

transcript, and is detected by western blot as 2 stable

proteins at approximately 50 kDa (MBD2a) and 30 kDa

(MBD2b). Human MBD2a (Q9UBB5) has 411 amino

acids. It is unknown whether MBD2b is due to use of

an alternative translation start site (creating protein of

262 amino acids) or due to protein

cleavage/processing/degradation.

Human germ cells express a short form of MBD2 from

the alternative transcript with an expected length of 302

amino acids.

Expression

MBD2a and MBD2b are expressed in all tissues tested

with highest levels in spleen and colon nuclei (non-

published observation).

Localisation

MBD2 is a nuclear protein. MBD2-GFP localises to

major satellite in mouse ES cells, but not in DNA

methylation deficient cells (Hendrich and Bird, 1998).

MBD2 is expressed as 2 transcripts. NM_003927.3 coding sequence in blue and NM_015832.3 in red. Boxes represent exons and arrows represent transcriptional start sites.

http://symatlas.gnf.org/

http://symatlas.gnf.org/

MBD2 (methyl CpG binding domain protein 2) Owen H


MBD: methyl binding domain, P: phosphorylation detected.

Function

MBD2 is a methyl binding protein that is thought to

repress gene expression as part of the NuRD complex.

The NuRD complex was identified independently by

four separate groups (Wade et al., 1998; Tong et al.,

1998; Xue et al., 1998; Zhang et al., 1998). NuRD

consists of a chromatin remodelling ATPase Mi2alpha

or beta, histone deacetylase HDAC1/HDAC2, MTA1

or MTA2, RbAp46/RbAp48, p66alpha/beta and can

also contain MBD2 or MBD3. TAP tagged MBD2a

associates with NuRD with equimolar stoichometry

implying that most MBD2a is complexed with NuRD

in cells (Le Guezennec et al., 2006). MBD2 is required

for repression of methylated reporter genes (Hendrich,

2001) and many endogenous target genes of MBD2

have been reported. However the global genomic

targets of MBD2 have not been characterised. MBD2

knock out are viable and fertile, and show only mild

physiological defects. These are abnormal maternal

behaviour and T helper cell deficiencies (Hendrich,

2001; Hutchins, 2002; Hutchins, 2005).

Homology

MBD2 is a member of the methyl-binding domain

proteins (Hendrich and Bird, 1998). Other members of

this family are MeCp2, MBD2, MBD3 and MBD4

(Klose and Bird, 2006). These proteins share a region

of homology (145-213 of MBD2a), which have been

shown to form a stable domain consisting of a beta

sheet, an alpha helix and a positioned loop (Ohki et al.,

2001). The crystal structure of the MBD of MeCP2



complexed with a methylated CpG containing 20mer of

DNA indicates that the protein-DNA interactions are

dependent on water molecules (Ho et al., 2008). The

protein with closest homology to MBD2 is MBD3,

however MBD3 has two crucial amino acid

substitutions in the MBD and does not specifically bind

to methylated DNA (Hendrich and Tweedie, 2003).

Mutations

Note

MBD2 is mutated only infrequently in human cancer

tissues.

Implicated in

Intestinal tumorigenesis

Note

MBD2-/-

APCmin/+

mice have fewer intestinal tumors

and survive longer than MBD2+/+

APCmin

/+ mice

(Sansom, 2003).

These results imply MBD2 is required for

tumorigenesis. Although the mechanism is unknown,

possibilities are listed below:

1) MBD2 may repress tumor supressor genes (therefore

in the absence of MBD2, tumor repressor expression

would be upregulated). In cancer cell lines MBD2 has

been found to bind to methylated regions of tumor

supressor genes GSTP1, p14 and p16 (Stirzaker, 2004;

Le Guezennec, 2006; Martin, 2008).

2) MBD2 may repress a repressor of WNT signalling

(therefore in the absence of MBD2, WNT signalling

would be reduced). One candidate for this is Lect2

(Phesse, 2008).

3) In mice MBD2 is required for normal T cell

differentiation and MBD2-/- mice have impaired

immune responses. This could contribute to the MBD2

requirement in tumor formation in the APCmin/+ strain

(Hutchins, 2002; Hutchins, 2005).

4) Other mechanisms are possible, such as a role of

mbd2 in higher order chromatin or silencing of

heterochromatin regulating tumorigenesis. However

this has not been tested.

Knock down of MBD2 in human cancer cell lines

reduced tumor volume when implanted into nude mice

(Campbell, 2004).

MBD2 expression levels in human cancer tissues have

been analysed in multiple studies with differing results.

One study found MBD2 expression was low in

colorectal and stomach cancers (Kanai, 1999), whereas

other studies found high expression in cancer tissues.

These discrepancies are likely due to differences

between control genes used as well as differences

between cancer tissues.

References Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998 Nov;18(11):6538-47

Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature. 1998 Oct 29;395(6705):917-21

Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998 Jul 2;8(14):843-6

Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998 Dec;2(6):851-61

Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell. 1998 Oct 16;95(2):279-89

Hendrich B, Abbott C, McQueen H, Chambers D, Cross S, Bird A. Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome. 1999 Sep;10(9):906-12

Kanai Y, Ushijima S, Nakanishi Y, Hirohashi S. Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers. Biochem Biophys Res Commun. 1999 Nov 2;264(3):962-6

Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999 Sep;23(1):58-61

Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001 Mar 15;15(6):710-23

Ohki I, Shimotake N, Fujita N, Jee J, Ikegami T, Nakao M, Shirakawa M. Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA. Cell. 2001 May 18;105(4):487-97

Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA, Hendrich BD, Bird AP, Reiner SL. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002 Jul;10(1):81-91

Bader S, Walker M, McQueen HA, Sellar R, Oei E, Wopereis S, Zhu Y, Peter A, Bird AP, Harrison DJ. MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers. Oncogene. 2003 May 29;22(22):3506-10

Hendrich B, Tweedie S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 2003 May;19(5):269-77

Lin X, Nelson WG. Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells. Cancer Res. 2003 Jan 15;63(2):498-504

Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke AR. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet. 2003 Jun;34(2):145-7

Campbell PM, Bovenzi V, Szyf M. Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo. Carcinogenesis. 2004 Apr;25(4):499-507

Stirzaker C, Song JZ, Davidson B, Clark SJ. Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells. Cancer Res. 2004 Jun 1;64(11):3871-7



Berger J, Bird A. Role of MBD2 in gene regulation and tumorigenesis. Biochem Soc Trans. 2005 Dec;33(Pt 6):1537-40

Hutchins AS, Artis D, Hendrich BD, Bird AP, Scott P, Reiner SL. Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity. J Immunol. 2005 Nov 1;175(9):5606-10

Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006 Feb;31(2):89-97

Le Guezennec X, Vermeulen M, Brinkman AB, Hoeijmakers WA, Cohen A, Lasonder E, Stunnenberg HG. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol. 2006 Feb;26(3):843-51

Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell. 2008 Feb 29;29(4):525-31

Martin V, Jørgensen HF, Chaubert AS, Berger J, Barr H, Shaw P, Bird A, Chaubert P. MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells. Pathobiology. 2008;75(5):281-7

Phesse TJ, Parry L, Reed KR, Ewan KB, Dale TC, Sansom OJ, Clarke AR. Deficiency of Mbd2 attenuates Wnt signaling. Mol Cell Biol. 2008 Oct;28(19):6094-103


Owen H. MBD2 (methyl CpG binding domain protein 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):768-771.





MEF2D (myocyte enhancer factor 2D) Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger

University of Florida College of Medicine, Gainesville, FL 32610, USA (VP, LGG); Children's Hospital and

the Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA

(SPH)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MEF2DID43636ch1q22.html DOI: 10.4267/2042/44827


Identity

Other names: DKFZp686I1536

HGNC (Hugo): MEF2D

Location: 1q22

Note: MEF2D is a member of the family of myocyte

enhancer factor MEF2 that includes MEF2A, MEF2B,

MEF2D, MEF2C.

DNA/RNA

Description

12 exons.

Transcription

5888 bp mRNA, coding sequence: from 391 bp to 1956

bp (NCBI, GenBank NM_005920); alternative splicing

in E3 (3alpha1 and 3alpha2) and beta produces 4

splicing isoforms: alpha1, alpha1beta, alpha2,

alpha2beta (Zhu et al., 2005).

Protein

Note

MEF2D belongs to MEF2 (myocyte enhancer factor 2)-

like/Type II subfamily of MADS (MCM1, Agamous,

Deficiens, and SRF (serum response factor) box family

of eukaryotic transcriptional regulators).

Description

MEF2D encodes approximately a 521 aa-long protein

(GenBank at NCBI presented 4 isoforms: CRA_a, 521

aa, EAW52952.1; CRA_b, 143 aa, EAW52949.1;

CRA_c, 288 aa, EAW52950.1; CRA_d, 523 aa,

EAW52951.1). It is composed of several domains: the

MADS-box on N terminus (2-78 aa, MAD MEF2 like);

the 29-aa MEF2 domain immediately C-terminal to the

MADS- box (unique to the MEF2 factors); C-terminal

transcriptional activation domains. Both MADS and

MEF2 domains are necessary and sufficient for

dimerization and binding to the DNA sequence

CTA(A/T)4TAG/A. MEF2 domain influences cofactor

interactions (Pollock and Treisman, 1991; Molkentin

and Olson, 1996). Regions: 2-38 aa of the MADS

domain confer DNA binding site specificity; 21-73 aa,

dimerization interface; 59 aa, putative phosphorylation

site.

Expression

High level expression in muscles and neurons, at lower

levels in a wide range of cell types (Black and Olson,

1998).

Localisation

Nuclear (Neely et al., 2009).

Function

DNA binding, transcriptional activation. Transmission

of extracellular signals to the genome, control of cell

differentiation, proliferation, morphogenesis, survival

and apoptosis of a wide range of cell types. Important

in immediate-early development in animals. MEF2D

dimers regulate expression of genes involved in

muscle-specific and/or growth factor-related

transcription.

It seems to be transcriptional effector of mitogenic

signaling pathways initiated by mitogen-activated

protein kinases (MAPKs) including p38 and ERK5

(extracellular signal-related kinase 5)/Big MAPK-1,

and also plays critical roles in calcium-regulated

MEF2D (myocyte enhancer factor 2D) Prima V, et al.


A. Localization of TS-2 chromosome 19 breakpoint via FISH. Metaphase FISH was performed using cosmids containing chromosome 19 genomic DNA. Cosmids that hybridize to the der(19) are located centromeric to the chromosome 19 breakpoint (green signal), while cosmids that hybridize to the der(1) are located telomeric to the chromosome 19 breakpoint (red signal). Split signals on both the der(1) and der(19) chromosomes indicate that the chromosome 19 breakpoint is located within the region homologous to the cosmid. B. Alignment of genomic DNA sequences of TS-2 chromosomes. Genomic sequence (accession AY681494) of der(19) aligned with chromosome 19 (gi: 37552371) and 1 (gi: 37549803) genomic contigs. Non- homologous insert shown in bold uppercase. Genomic sequence (accession AY681493) of der(1) aligned with chromosome 19 and 1 genomic contigs. (Prima et al., 2007).

signaling pathways that control survival of neurons and

T-cells; induces expression of c-jun, a known

transforming oncogene, and has recently been

identified in murine retroviral mutagenesis studies as a

candidate oncogene involved in the pathogenesis of

lymphoid malignancies (Lund et al., 2002; Suzuki et

al., 2002; Han and Prywes, 1995).

Homology

Belongs to MEF2-like/Type II subfamily of MADS

box family of eukaryotic transcriptional regulators. The



MADS-box is found so far in a diverse group of

transcription factors from yeast, animals and seed

plants.

Implicated in

Acute lymphoblastic leukemia (ALL)

Hybrid/Mutated gene

A variant t(1;19)(q23;p13.3) 1048 translocation creates

reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1

fusion genes that are expressed in acute lymphoblastic

leukemia (ALL).

DAZAP1 is expressed most abundantly in the testis and

mapped to 19p13.3. DAZAP1 is fused to MEF2D by

the t(1;19); the genomic breakpoints occur in introns of

MEF2D and DAZAP1 (der(1) (Genbank accession

AY681493) and der(19) (accession AY681494)).

der(19) breakpoint is located within the 1500 kilobases

(kb) of DNA telomeric to E2A. Rearrangments are seen

only in TS-2 (ALL cell line) establishing that the

t(1;19) interrupts the 19p13.3 gene DAZAP1 with the

breakpoint region in approximately the middle of the

gene. There is a 5 base pairs insertion at the site of

genomic fusion on the der(19) that is not derived from

either germline chromosome 1 or 19. Homologous

breakpoints occur on the der(1) chromosome with a

deletion of 97 bp and a 21 bp GC-rich insertion.

MEF2D/DAZAP1 and DAZAP1/MEF2D fusion

transcripts are expressed in-frame in TS-2 cells in

addition to wild-type DAZAP1 and MEF2D transcripts

(Prima et al., 2005).

Abnormal protein

In-frame MEF2D/DAZAP1 and DAZAP1/MEF2D

fusion transcripts are expressed in TS-2 cell line and

define the DNA-, RNA-binding, and transcriptional

regulatory properties of the resultant chimeric proteins.

Native DAZAP1 (NP_061832) includes two identified

RNA recognition motifs (RRM) specified by amino

acids 1-87 and 105-190. DAZAP1/MEF2D fusion

cDNAs (accession

AY678451) are predicted to encode a chimeric protein

that contains all of the first DAZAP1 RRM and a

truncated portion of the second RRM joined to the

carboxy terminal portion of MEF2D that includes the

second TAD. Reciprocal MEF2D/DAZAP1 fusion

transcripts (accession AY675556) are predicted to

encode a chimera that includes the MEF2D MADS-

box, MEF2 domain, and the first TAD joined to the

carboxy terminus of DAZAP1 including a truncated

portion of RRM 2.

DAZAP1 bound strongly to poly(U) and poly(G) at 0.1

M NaCl, whereas DAZAP1/MEF2D bound to the same

homopolymers to a lesser degree; MEF2D/DAZAP1

retains DNA-binding properties of wild type MEF2D;

MEF2D/DAZAP1 is a more potent transcriptional

activator than wild type MEF2D. MEF2D-DAZAP1

was co-immunoprecipitated with wild type MEF2D

from HEK293 cells, suggesting that the wild type and

chimeric MEF2D proteins could form heterodimers

and/or associate with one another in a higher order

protein complex in vivo (Yuki et al., 2004).

Oncogenesis

MEF2D and DAZAP1 fusion proteins were identified

as components of novel pathways that contribute to

human leukemogenesis. Both MEF2D/DAZAP1 and

DAZAP1/MEF2D have oncogenic properties, and co-

expression of both fusion proteins is synergistic (Prima

and Hunger, 2007).

MEF2D/DAZAP1 might directly activate transcription

of genes critical for lymphocyte growth and/or survival

such as interleukin-2, a known transcriptional target of

MEF2D in T-cells. Alternatively, MEF2D/DAZAP1

could contribute to leukemogenesis via dysregulated

activation of MAPK-mediated cell proliferation

pathways, analogous to constitutive activation of a

growth factor receptor.

Structural features of wild type and chimeric MEF2D and DAZAP1 proteins. Predicted functional domains of DAZAP1, MEF2D, DAZAP1/MEF2D and MEF2D/DAZAP1 proteins. Arrows indicate predicted protein breakpoints. (RRM- RNA recognition motif; MADS- DNA binding, protein dimerization domain; MEF2- cofactor interactions domain; TAD- transcriptional activation domain) (Prima et al., 2007).



References Pollock R, Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327-41

Han TH, Prywes R. Regulatory role of MEF2D in serum induction of the c-jun promoter. Mol Cell Biol. 1995 Jun;15(6):2907-15

Molkentin JD, Olson EN. Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9366-73

Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol. 1998;14:167-96

Lund AH, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D, Russell R, DePinho RA, Lenz J, van Lohuizen M. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet. 2002 Sep;32(1):160-5

Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ, Jenkins NA, Copeland NG. New genes involved in cancer identified by retroviral tagging. Nat Genet. 2002 Sep;32(1):166-74

Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, Inazawa J. Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13). Cancer Sci. 2004 Jun;95(6):503-7

Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger SP. Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia. Leukemia. 2005 May;19(5):806-13

Zhu B, Ramachandran B, Gulick T. Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. J Biol Chem. 2005 Aug 5;280(31):28749-60

Prima V, Hunger SP. Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia. Leukemia. 2007 Dec;21(12):2470-5

Neely MD, Robert EM, Baucum AJ, Colbran RJ, Muly EC, Deutch AY. Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A. Brain Res. 2009 Jun 5;1274:55-65


Prima V, Glushakova LG, Hunger SP. MEF2D (myocyte enhancer factor 2D). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):772-775.

Gene Section Review




NDRG1 (N-myc downstream regulated 1) Michel Wissing, Nadine Rosmus, Michael Carducci, Sushant Kachhap

Johns Hopkins Medical Institute, The Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street,

CRB-I 162E, Baltimore, MD 21231, USA (MW, NR, MC, SK)


Online updated version : http://AtlasGeneticsOncology.org/Genes/NDRG1ID41512ch8q24.html DOI: 10.4267/2042/44828


Identity

Other names: CAP43; CMT4D; DRG-1; DRG1; GC4;

HMSNL; NDR1; NMSL; PROXY1; RIT42; RTP;

Rit42; TARG1; TDD5

HGNC (Hugo): NDRG1

Location: 8q24.22

DNA/RNA

Description

NDRG1 consists of 60,085 basepairs, starting at

basepair 134,318,596 and ending at basepair

134,378,680 from the p-terminus. It is a member of the

NDRG family, consisting of NDRG1, NDRG2,

NDRG3 and NDRG4 (of which three isoforms exist:

NDRG-4B, NDRG-4Bvar

and NDRG-4H), which are

part of the alpha/beta hydrolase superfamily.

Transcription

The DNA of NDRG1 contains 16 exons, see diagram

for details about their location. The DNA encodes a 3.0

kb mRNA with a coding region of 1.185 kb.

Protein

Description

NDRG1 is a 43 kD protein, composed of 394 amino

acids, with an iso-electric point of 5.7. NDRG1 has an

alpha/beta hydrolase-fold motif, however, the presence

of hydrolytic catalytic activity is still questionable.

NDRG1 has more than seven phosphorylation sites,

among others a phosphopantetheine attachment site,

protein kinase C, casein kinase II, tyrosine kinase,

protein kinase A and calmodulin kinase II. NRDG1 is

phosphorylated by protein kinase A and calmodulin

kinase II, and is a physiological substrate of SGK1 and

GSK-3-beta kinase, a kinase involved in cancer growth

and progression.

Expression

NDRG1 is relatively ubiquitously expressed in normal

human cells, and especially highly expressed in

prostate, brain, kidney, placenta, ovarian, testicular and

intestinal cells. NDRG1 is mostly found in epithelial

cells.

Localisation

NDRG1 is primarily a cytoplasmic protein. 47.8% of

the NDRG1 is expressed in the cytosol, 26.1% in the

nucleus (such as in prostate epithelial cells), and 8.7%

in the mitochondria (such as in proximal tubule cells in

the kidney). NDRG1 is also found in the adherens

junctions. Additionally, in intestinal and lactating

breast epithelia NDRG1 is located in the plasma

membrane. NDRG1 can also be found in vacuoles, the

peroxisome, early and recycling endosomes, and the

cytoskeleton.

DNA size: 60.05 kb; mRNA size: 2997 bp; 16 exons.

NDRG1 (N-myc downstream regulated 1) Wissing M, et al.


Function

NDRG1 is reported to be a metastasis suppressor gene

which is downregulated in prostate, colon and breast

cancers. It has been found to be a Rab4a effector

protein that recruits to the recycling endosomes in the

Trans Golgi network by binding to the lipid

phosphotidylinositol 4-phosphate (PI4P), where it plays

a role in the recycling of E-cadherin. NDRG1 also

interacts with HSP70. NDRG1 co-localizes with APO

A-I and A-II, and may be involved in lipid transport.

The function of NDRG1 may be controlled at least in

part by phosphorylation. It has also been identified as a

stress response gene, upregulated by homocysteine and

hypoxia. Hif-1-dependent and independent mechanisms

have been implicated in NDRG1 induction. It is also

controlled by AP-1 transcription factors. When exposed

to stress, for example hypoxia, NDRG1 may play a

cytoprotective role in normal healthy cells. There is

evidence that NDRG1 is involved in the induction of

differentiation. NDRG1 is downregulated under

conditions of cell growth. NDRG1 expression peaks in

the G1 and G2/M phases, and is lowest in the S phase.

NDRG1 is also a microtubule-associated protein, which

may play an important role in maintaining spindle

structure during cell division. In the Schwann cells,

NDRG1 is essential for myelin sheath maintenance.

Hence, NDRG1 is a multifunctional protein with roles

that may be tissue- and/or cell-type specific.

Certain transcription factors such as MYC, ERG1,

HIF1-ALPHA bind to the NDRG1 promoter region and

regulate its expression.

NDRG1 is upregulated during colon epithelial cell

differentiation. It is regulated by hormones such as

androgens and estradiol. Small molecules such as N-

hydroxy-N'-phenol-octane-1,8-diotic acid diamide,

calcium ionophores like BAPTA, metal ions such as

Nickel and Cobalt, iron chelators and differentiating

agents like retinoic acid induce NDRG1 expression.

Additionally, NDRG1 is induced during cellular DNA

damage and endoplasmic reticulum stress.

Homology

NDRG1 amino acid sequence is 53% homologous to

NDRG2, 62% to NDRG3, 62% to NDRG4, and 94%

homologous to the mouse analog, Ndr-1 (also known as

TDD5). NDRG1 homologs have been found in

Helianthus, Caenorhabditis, Xenopus and Drosophilia.

Implicated in

Various solid cancers

Disease

Prostate, breast, colon, renal, bladder, pancreatic,

hepatic cancer.

Prognosis

Downregulation of NDRG1 in cancer worsens the

prognosis of cancer. There is an inverse relationship in

the levels of NDRG1 expression and the Gleason grade

of the tumor in prostate cancer. A high PTEN (a tumor

suppressor which positively regulates NDRG1) and

NDRG1 expression improves survival rates in patients

with breast and prostate cancer. In patients with

colorectal cancer, the 2 year survival rate for patients

with high NDRG1-expression was 82.4%, while for

patients with a low NDRG1-expression it was only

69.6%. In pancreatic cancer patients, the median

survival time for patients with high NDRG1-expression

was 24.7 months, while the median survival time for

patients with low NDRG1-expression was only 10.9

months. High expression of NDRG1 in colon tumors

was found to correlate with increased resistance to

irinotecan.



Oncogenesis

An inverse relationship exists between NDRG1 and the

oncogenes N-myc and c-myc, suggesting that members

of the MYC family suppress expression of NDRG1.

Experimental evidence exist that both N-myc and c-

myc downregulate NDRG1 gene expression by directly

binding to NDRG1 promoter.

NDRG1 is downregulated in colon, breast, prostate and

pancreatic neoplasms, by c-myc and N-myc

transcription factors. In cancer cells, NDRG1

expression is consistent through all phases in the cell

cycle, instead of the biphasic expression in normal

cells. PTEN expression is positively related to NDRG1

expression. NDRG1 is induced in cancer cells by

histone deacetylase inhibitors and DNA methyl

transferase inhibitors indicating that NDRG1 is

regulated by chromatin modulation and DNA

methylation.

Although NDRG1 has been reported to be

downregulated in a variety of cancers, it has been

shown to be upregulated in hepatic, pancreatic and

kidney cancers. Induction of NDRG1 in these tumors is

speculated to be in response to tumor stress or hypoxia

and NDRG1 is proposed as a marker of tumor hypoxia.

However, in pancreatic cancer, cellular differentiation

and not hypoxia was demonstrated to be the

determining factor for NDRG1 expression. In renal

cancer, induction of NDRG1 in the tumor tissue was

restricted to infiltrating macrophages and not cancer

cells.

NDRG1 is suggested to be an early target for p53. Loss

of p53 expression in cancer is suggested to reduce

NDRG1 expression. However, p53 knockout mice

show expression of NDRG1, suggesting that there are

other mechanisms regulating NDRG1 levels.

NDRG1 expression plays a role in vitro in primary

tumor growth in prostate, breast, and bladder cancer: a

higher expression of NDRG1 lowers the proliferation

rates of these cancers. In pancreatic and bladder cancer

cells, this reduction was proven in vivo: in pancreatic

cells it was suggested that the reduced proliferation was

caused by NDRG1 by modulating tumor stroma and

angiogenesis. NDRG1 can recruit onto the recycling

endosome in the Trans-Golgi network by binding to

phosphotidylinositol 4-phosphate. There, NDRG1 may

be involved in the transport of various cargo back to the

cells' surface. At the molecular level, NDRG1 may

stabilize the E-cadherin molecule by recycling it back

to the cells' surface, thereby preventing tumor invasion.

Hereditary motor and sensory neuropathy-Lom (HMSNL) / Charcot-Marie-Tooth disease (CMT 4D)

Note

Caused by the Gypsy founder mutation, homozygote

R148X, also called homozygote C564t. In patients with

CMT disease, apart from the R148X mutation, another

disease-causing mutation was identified, namely IVS8-

1G>A (g.2290787G>A), which results in skipping of

exon 9. The homozygote phenotype of this mutation

was very closely related to the phenotype of HMSNL

patients.

Disease

A hereditary autosomal recessive disease, caused by

demyelination of peripheral nerves. It is the most

common form of demyelinating Charcot-Marie-Tooth

disease in the Roma population.

Prognosis

Severe disability in adulthood. It begins consistently in

the first decade of life with a gait disorder, followed by

upper limb weakness in the second decade and, in most

subjects, by deafness setting in in the third decade of

life. Sensory loss affecting all modalities is present;

both this and the motor involvement predominating

distally in the limbs. Skeletal deformity, particularly

foot deformities, are frequent.

Atherosclerosis

Note

Patients with HMSNL were found to have a high total

cholesterol: HDL-C ratio.

Disease

Atherosclerosis is an important factor for the

development of cardiovascular diseases, like

myocardial infarction and angina pectoris. NDRG1

contributes to HDL-C (high-density lipoprotein-

cholesterol) levels most likely by its

phosphopantetheine-binding domain interacting with

the high-density lipoproteins apolipoprotein A-I and A-

II.

References Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. J Biol Chem. 1996 Nov 22;271(47):29659-65

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van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosman FT. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab Invest. 1997 Jul;77(1):85-92

Kalaydjieva L, Nikolova A, Turnev I, Petrova J, Hristova A, Ishpekova B, Petkova I, Shmarov A, Stancheva S, Middleton L, Merlini L, Trogu A, Muddle JR, King RH, Thomas PK. Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings. Brain. 1998 Mar;121 ( Pt 3):399-408

Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res. 1998 Oct 1;58(19):4439-44



Zhou D, Salnikow K, Costa M. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res. 1998 May 15;58(10):2182-9

Piquemal D, Joulia D, Balaguer P, Basset A, Marti J, Commes T. Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells.

Biochim Biophys Acta. 1999 Jul 8;1450(3):364-73

Salnikow K, An WG, Melillo G, Blagosklonny MV, Costa M. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis. 1999 Sep;20(9):1819-23

Shimono A, Okuda T, Kondoh H. N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev. 1999 May;83(1-2):39-52

Ulrix W, Swinnen JV, Heyns W, Verhoeven G. The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells. FEBS Lett. 1999 Jul 16;455(1-2):23-6

Agarwala KL, Kokame K, Kato H, Miyata T. Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein. Biochem Biophys Res Commun. 2000 Jun 16;272(3):641-7

Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 2000 Feb 1;60(3):749-55

Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet. 2000 Jul;67(1):47-58

Salnikow K, Costa M, Figg WD, Blagosklonny MV. Hyperinducibility of hypoxia-responsive genes without p53/p21-dependent checkpoint in aggressive prostate cancer. Cancer Res. 2000 Oct 15;60(20):5630-4

Salnikow K, Su W, Blagosklonny MV, Costa M. Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism. Cancer Res. 2000 Jul 1;60(13):3375-8

Gómez-Casero E, Navarro M, Rodríguez-Puebla ML, Larcher F, Paramio JM, Conti CJ, Jorcano JL. Regulation of the differentiation-related gene Drg-1 during mouse skin carcinogenesis. Mol Carcinog. 2001 Oct;32(2):100-9

Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene. 2001 Jul 27;20(33):4457-65

Zoroddu MA, Kowalik-Jankowska T, Kozlowski H, Salnikow K, Costa M. Ni(II) and Cu(II) binding with a 14-aminoacid sequence of Cap43 protein, TRSRSHTSEGTRSR. J Inorg Biochem. 2001 Mar;84(1-2):47-54

Lachat P, Shaw P, Gebhard S, van Belzen N, Chaubert P, Bosman FT. Expression of NDRG1, a differentiation-related gene, in human tissues. Histochem Cell Biol. 2002 Nov;118(5):399-408

Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F. Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem. 2002 Jan;229(1-2):35-44

Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV. The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol. 2002 Mar;22(6):1734-41

Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M, Watabe K. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 2003 Apr 15;63(8):1731-6

Hunter M, Bernard R, Freitas E, Boyer A, Morar B, Martins IJ, Tournev I, Jordanova A, Guergelcheva V, Ishpekova B, Kremensky I, Nicholson G, Schlotter B, Lochmüller H, Voit T, Colomer J, Thomas PK, Levy N, Kalaydjieva L. Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease. Hum Mutat. 2003 Aug;22(2):129-35

Li J, Kretzner L. The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc. Mol Cell Biochem. 2003 Aug;250(1-2):91-105

Masuda K, Ono M, Okamoto M, Morikawa W, Otsubo M, Migita T, Tsuneyoshi M, Okuda H, Shuin T, Naito S, Kuwano M. Downregulation of Cap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells. Int J Cancer. 2003 Jul 20;105(6):803-10

Taketomi Y, Sugiki T, Saito T, Ishii S, Hisada M, Suzuki-Nishimura T, Uchida MK, Moon TC, Chang HW, Natori Y, Miyazawa S, Kikuchi-Yanoshita R, Murakami M, Kudo I. Identification of NDRG1 as an early inducible gene during in vitro maturation of cultured mast cells. Biochem Biophys Res Commun. 2003 Jun 27;306(2):339-46

Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, Gross SC, Wang Y, Ran S, Watabe K. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene. 2004 Jul 22;23(33):5675-81

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Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW. Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint. J Biol Chem. 2004 Sep 10;279(37):38597-602

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Cui DX, Zhang L, Yan XJ, Zhang LX, Xu JR, Guo YH, Jin GQ, Gomez G, Li D, Zhao JR, Han FC, Zhang J, Hu JL, Fan DM, Gao HJ. A microarray-based gastric carcinoma prewarning system. World J Gastroenterol. 2005 Mar 7;11(9):1273-82

Hunter M, Angelicheva D, Tournev I, Ingley E, Chan DC, Watts GF, Kremensky I, Kalaydjieva L. NDRG1 interacts with APO A-I and A-II and is a functional candidate for the HDL-C QTL on 8q24. Biochem Biophys Res Commun. 2005 Jul 15;332(4):982-92

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SLC5A8 (solute carrier family 5 member 8) Julie Di Bernardo, Kerry J Rhoden

Medical Genetics Unit, Department of Gynaecologic, Obstetric and Pediatric Sciences, University of

Bologna, Bologna, Italy (JDB, KJR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC5A8ID44089ch12q23.html DOI: 10.4267/2042/44829


Identity

Other names: AIT; MGC125354; SMCT; SMCT1

HGNC (Hugo): SLC5A8

Location: 12q23.2

Local order: Telomeric to TMEM16D, centromeric to

UTP20.

DNA/RNA

Description

15 exons, spanning 54023 bp.

Transcription

3286 bases, open reading frame: 1833 bp. No

alternative splicing variants have been reported.

SLC5A8 transcription is regulated by hypermethylation

of CpG-rich islands in the promoter region.

Pseudogene

No pseudogenes identified.

Protein

Description

610 amino acids; 66,560 Da; 13 transmembrane

domains, extracellular N-terminal, cytosolic C-

terminal.

Expression

Gastrointestinal tract (stomach, colon, ileum), kidney,

thyroid, brain, retina, breast, prostate, salivary gland

ducts.

Localisation

Cell membrane; apical membrane in thyrocytes and

colonocytes.

SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ


Diagram drawn following UniProtKB/Swiss-Prot database prediction and maintaining approximate length proportions among extracellular and intracellular segments. Transmembrane segments are represented by rectangles.

Function

Sodium coupled transport of short-chain

monocarboxylates, including lactate, butyrate,

pyruvate, acetate, proprionate, ketone bodies and

nicotinate. The sodium/substrate stoichiometry depends

on the transported substrate. SLC5A8 is considered a

tumor suppressor, and its expression is downregulated

in several kinds of tumor. Its tumor suppressor activity

may be due to its ability to transport and accumulate

histone deacetylase inhibitors such as butyrate and

pyruvate.

- Gastrointestinal tract: colonocyte absorption and

accumulation of short chain fatty acids produced by

bacteria in the intestinal lumen. In particular, butyrate

and pyruvate are inhibitors of histone deacetylases and

are known to promote differentiation in normal colon

epithelial cells but selectively induce apoptosis in

tumor cells.

- Kidney: lactate transport; reabsorption of lactate from

urine to blood.

- Thyroid: unknown function. When first identified,

SLC5A8 was shown to localize on the apical

membrane of thyrocytes and to transport iodide by a

passive mechanism. Lately, this evidence has been

rejected by different groups that showed that iodide is

not a SLC5A8 substrate.

- Brain: transport of lactate and ketone bodies; role in

energy maintenance in neurons.

Homology

Belongs to the SLC superfamily of solute carriers; the

SLC5 family has 12 members to date (SLC5A1-

SLC5A12) and includes Na+-coupled cotransporters

that rely on the Na+ electrochemical gradient to drive

solute transport into cells. 53% identity with SLC5A12,

a sodium/monocarboxylate transporter; 46% identity

with SLC5A5, the Sodium-Iodide Symporter.

Mutations

Germinal

No germinal mutations implicated in human disease to

date.

SLC5A8 knockout mouse (deletion of exons 4 and 5) is

viable and fertile, with no evident malformation;

affected by lactaturia and loss of sodium-dependent

lactate uptake in the colon.

Somatic

No somatic mutations implicated in human disease to

date.

Implicated in

Colorectal cancer

Prognosis

SLC5A8 expression may be a favorable indicator of

colorectal cancer prognosis; higher expression

correlates with longer disease-free survival (Paroder et

al., 2006).

Oncogenesis

SLC5A8 is expressed in normal colon, but is silenced

in colon cancer due to gene methylation. SLC5A8

exerts a tumor suppressor function, possibly due to its

ability to transport and accumulate histone deacetylase

inhibitors such as butyrate and pyruvate.

- 59% of primary colon cancers and colonic adenomas

(dysplastic polyps, precursor lesions of colon cancer),

and 52% of colon cancer cell lines show aberrant

methylation of SLC5A8 exon 1 (Li et al., 2003).



- 82,5% of serrated adenomas (polyps with mixed

hyperplastic/adenomatous features, precursor lesions of

colon cancer), exhibit tumor-specific

promoter methylation of SLC5A8; methylation of CpG

islands increases with the histological progression of

serrated adenomas (Dong et al., 2005).

- 66.4% of Duke C stage colorectal cancers (i.e.

colorectal cancer with lymph node metastases) express

low levels of SLC5A8 (Paroder et al., 2006).

Papillary thyroid cancer (PTC)

Prognosis

SLC5A8 methylation and silencing of gene expression

is significantly associated with aggressive features of

PTC, including extrathyroidal invasion, lymph node

metastasis, multifocality and advanced tumor stages

(Hu et al., 2006).

Oncogenesis

SLC5A8 expression is selectively down-regulated in

papillary thyroid carcinomas: SLC5A8 is methylated in

90% of classical PTC and in 20% of other PTC

subtypes, including the follicular variant. SLC5A8

methylation and low expression is highly associated

with the prescence of the BRAF T1796A mutation

(Porra et al., 2005; Hu et al., 2006).

Various cancers

Disease

Acute myeloid leukemia (AML), astrocytoma and

oligodendroglioma, breast cancer, gastric cancer, head

and neck squamous cells carcinoma, pancreatic cancer,

prostate cancer.

Oncogenesis

SLC5A8 expression is decreased in various cancers due

to DNA methylation in the SLC5A8 promoter region.

To be noted

Note

Several single nucleotide polymorphisms have been

found, mostly in introns, or resulting in synonymous

codons with no change in amino acid. A single

nonsynonymous coding polymorphism (Phe251Val)

has been reported to negatively affect transport activity.

References Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab. 2002 Jul;87(7):3500-3

Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8412-7

Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY. The human

tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol. 2004 Jun 15;557(Pt 3):719-31

Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J Biol Chem. 2004 Oct 22;279(43):44522-32

Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J Biol Chem. 2004 Apr 2;279(14):13293-6

Ueno M, Toyota M, Akino K, Suzuki H, Kusano M, Satoh A, Mita H, Sasaki Y, Nojima M, Yanagihara K, Hinoda Y, Tokino T, Imai K. Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol. 2004 May-Jun;25(3):134-40

Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol. 2005 Feb;18(2):170-8

Ganapathy V, Gopal E, Miyauchi S, Prasad PD. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem Soc Trans. 2005 Feb;33(Pt 1):237-40

Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V. Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem J. 2005 May 15;388(Pt 1):309-16

Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res. 2005 May 1;65(9):3617-23

Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, Borson-Chazot F, Dante R, Rousset B. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab. 2005 May;90(5):3028-35

Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 2006 Apr 18;78(21):2419-25

Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Nov 15;119(10):2322-9

Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S Jr, Mariadason JM, Augenlicht LH, Eskandari S, Carrasco N. Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7270-5

Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, Sterneck E, Ganapathy V. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res. 2006 Dec 15;66(24):11560-4

Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V. Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3356-63



Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, Pow-Sang J. Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor. Cancer Detect Prev. 2007;31(5):359-65

Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 2008 Jun 15;68(12):4494-9

Frank H, Gröger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J Biol Chem. 2008 Sep 5;283(36):24729-37

Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193-9

Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, Malafa MP. Silencing of the candidate tumor suppressor gene

solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas. 2008 May;36(4):e32-9

Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2

Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009 Jan;121(1):29-40

Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J. 2009 Jan 1;417(1):379-89


Di Bernardo J, Rhoden KJ. SLC5A8 (solute carrier family 5 member 8). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):781-784.





TMPRSS4 (transmembrane protease, serine 4) Youngwoo Park

Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon,

Korea (YP)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TMPRSS4ID42594ch11q23.html DOI: 10.4267/2042/44830


Identity

Other names: EC 3.4.21.-; MT-SP2; TMPRSS3

HGNC (Hugo): TMPRSS4

Location: 11q23.3

Note: Not to be confused with TMPRSS3 (21q22.3),

which was originally named for TMPRSS4 (11q23.3).

DNA/RNA

Description

TMPRSS4 gene approximately extends 41.38 kb-long

on chromosome 11 in the region p23.3, containing 13

exons.

Transcription

Two alternative splicing variants have been described,

producing transcripts of 2.12 kb and 1.98 kb,

respectively.

Protein

Description

TMPRSS4 is a 437 amino acid type II transmembrane

serine protease (TTSPs) which are expressed at the cell

surface and are thus ideally located to regulate cell-cell

and cell-matrix interactions.

Expression

TMPRSS4 is highly expressed in pancreatic, colon,

lung and gastric cancer tissues, and TMPRSS4 is also

broadly expressed in a variety of human cancer cell

lines, such as NCI-H322, Colo205 and HCT15.

Localisation

Membrane; single-pass type II membrane protein.

Function

TMPRSS4 plays a role in invasion, metastasis,

migration and adhesion, as well as in the EMT in

cancer cells.

TMPRSS4 is a 437 amino acid single-pass type II membrane protein. It contains a Serine protease domain at the C-terminus, followed by a Scavenger receptor cysteine-rich domain (SRDR) and a Low Density Lipoprotein Receptor Class A domain. Letters H, D and S in the serine protease domain indicate the position of the three catalytic residues histidine, aspartate and serine, respectively.

TMPRSS4 (transmembrane protease, serine 4) Park Y


Loss of E-cadherin transcript, a hallmark of EMT, was

induced by TMPRSS4. It also modulates cell growth in

a cell type-dependent manner. TMPRSS4 expression is

upregulated in lung cancer tissues compared with

normal tissues, and various cancer cell lines themselves

express TMPRSS4 at various levels.

Homology

TMPRSS4 is a type II transmembrane serine protease

(TTSPs) which contains a serine protease domain.

Human TTSPs, which consists of 17 members, were

grouped into four subfamilies based on similarity in

domain structure and phylogenetic analysis of the

serine protease domains, namely the matriptase, corin,

hepsin/TMPRSS and HAT/DESC subfamilies.

Implicated in

Colon cancer

Oncogenesis

TMPRSS4 is an important mediator of invasion,

metastasis, migration, adhesion and EMT (epithelial-

mesenchymal transition) in human epithelial colon

cancer cells and also modulates in vitro cell growth in a

cell type- and/or signaling context dependent manner,

suggesting that TMPRSS4 may represent a novel

therapeutic target for cancer.

TMPRSS4 overexpression induces an EMT associated

with SIP1/ZEB2 induction and E-cadherin loss in

SW480 cells, and also promotes metastasis of SW480

cells.

TMPRSS4 overexpression is associated with

morphological changes and actin cytoskeleton

rearrangement.

Pancreatic cancer

Oncogenesis

TMPRSS4 is strongly expressed in a subset of

pancreatic cancer and various other cancer tissues, and

its expression correlates with the metastatic potential of

the pancreatic cancer cell lines.

Multidomain structure of human TTSPs. Human TTSPs were grouped into four subfamilies based on similarity in domain structure and phylogenetic analysis of the serine protease domains, namely the matriptase, corin, hepsin/TMPRSS and HAT/DESC subfamilies. Consensus domains are shown above. Each diagram was drawn using the web-based SMART software (http://smart.embl-heidelberg.de) with TTSP amino acid sequences obtained from GenBank. Abbreviations: CUB, Cls/Clr, urchin embryonic growth factor and bone morphogenic protein-1 domain; DESC1, differentially expressed squamous cell carcinoma gene 1; FRZ, frizzled domain; HAT, human airway trypsin-like protease; LDLA, low-density lipoprotein receptor domain class A; MAM, a meprin, A5 antigen and receptor protein phosphatase m domain; MSPL, mosaic serine protease long-form; Polyserase-1, polyserine protease-1; SEA, a single sea urchin sperm protein, enteropeptidase, agrin domain; SR, scavenger receptor cysteine-rich domain; TM, transmembrane domain. Letters H, D and S in the serine protease domain (active) indicate the position of the three catalytic residues histidine, aspartate and serine, respectively. Letter A in the serine protease domain (inactive) indicates a serine to alanine exchange.

TMPRSS4 (transmembrane protease, serine 4) Park Y


References Wallrapp C, Hähnel S, Müller-Pillasch F, Burghardt B, Iwamura T, Ruthenbürger M, Lerch MM, Adler G, Gress TM. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Res. 2000 May 15;60(10):2602-6

Jarzab B, Wiench M, Fujarewicz K, Simek K, Jarzab M, Oczko-Wojciechowska M, Wloch J, Czarniecka A, Chmielik E, Lange D, Pawlaczek A, Szpak S, Gubala E, Swierniak A. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 2005 Feb 15;65(4):1587-97

Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Ann Surg. 2005 Sep;242(3):353-61; discussion 361-3

Yamada H, Shinmura K, Tsuneyoshi T, Sugimura H. Effect of splice-site polymorphisms of the TMPRSS4, NPHP4 and ORCTL4 genes on their mRNA expression. J Genet. 2005 Aug;84(2):131-6

Kebebew E, Peng M, Reiff E, McMillan A. Diagnostic and extent of disease multigene assay for malignant thyroid neoplasms. Cancer. 2006 Jun 15;106(12):2592-7

Choi SY, Shin HC, Kim SY, Park YW. Role of TMPRSS4 during cancer progression. Drug News Perspect. 2008 Oct;21(8):417-23

Jung H, Lee KP, Park SJ, Park JH, Jang YS, Choi SY, Jung JG, Jo K, Park DY, Yoon JH, Park JH, Lim DS, Hong GR, Choi C, Park YK, Lee JW, Hong HJ, Kim S, Park YW. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene. 2008 Apr 17;27(18):2635-47

Li BH, Yang XZ, Li PD, Yuan Q, Liu XH, Yuan J, Zhang WJ. IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem Biophys Res Commun. 2008 May 2;369(2):554-60

Chaipan C, Kobasa D, Bertram S, Glowacka I, Steffen I, Tsegaye TS, Takeda M, Bugge TH, Kim S, Park Y, Marzi A, Pöhlmann S. Proteolytic activation of the 1918 influenza virus hemagglutinin. J Virol. 2009 Apr;83(7):3200-11

Choi SY, Bertram S, Glowacka I, Park YW, Pöhlmann S. Type II transmembrane serine proteases in cancer and viral infections. Trends Mol Med. 2009 Jul;15(7):303-12


Park Y. TMPRSS4 (transmembrane protease, serine 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):785-787.





TSPAN8 (tetraspanin 8) Uwe Matthias Galli

Department of Tumour Cell Biology, University Hospital of Surgery, Heidelberg, Germany (UMG)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TSPAN8ID42585ch12q21.html DOI: 10.4267/2042/44831


Identity

Other names: CO-029; TM4SF3; Tspan-8

HGNC (Hugo): TSPAN8

Location: 12q21.1

DNA/RNA

The human Tspan8 gene contains 9 exons and 8 introns

and was predicted to span over 32,9 kb appoximately of

the genomic DNA. Transcript length: 1130 bps,

translation length: 237 residues.

Tetraspanin 8 has a short amino- and carboxy-terminal tail, a small intracellular loop between transmembrane region 2 (TM2) and TM3, a small extracellular loop (ECL1) between TM1 and TM2 and a large extracellular loop (ECL2) between TM3 and TM4. Extracellular loop 2 contains six conserved cysteine residues (red) including the CCG motif; disulphide bonds are indicated. The transmembrane regions 1 and 4 have polar amino acids (green), the cytoplasmic domains contain palmitoylation sites (pink) and the carboxy-terminal domain contains a sorting motif (blue).

TSPAN8 (tetraspanin 8) Galli UM


Protein

Description

Tspan8 is a member of the transmembrane 4

superfamily, also known as the tetraspanin family.

Expression

Tetraspanin 8 is expressed in squamous epithelial cells

(not epidermis), capillary endothelial cells, nerves,

smooth and striated muscle cells, and subpopulations of

hematopoietic progenitor cells.

Function

Like other tetraspanins, Tspan8 act as a "molecular

facilitator" by forming a web in glycolipid-enriched

membrane microdomains, called TEM (tetraspanin

enriched membrane domains). Tspan8 associates with

additional tetraspanins, integrins, preferentially CD49c,

CD104, but also CD49d. It is directly associated with

EWI-F, CD13 and intersectin 2. Via its associated

molecules Tspan8 becomes involved in cell adhesion

and motility as well as signal transduction. Motility

promotion mostly proceeds via its association with

CD104 and is in line with pronounced metastatic

spread of Tspan8 overexpressing tumors as described

for hepatocellular cancer. Similar to other tetraspanins,

Tspan8 is abundantly present in exosomes, where it

accounts via its association with CD49d for endothelial

cell and endothelial cell progenitor targeting with the

consequence of endothelial cell activation and

endothelial cell progenitor maturation.

Regulates cell motility and survival and is involved in

the promotion of angiogenesis.

Mutations

Note

Not known in Homo sapiens.

Implicated in

Tumors of the gastrointestinal tract

Note

CO-029 is associated with tumor progression and is

supposed to promote metastasis formation. It has been

described as a marker of several types of carcinomas

and sarcomas. In gastrointestinal tumors the expression

of CO-029 has been associated with a poor pognosis.

Disease

Gastric tumors, colorectal tumors, pancreatic tumors

and liver tumors.

Hepatocellular carcinoma (HCC)

Note

Tetraspanin CO-029 was found to be frequently and

significantly overexpressed in HCC. CO-029 was

overexpressed in poorly differentiated HCCs compared

with well to moderately differentiated tumors, and in

HCCs showing intrahepatic spreading compared with

those without spreading.

References Szala S, Kasai Y, Steplewski Z, Rodeck U, Koprowski H, Linnenbach AJ. Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6833-7

Claas C, Seiter S, Claas A, Savelyeva L, Schwab M, Zöller M. Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J Cell Biol. 1998 Apr 6;141(1):267-80

Kanetaka K, Sakamoto M, Yamamoto Y, Yamasaki S, Lanza F, Kanematsu T, Hirohashi S. Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. J Hepatol. 2001 Nov;35(5):637-42

Kanetaka K, Sakamoto M, Yamamoto Y, Takamura M, Kanematsu T, Hirohashi S. Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells. J Gastroenterol Hepatol. 2003 Nov;18(11):1309-14

Gesierich S, Paret C, Hildebrand D, Weitz J, Zgraggen K, Schmitz-Winnenthal FH, Horejsi V, Yoshie O, Herlyn D, Ashman LK, Zöller M. Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. Clin Cancer Res. 2005 Apr 15;11(8):2840-52

Le Naour F, André M, Greco C, Billard M, Sordat B, Emile JF, Lanza F, Boucheix C, Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells. Mol Cell Proteomics. 2006 May;5(5):845-57

Kuhn S, Koch M, Nübel T, Ladwein M, Antolovic D, Klingbeil P, Hildebrand D, Moldenhauer G, Langbein L, Franke WW, Weitz J, Zöller M. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res. 2007 Jun;5(6):553-67

Zhou Z, Ran YL, Hu H, Pan J, Li ZF, Chen LZ, Sun LC, Peng L, Zhao XL, Yu L, Sun LX, Yang ZH. TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clin Exp Metastasis. 2008;25(5):537-48

Zöller M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer. 2009 Jan;9(1):40-55


Galli UM. TSPAN8 (tetraspanin 8). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):788-789.

Gene Section Review




TXN (thioredoxin) Zhe Chen, Eiji Yoshihara, Hajime Nakamura, Hiroshi Masutani, Junji Yodoi

Department of Biological Responses, Institute for Virus Research, Kyoto University, Shogoin, Kawahara-

cho, Sakyo-ku, Kyoto, Japan (ZC, EY, HN, HM, JY)


Online updated version : http://AtlasGeneticsOncology.org/Genes/TXNID44354ch9q31.html DOI: 10.4267/2042/44832


Identity

Other names: ADF; DKFZp686B1993; MGC61975;

SASP; TRDX; TRX; TRX1; Trx

HGNC (Hugo): TXN

Location: 9q31.3

Local order: 9q telomere-3'TXN 5'-centromere.

DNA/RNA

Description

5 exons, 5' part of exon 1 and 3' part of exon 5 are non-

coding.

Transcription

508 bps mRNA, transcribed in a telomere to

centromere direction.

Chromosome : 9, Location : 9q31. (Please visit http://www.ncbi.nlm.nih.gov for more details).

5 exons of thioredoxin. (Please visit http://www.ncbi.nlm.nih.gov for more details).

TXN (thioredoxin) Chen Z, et al.


Alternative splicing of human thioredoxin (lacking

exon 2 and 3) was reported in cancer cells.

Thioredoxin (TRX/TXN/ADF) expression is induced

by a variety of physiochemical stresses, including virus

infection, mitogens, UV-irradiation, hydrogen

peroxide, ischemia reperfusion and so on. Natural

substances including hemin, estrogen, prostaglandins,

sulforaphane, and cAMP can also induce the expression

and secretion of TRX. Geranylgeranylacetone (GGA),

an acyclic polyisoprenoid as anti-ulcer drug, or tert-

butylhydroquinone (tBHQ), a xenobiotics, can also

induce TRX expression.

The 5' flanking sequence of TRX gene contains a series

of stress-responsive elements, antioxidant responsive

element (ARE), cAMP responsive element (CRE),

xenobiotics responsive element (XRE) and Sp1.

Protein

Note

Thioredoxin is a 12 kDa ubiquitous protein that has

disulfide-reducing activity. The structural fold of

thioredoxin, including redox-active site, is called

"TRX-family domain", which is shared by other TRX

superfamily proteins.

Description

In 1964, thioredoxin, named by one Swedish group,

was first identified from extracts of Escherichia coli B

as hydrogen donor from NADPH to ribonucleotide

reductase. Human thioredoxin was originally cloned by

a Japanese group as an IL-2Ralpha (CD25) induced

factor in HTLV-1 infected T-cell lines and designated

as Adult T cell leukemia derived factor (ADF). It was

also cloned independently by a French group as an IL-1

like growth factor produced by Epstein-Barr virus-

transformed cells.

Thioredoxin is a 12 kDa multifunctional protein with a

redox-active site (Cys-Gly-Pro-Cys), which is involved

in dithiol/disulfide exchange reaction. Reduced TRX

can reduce protein disulfide bonds and oxidized TRX is

reduced by NADPH and thioredoxin reductase.

Expression

Thioredoxin is ubiquitously expressed in normal tissues

or cells. Plasma levels of TRX in normal individuals

vary between 10 and 80 ng/mL. The plasma TRX level

is elevated in certain human diseases including HIV

infection and cancer. As mentioned above, thioredoxin

can also be induced by various physiochemical stress

and some natural agents or drugs.

Localisation

Thioredoxin is mainly localized in the cytoplasm.

Under environmental stress, such as UVB irradiation,

PMA, H2O2, hypoxia, the cancer drug cisplatin, hemin

and so on, it can translocate to the nucleus, possibly

participating to the regulation of nuclear transcription

factors, such as Ref-1. Thioredoxin can also be secreted

in response to oxidative stress and function as a

cytokine to alleviate inflammation. The secretion

mechanism of thioredoxin remains unclear.

Thioredoxin accumulation in the membrane fraction

has long been implied by Holmgren's group in 1989.

Later it is found to be expressed on the surface of

HUVECs (human umbilical vein endothelial cells),

including lipid raft which may be involved in redox

signalling.

Function

Thioredoxin plays an important role in scavenging

reactive oxygen intermediates (ROIs) produced in

various oxidative stress. Redox-associated signal

transduction inside the cell may be attributed to

enhanced DNA binding ability of several transcription

factors, such as Ref-1, AP-1, NF-kappaB, which have

been proved to be modulated directly or indirectly by

thioredoxin. Acting as an intracellular reductase,

thioredoxin promotes cellular proliferation to alleviate

oxidative stress. Besides reducing activity, thioredoxin

inhibit apoptosis through direct binding to apoptosis

signal regulating kinase-1 (ASK-1). Thioredoxin is

essential for early differentiation and morphogenesis of

mouse embryo. Thioredoxin-transgenic (TRX-TG)

mice are more resistant to oxidative stress and survive

longer than normal mice.

Extracellular thioredoxin shows cytokine or

chemokine-like effects. It was reported to show

mitogenic effects on leukemia cells, which is also

dependent on the presence of reducing agents like 2-

ME, and the intact active di-thiol site. It was also

reported to show cytoprotective effects through

suppressing the production of some inflammatory

cytokines.

Active site and conserved domain of thioredoxin. (Please see http://www.ncbi.nlm.nih.gov for more details).



Chemotactic effects of thioredoxin was also observed

which may be immune cell type specific and dose

dependent since TRX in higher concentration (>1

microg/ml) in circulation shows anti-chemotactic

effects. How extracellular thioredoxin interacts with

potential target proteins at the plasma membrane may

be a key for clarifying the complicated mechanisms.

Several TRX-binding proteins have been identified so

far. Reduced TRX in cytosol can bind ASK-1, which

activate c-Jun N-terminal kinase (JNK) and p38 MAPK

kinase pathway and is required for TNF-a-induced

apoptosis. TRX also regulates transcription factor by

interaction with redox factor 1 (Ref-1), which has a

reducing activity and apurine/apyrimidine

endonuclease repair activity. TRX was also reported to

bind conserved DNA binding domain of glucocorticoid

receptor under oxidative conditions to regulate nuclear

receptor-mediated signal transduction. More well-

known binding partner of TRX is thioredoxin binding

protein-2 (TBP-2/TXNIP/VDUP-1). TBP-2 can

downregulate the expression and the reducing activity

of TRX.

TBP-2 shows potent growth suppressive effect and

until recently it was reported to be a metabolic

mediator of lipid and glucose metabolisms. All these

findings suggest that TRX/TBP-2 binding may regulate

redox and metabolic responses in vivo.

Homology

Thioredoxin is ubiquitously expressed in different

organisms. Chicken, mouse, rat and bovine TRXs have

also been cloned. Human and other mammalian TRXs

contain, in addition to the two cysteins in Trp-Cys32-

Gly-Pro-Cys35-Lys, three other Cys redidues, Cys62,

Cys69, and Cys73 (numbers are based on human TRX),

which are not found in TRX of bacterial origins. The

C-terminal Cys73 residue of mammalian TRX is shown

to be involved in dimmer formation.

Proteins sharing the similar active sites Cys-Xxx-Yyy-

Cys, are called as members of TRX superfamily. TRX-

2 is one homologous protein of TRX, which also

contains Cys-Gly-Pro-Cys active site. However, TRX-2

is located in mitochondrial with extra N-terminal

mitochondrial translocation signal peptide. TRX2 may

play an important role in the mitochondria-mediated

apotosis. Other TRX superfamilly proteins consist of

MIF (macrophage migration inhibitory factor), PDI

(protein disulfide isomerase), TMX, glutaredoxin,

nucleoredoxin, etc... These proteins have different

redox-relative functions in respective cellular

compartment.

Implicated in

Various cancers

Note

Elevated expression of thioredoxin was reported in

various human cancers, including hepatocellular

carcinoma, pancreatic, lung, cervical, gastric, colorectal

cancer, adult T cell leukemia, myeloma, non-Hodgkin

lymphoma, and acute lymphocytic leukemia. The

overexpression of TRX in cancer cells seems to be

associated with the growth promotion of cancer cells, a

worse prognosis for patients, and the development of

resistance to anti-cancer agents.

However, there is no evidence showing that

exogenously administered rhTRX promotes the growth

of cancer, although exogenous rhTRX may alleviate

local or systemic inflammatory disorders in these

cancer patients.

Prognosis

In non-small cell lung carcinomas, intracellular TRX

expression is indicative of a more aggressive tumor

phenotype and worse prognosis.

Oncogenesis

Unknown.

Adult T cell leukemia (ATL), acquired immunodeficiency syndrome (AIDS), hepatitis C virus (HCV), originated from virus infection

Note

As mentioned above, human thioredoxin was first

cloned as a secreted adult T cell leukemia (ATL)

derived factor. Its expression is markedly enhanced in

HTLV-I-infected T cells.

The elevated level of plasma thioredoxin was reported

in AIDS patients with worse prognosis and inversely

correlated with intracellular glutathion level.

In hepatitis C virus infection, serum levels of TRX is

also elevated. The serum TRX levels of patients with

HCV infection increased with their serum ferritin levels

and the progression of liver fibrosis. Furthermore,

serum thioredoxin and ferritin are good markers for the

efficacy of interferon therapy.

Prognosis

As above, the plasma or serum level of thioredoxin is a

good marker for oxidative stress associated with virus

infection, so as to be possibily used in clinics.

Oncogenesis

Unknown.

References LAURENT TC, MOORE EC, REICHARD P. ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEOTIDES. IV. ISOLATION AND CHARACTERIZATION OF THIOREDOXIN, THE HYDROGEN DONOR FROM ESCHERICHIA COLI B. J Biol Chem. 1964 Oct;239:3436-44

Teshigawara K, Maeda M, Nishino K, Nikaido T, Uchiyama T, Tsudo M, Wano Y, Yodoi J. Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression. J Mol Cell Immunol. 1985;2(1):17-26

Wollman EE, d'Auriol L, Rimsky L, Shaw A, Jacquot JP, Wingfield P, Graber P, Dessarps F, Robin P, Galibert F. Cloning and expression of a cDNA for human thioredoxin. J Biol Chem. 1988 Oct 25;263(30):15506-12



Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem. 1989 Aug 25;264(24):13963-6

Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, Brown N, Arai K, Yokota T, Wakasugi H. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989 Mar;8(3):757-64

Wakasugi N, Tagaya Y, Wakasugi H, Mitsui A, Maeda M, Yodoi J, Tursz T. Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8282-6

Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT. Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res. 1992 Aug 11;20(15):3821-30

Rubartelli A, Bajetto A, Allavena G, Wollman E, Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem. 1992 Dec 5;267(34):24161-4

Chen KS, DeLuca HF. Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta. 1994 Sep 13;1219(1):26-32

Gasdaska PY, Oblong JE, Cotgreave IA, Powis G. The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors. Biochim Biophys Acta. 1994 Aug 2;1218(3):292-6

Kaghad M, Dessarps F, Jacquemin-Sablon H, Caput D, Fradelizi D, Wollman EE. Genomic cloning of human thioredoxin-encoding gene: mapping of the transcription start point and analysis of the promoter. Gene. 1994 Mar 25;140(2):273-8

Kitaoka Y, Sorachi K, Nakamura H, Masutani H, Mitsui A, Kobayashi F, Mori T, Yodoi J. Detection of adult T-cell leukemia-derived factor/human thioredoxin in human serum. Immunol Lett. 1994 Jul;41(2-3):155-61

Holmgren A, Björnstedt M. Thioredoxin and thioredoxin reductase. Methods Enzymol. 1995;252:199-208

Schenk H, Vogt M, Dröge W, Schulze-Osthoff K. Thioredoxin as a potent costimulus of cytokine expression. J Immunol. 1996 Jan 15;156(2):765-71

Taniguchi Y, Taniguchi-Ueda Y, Mori K, Yodoi J. A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene. Nucleic Acids Res. 1996 Jul 15;24(14):2746-52

Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8

Kurooka H, Kato K, Minoguchi S, Takahashi Y, Ikeda J, Habu S, Osawa N, Buchberg AM, Moriwaki K, Shisa H, Honjo T. Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin. Genomics. 1997 Feb 1;39(3):331-9

Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol. 1997;15:351-69

Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998 May 1;17(9):2596-606

Hirota K, Murata M, Sachi Y, Nakamura H, Takeuchi J, Mori K, Yodoi J. Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB. J Biol Chem. 1999 Sep 24;274(39):27891-7

Kleemann R, Kapurniotu A, Mischke R, Held J, Bernhagen J. Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81Ser MIF. Eur J Biochem. 1999 May;261(3):753-66

Makino Y, Yoshikawa N, Okamoto K, Hirota K, Yodoi J, Makino I, Tanaka H. Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. J Biol Chem. 1999 Jan 29;274(5):3182-8

Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem. 1999 Jul 30;274(31):21645-50

Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, Spitz DR, Goswami PC, Yodoi J, Gius D. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res. 2000 Dec 1;60(23):6688-95

Berggren MM, Powis G. Alternative splicing is associated with decreased expression of the redox proto-oncogene thioredoxin-1 in human cancers. Arch Biochem Biophys. 2001 May 1;389(1):144-9

Kakolyris S, Giatromanolaki A, Koukourakis M, Powis G, Souglakos J, Sivridis E, Georgoulias V, Gatter KC, Harris AL. Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 2001 Oct;7(10):3087-91

Sun QA, Kirnarsky L, Sherman S, Gladyshev VN. Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3673-8

Hirota K, Nakamura H, Masutani H, Yodoi J. Thioredoxin superfamily and thioredoxin-inducing agents. Ann N Y Acad Sci. 2002 May;957:189-99

Bai J, Nakamura H, Kwon YW, Hattori I, Yamaguchi Y, Kim YC, Kondo N, Oka S, Ueda S, Masutani H, Yodoi J. Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells. J Neurosci. 2003 Jan 15;23(2):503-9

Bloomfield KL, Osborne SA, Kennedy DD, Clarke FM,

Tonissen KF. Thioredoxin-mediated redox control of the transcription factor Sp1 and regulation of the thioredoxin gene promoter. Gene. 2003 Nov 13;319:107-16

Hosoda A, Kimata Y, Tsuru A, Kohno K. JPDI, a novel endoplasmic reticulum-resident protein containing both a BiP-interacting J-domain and thioredoxin-like motifs. J Biol Chem. 2003 Jan 24;278(4):2669-76

Kim YC, Yamaguchi Y, Kondo N, Masutani H, Yodoi J. Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response. Oncogene. 2003 Mar 27;22(12):1860-5



Matthias LJ, Hogg PJ. Redox control on the cell surface: implications for HIV-1 entry. Antioxid Redox Signal. 2003 Feb;5(1):133-8

Sadek CM, Jiménez A, Damdimopoulos AE, Kieselbach T, Nord M, Gustafsson JA, Spyrou G, Davis EC, Oko R, van der Hoorn FA, Miranda-Vizuete A. Characterization of human thioredoxin-like 2. A novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme. J Biol Chem. 2003 Apr 11;278(15):13133-42

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Haugstetter J, Blicher T, Ellgaard L. Identification and characterization of a novel thioredoxin-related transmembrane protein of the endoplasmic reticulum. J Biol Chem. 2005 Mar 4;280(9):8371-80

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Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ, Jensen CB, Krook A, Björnholm M, Tornqvist H, Zierath JR, Ridderstråle M, Altshuler D, Lee RT, Vaag A, Groop LC, Mootha VK. TXNIP regulates peripheral glucose metabolism in humans. PLoS Med. 2007 May;4(5):e158

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Chen Z, Yoshihara E, Nakamura H, Masutani H, Yodoi J. TXN (thioredoxin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):790-794.

Leukaemia Section Short Communication




t(1;12)(q21;q24) Sang-Guk Lee, Tae Sung Park, Jong Rak Choi

Department of Laboratory Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-

gu, Seoul 120-752, Korea (SGL); Department of Laboratory Medicine, Kyung Hee University College of

Medicine, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea (TSP); Department of Laboratory

Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea

(JRC)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112q21q24ID1531.html DOI: 10.4267/2042/45124

This article is an update of : Huret JL. t(1;12)(q21;q24). Atlas Genet Cytogenet Oncol Haematol 2009;13(11):880. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Clinics and pathology

Disease

Acute myeloid leukaemia (AML), myelodysplastic

syndrome (MDS)

Epidemiology

Only 3 cases to date, a 24-year-old female patient with

a M2-AML, a patient with a treatment related AML (t-

AML), and a 48-year-old patient with MDS (Koo et al.,

1998; Olney et al., 2002; Park et al., 2009). Although it

is a rare chromosomal abnormality, it may be an

aberration related to myeloid neoplasms including

AML and MDS.

Prognosis

No detailed data available. However, one of them (Park

et al., 2009) received bone marrow transplantation;

complete donor chimerism was maintained for thirteen

months until last follow up.

t(1;12)(q21;q24) Lee SG, et al.


Cytogenetics

Cytogenetics morphological

It shows balanced chromosomal translocation between

1q21 and 12q24.

Additional anomalies

The patient with a M2-AML also had an i(17q).

The patient with a MDS had +8, +der(12)t(1;12)

additionally.

Genes involved and proteins

Note

The genes involved in this anomaly are unknown.

References Koo SH, Kwon GC, Chun HJ, Park JW. Cytogenetic and fluorescence in situ hybridization analyses of hematologic

malignancies in Korea. Cancer Genet Cytogenet. 1998 Feb;101(1):1-6

Olney HJ, Mitelman F, Johansson B, Mrózek K, Berger R, Rowley JD. Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):413-23

Park TS, Lee SG, Song J, Kim JS, Choi JR. A novel t(1;12)(q21;q24) in a patient with myelodysplastic syndrome. Ann Hematol. 2010 May;89(5):513-6


Lee SG, Park TS, Choi JR. t(1;12)(q21;q24). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):795-796.

Leukaemia Section Mini Review




t(1;14)(q21;q32), t(1;22)(q21;q11) Jean-Loup Huret

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

(JLH)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1548.html DOI: 10.4267/2042/44833



Disease

Non Hodgkin lymphoma and acute lymphoblastic

lymphoma.

Phenotype/cell stem origin

23 cases to date: follicular lymphomas (FL, n=9),

diffuse large B-cell lymphomas (DLBCL, n=5),

marginal zone lymphoma (n=1), other B-cell non

Hodgkin lymphomas, not otherwise specified (NHL

NOS, n=4), pre-B acute lymphoblastic leukaemia (B-

ALL, n=1), B-cell clonal hyperplasia without any sign

of malignant transformation (n=1), and a myeloma cell

line (Koduru et al., 1987; Oscier et al., 1996; Pinkerton

et al., 1992; Willis et al., 1998; Callanan et al., 2000;

Dyomin et al., 2000; Gilles et al., 2000; Chen et al.,

2001; Hatzivassiliou et al., 2001; Le Baccon et al.,

2001; Mohamed et al., 2001; Sato et al., 2001; Bosga-

Bouwer et al., 2003; Sonoki et al., 2004; Keller et al.,

2006; Johnson et al., 2009).

Also a case of T-cell angioimmunoblastic lymphoma

was described with this translocation, but it is likely

that IgH was not involved in the cancer process in the

latter case (Kanda-Akano et al., 2004).

Epidemiology

There were 9 male and 5 female patients. Median age

was 56-57 years (range 30-81 years, data from 14

patients).

Prognosis

Insufficient data.

Cytogenetics


The t(1;14)(q21;q32) was found in 12 of 23 cases, and

the t(1;22)(q21;q11) was found in 11 of 23 cases, a

much higher percentage than for the variant

translocations of the t(8;14)(q24;q32), or those of the

t(14;18)(q32;q21). No case with t(1;2)(q21;p11) has so

far been described.

Surprisingly also was that out of 11 well documented

cases of t(1;14), there was no one case with a t(14;18),

whereas out 8 well documented cases of t(1;22), 100%

of the cases also had a t(14;18).


Out of 16 cases with complete data on the karyotype,

the translocation was found as the sole anomaly in 2

cases, and complex karyotypes were found in 13 cases.

Accompanying anomalies were the following there was

a t(14;18)(q32;q21) in 8 cases, only found in FL or in

"NHL-NOS" cases, +7 in 5 cases, the rare

t(8;9)(q24;p13) was found in 3 instances, +18 in 3

cases, +X, +12, +18, a 3q27 rearrangement, a del(6q), a

del(7q), and/or a del(13q) in 2 cases each, +3, +8, +9,

+17, a t(2;12)(p11;p13), a t(8;14)(q24;q32), a

t(18;22)(q21;q11), and/or an i(6p) in one case each.


Note

In 14q32 sits IgH, and IgL in 22q11.

The translocation t(1;14 or 22)(q21;q32 or q11) is

heterogeneous, since different cases have shown

different genes in 1q21 deregulated by the

translocation:

t(1;14)(q21;q32), t(1;22)(q21;q11) Huret JL


- BCL9 (Willis et al., 1998). BCL9 binds to CTNNB1

(beta-catenin) and is required for Wnt signal

transduction (Kramps et al., 2002). BCL9 starts at

145479806 and ends at 145564639 bp from pter.

- MUC1 (Dyomin et al., 2000; the same case was

independantly reported in Gilles et al., 2000). MUC1 is

a membrane bound mucin expressed on the surface of

epithelial cells to in protect epithelia (Carson, 2008).

MUC1 starts at 153424924 and ends at 153429324 bp

from pter.

- FCRL4 and/or FCRL5 (Hatzivassiliou et al., 2001;

Sonoki et al., 2004). FCRL4 is a cell surface receptor

related to the Fc receptor, inhibitory receptor

superfamily, and cell adhesion molecule (CAM)

families (Falini et al., 2003). FCRL4 starts at

155810163 and ends at 155834494 bp from pter.

- FCGR2B (Callanan et al., 2000; Chen et al., 2001).

FCGR2B is a Low affinity IgG Fc receptor (Callanan

and Leroux, 2002). FCGR2B starts at 159899564 and

ends at 159914575 bp from pter.

As a matter of fact, these translocations span 1q21 to

1q23. Also, many other genes of interest are in the area

delimited by BCL9 and FCGR2B (see

http://atlasgeneticsoncology.org/Indexbychrom/idxa_1.

html "Ordered by Location").

From the very short sample of cases for each partner

gene, it is impossible to delineate different entities with

different epidemiologies and prognoses. They are

therefore needed, for clinical goals.

Result of the chromosomal anomaly

Fusion protein

Oncogenesis

No fusion protein, but promoter exchange; the

immunoglobulin gene enhancer stimulates the

expression of the partner gene.

References Koduru PR, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RS. Cytogenetic and histologic correlations in malignant lymphoma. Blood. 1987 Jan;69(1):97-102

Pinkerton PH, Reis MD, DeCoteau J, Srigley JR, Dubé ID, London B. A lineage-specific t(1;14)(q21;q32) as an early event in development of B-cell clonal expansion. Cancer Genet Cytogenet. 1992 Dec;64(2):166-9

Oscier DG, Gardiner A, Mould S. Structural abnormalities of chromosome 7q in chronic lymphoproliferative disorders. Cancer Genet Cytogenet. 1996 Nov;92(1):24-7

Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, Bastard C, Treleaven JG, Catovsky D, Silva ML, Dyer MJ. Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21. Blood. 1998 Mar 15;91(6):1873-81

Callanan MB, Le Baccon P, Mossuz P, Duley S, Bastard C, Hamoudi R, Dyer MJ, Klobeck G, Rimokh R, Sotto JJ, Leroux

D. The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):309-14

Dyomin VG, Palanisamy N, Lloyd KO, Dyomina K, Jhanwar SC, Houldsworth J, Chaganti RS. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood. 2000 Apr 15;95(8):2666-71

Gilles F, Goy A, Remache Y, Shue P, Zelenetz AD. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood. 2000 May 1;95(9):2930-6

Chen W, Palanisamy N, Schmidt H, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Houldsworth J, Chaganti RS. Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. Oncogene. 2001 Nov 15;20(52):7686-93

Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity. 2001 Mar;14(3):277-89

Le Baccon P, Leroux D, Dascalescu C, Duley S, Marais D, Esmenjaud E, Sotto JJ, Callanan M. Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma. Genes Chromosomes Cancer. 2001 Nov;32(3):250-64

Mohamed AN, Palutke M, Eisenberg L, Al-Katib A. Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant. Cancer Genet Cytogenet. 2001 Apr 1;126(1):45-51

Sato Y, Kobayashi H, Suto Y, Olney HJ, Davis EM, Super HG, Espinosa R 3rd, Le Beau MM, Rowley JD. Chromosomal instability in chromosome band 12p13: multiple breaks leading to complex rearrangements including cytogenetically undetectable sub-clones. Leukemia. 2001 Aug;15(8):1193-202

Callanan M, Leroux D.. FCGR2B. Atlas Genet Cytogenet Oncol Haematol. February 2002. URL: http://AtlasGeneticsOncology.org/Genes/FCGR2BID397.html

Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Züllig S, Basler K. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell. 2002 Apr 5;109(1):47-60

Bosga-Bouwer AG, van Imhoff GW, Boonstra R, van der Veen A, Haralambieva E, van den Berg A, de Jong B, Krause V, Palmer MC, Coupland R, Kluin PM, van den Berg E, Poppema S. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive. Blood. 2003 Feb 1;101(3):1149-54

Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, Cattoretti G. Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT). Blood. 2003 Nov 15;102(10):3684-92

Kanda-Akano Y, Nomura K, Fujita Y, Horiike S, Nishida K, Nagai M, Miura I, Nakamura S, Seto M, Iida S, Ueda R, Taniwaki M. Molecular-cytogenetic characterization of non-Hodgkin's lymphoma with double and cryptic translocations of the immunoglobulin heavy chain gene. Leuk Lymphoma. 2004 Aug;45(8):1559-67

t(1;14)(q21;q32), t(1;22)(q21;q11) Huret JL


Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, Dyer MJ. Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR. Leukemia. 2004 Dec;18(12):2026-31

Keller CE, Nandula S, Vakiani E, Alobeid B, Murty VV, Bhagat G. Intrachromosomal rearrangement of chromosome 3q27: an under recognized mechanism of BCL6 translocation in B-cell non-Hodgkin lymphoma. Hum Pathol. 2006 Aug;37(8):1093-9

Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signal. 2008 Jul 8;1(27):pe35

Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, Dyer MJ, Siebert R, Kuruvilla J, Klasa R, Connors JM, Gascoyne RD, Horsman DE. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009 Sep 10;114(11):2273-9


Huret JL. t(1;14)(q21;q32), t(1;22)(q21;q11). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):797-799.

Leukaemia Section Mini Review




dic(9;20)(p11-13;q11) Jon C Strefford

Cancer Genomics Group, Cancer Sciences Division, University of Southampton, UK (JCS)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic920ID1143.html DOI: 10.4267/2042/44834

This article is an update of : Gibbons B. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet Oncol Haematol 1999;3(3):144 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology


Disease

Acute lymphoblastic leukaemia (ALL)

Phenotype/cell stem origin

B-cell precursor acute lymphoblastic leukemia (BCP-

ALL).

Prognosis

On a limited series, the median patient age is 3 years,

the female/male ratio of 2.0 has been reported. Risk

group stratification was nonstandard risk in 79%. The

event-free survival and overall survival at 5 years for

the 24 Nordic cases was 0.62 and 0.82, respectively.

Thus, although relapses are quite common, post-relapse

treatment of many patients is successful.

Cytogenetics


Chromosomes 7, 9, 12 and 20 are frequently involved

in the formation of dicentric chromosomes in BCP-

ALL. The dic(9;20)(p11~13;q11) occurs in approx 2%

and approx 0.5% of childhood and adult BCP-ALL,

respectively. FISH has shown that dic(9;20) contains

the centromere of both chromosomes, resulting in loss

of 9p and 20q material. It is a subtle chromosome

abnormality, often appearing as monosomy 20,

sometimes with apparent deletion of 9p; confirmation

of the dic(9;20) translocation is obtained by FISH

(Figure 1).

Cytogenetics molecular

Even at the cytogenetic level, considerable breakpoint

heterogeneity is apparent on both chromosomes. Array-

based comparative genomic hybridization (aCGH),

with BAC clones at tiling resolution, has shown

clustering of breakpoints within 9p13.2 (genomic

position 37.1-38.7 Mb) and 20q11.2 (29.2-30.8 Mb).

Recent FISH mapping data has confirmed this

heterogeneity in a large series of dic(9;20) patients

(Figure 2).


The dic(9;20) can occur as a sole cytogenetic

abnormality, or in the context of a more complex

karyotype. Gains of chromosome X and 21 are the most

frequency additional findings in these patients.

Diagnostic FISH data shows that the dic(9;20) can

occur in the presence of the BCR-ABL1 and ETV6-

RUNX1 fusion genes.


PAX5

Location

9p13

DNA/RNA

The paired box 5 gene (PAX5) extends over 200 kb of

genomic DNA and contains 10 exons.

dic(9;20)(p11-13;q11) Strefford JC


Figure 1. Top: The left shows a G-banded karyogram of the dic(9;20). Monosomy 20 and the dicentric chromosome are highlighted with black arrows. The right shows a metaphase from the same patient using paints for chromosomes 9 (green) and 20 (red). The dicentric is shown by the white arrow - Courtesy Jon C Strefford; Bottom: M-FISH - Courtesy Melanie Zenger and Claudia Haferlach.

Protein

The gene encodes a transcription factor, with a highly

conserved DNA-binding domain, known as a paired

box. PAX5 is a 42 kDa protein of 391 amino acids that

encodes the B-cell lineage specific activator protein

that is expressed at early, but not late stages of B-cell

differentiation. The protein is expressed during B-cell

lineage commitment during early B-cell development

and maintenance.


Hybrid gene

Note

FISH analysis has shown that in spite of the breakpoint

heterogeneity, the PAX5 gene is targeted at high

frequencies, by a variety of genetic

mechanisms. Breakpoints proximal to PAX5 can be in

euchromatic or heterochromatic regions of the

chromosome and result in deletion of PAX5 in the

majority of cases. Less frequently, breakpoints can

occur within the PAX5 gene and result in aberrant

fusion sequences with regions of chromosome 20.

Breakpoint cloning experiments have shown PAX5

sequence juxtaposed to several genes on 20q including

ASXL1, C20ORF112 and KIF3B (Figure 3).

The genes involved in these fusion sequences are either

in opposing orientation, or in the same orientation and

out-of-frame, suggesting the biological consequence of

these fusion events in loss of function.

Quantitative PCR (qRT-PCR) has confirmed disruption

of PAX5 in the context of the dic(9;20), by showing

deregulated expression of PAX5 and several key

downstream PAX5 target genes, including, BLK, EBF1

and FLT3. In the case of PAX5-C20ORF112, it has

been shown that the C-terminal of the PAX5 protein is



replaced by that of the partner gene, which does not

change the affinity for the protein to bind to recognition

sites, but does effect the expression of certain

downstream PAX5 target genes. Furthermore,

transfected vectors encoding the PAX5-C20ORF112

are able to suppress the transcriptional activity of wild-

type PAX5, leading to the inhibition of B-cell

development. Sequence analysis and genomic

quantitative PCR have also shown that the PAX5 allele

not involved in the translocation can be targeted by

mutations and homozygous deletions.

Further sequence analysis of the dic(9;20) is beginning

to unravel the heterogeneity on chromosome 20, and

identify recurrent targets. It has been suggested that

C20ORF112 may be the recurrent target gene on

chromosome 20, but this has not been supported by

other studies. In addition to C20ORF112, FISH and

molecular investigations have implicated the recurrent

involvement of ASXL1.

Advances in recent years have expanded our

understanding of the dic(9;20), most notably with the

identification of PAX5 on 9p. However, there are

exceptionally rare cases where PAX5 is not deleted or

fused though mutations of deletions beyond the

resolution of FISH cannot be excluded. The key genes

on 20q remain to be fully elucidated.

Figure 2. Breakpoint heterogeneity on chromosome 9 and 20 in the dic(9;20). A partial idiogram for each of the chromosomes is shown on the left for chromosomes 9 and 20. Each black filled square shows the position of a FISH probe in relation to the gene of interest. Each column shows an individual patient with the position and extent of the deleted region represented by vertical red bar.



Figure 3. Schematic of PAX5 fusion sequences. The exons of the PAX5 and partner genes are shown in red and pink respectively. The gene orientation is shown by the horizontal arrow. Below each schematic is the corresponding predicted protein structure and domains.

References Rieder H, Schnittger S, Bodenstein H, Schwonzen M, Wörmann B, Berkovic D, Ludwig WD, Hoelzer D, Fonatsch C. dic(9;20): a new recurrent chromosome abnormality in adult acute lymphoblastic leukemia. Genes Chromosomes Cancer. 1995 May;13(1):54-61

Slater R, Smit E, Kroes W, Bellomo MJ, Mühlematter D, Harbott J, Behrendt H, Hählen K, Veerman AJ, Hagemeijer A. A non-random chromosome abnormality found in precursor-B lineage acute lymphoblastic leukaemia: dic(9;20)(p1?3;q11). Leukemia. 1995 Oct;9(10):1613-9

Heerema NA, Maben KD, Bernstein J, Breitfeld PP, Neiman RS, Vance GH. Dicentric (9;20)(p11;q11) identified by fluorescence in situ hybridization in four pediatric acute lymphoblastic leukemia patients. Cancer Genet Cytogenet. 1996 Dec;92(2):111-5

Clark R, Byatt SA, Bennett CF, Brama M, Martineau M, Moorman AV, Roberts K, Secker-Walker LM, Richards S, Eden OB, Goldstone AH, Harrison CJ. Monosomy 20 as a pointer to dicentric (9;20) in acute lymphoblastic leukemia. Leukemia. 2000 Feb;14(2):241-6

An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4

Forestier E, Gauffin F, Andersen MK, Autio K, Borgström G, et al. Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature. Genes Chromosomes Cancer. 2008 Feb;47(2):149-58

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

An Q, Wright SL, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Harrison CJ, Strefford JC. Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21. Haematologica. 2009 Aug;94(8):1164-9

Strefford JC, An Q, Harrison CJ. Modeling the molecular consequences of unbalanced translocations in cancer: lessons from acute lymphoblastic leukemia. Cell Cycle. 2009 Jul 15;8(14):2175-84


Strefford JC. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):800-803.

Solid Tumour Section Mini Review




Ovary: inv(10)(q11q11) in ovarian germ cell tumors Douglas S Richardson, Lois M Mulligan

Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer

Research Institute, Queen's University, Kingston, ON, Canada (DSR, LMM)


Online updated version : http://AtlasGeneticsOncology.org/Tumors/inv10q11q11OvaryGermID5465.html DOI: 10.4267/2042/44835


Identity

Note

Ovarian germ cell (OGC) tumours arise in the primitive

germ cells of the ovary and primarily affect younger

women. Struma ovarii are the most common

monodermal teratomas arising from OGCs. Struma

Ovarii are characterized by a composition of at least

50% mature thyroid tissue. Two reports have shown

that oncogenic mutations characteristic of thyroid

carcinoma in situ, most notably mutations found in

thyroid follicular cells that give rise to papillary thyroid

carcinoma (PTC), can be found within the thyroid

tissue of Struma Ovarii. These mutations can promote

oncogenesis, resulting in initiation of PTC within the

teratoma.


Disease

Papillary thyroid carcinoma arising in struma ovarii.

Phenotype / cell stem origin

Struma ovarii originate from ovarian germ cells.

Malignant transformation of these monodermal

teratomas primarily occurs in follicular-like cells of the

thyroid tissue contained within struma ovarii,

producing a tumour that resembles papillary thyroid

carcinoma.

Treatment

Surgical resection of tumour, 131

I radioablation therapy.

Cytogenetics

Cytogenetics Molecular

inv(10)(q11q11)


Note

The inv(10)(q11q11) fuses the promoter and 5' coding

regions of NCOA4 to the 3' kinase domain coding

region of RET.

RET

Location

10q11.21

Protein

RET encodes a 175 kDa transmembrane receptor

tyrosine kinase that is required for development of the

kidney and enteric nervous system. Three isoforms of

RET have been identified that arise through 3'

alternative splicing involving exons 19, 20 and 21, and

encode proteins of 1072, 1106, and 1114 amino acids.

NCOA4

Location

10q11.23

Protein

NCOA4 is a 70 kDa co-activator protein that serves to

enhance transcriptional activity downstream of the

androgen receptor, other steroid receptors, and

peroxisome proliferator-activated receptor gamma.

Diagrammatic representation of RET and NCOA4 exon locations on Chromosome 10. Introns and exons are to scale within respective genes. Breakpoints within each gene are indicated (BP).

Ovary: inv(10)(q11q11) in ovarian germ cell tumors Richardson DS, Mulligan LM


Diagrammatic representation of RET/NCOA4 (PTC3) fusion protein. Amino acids surrounding each breakpoint (arrows) are indicated, and numbered according to their position within RET or NCOA4, respectively. Peptide sequences from RET are in red, from NCOA4 in green. The transmembrane domain (TM) of RET is shown in yellow. IC - intracellular domain.


Hybrid Gene

The RET/NCOA4 fusion gene is also referred to as

PTC3.

Description

The inv(10)(q11q11) results in fusion of exons 1-6 of

NCOA4 with exon 12-through to the C-terminus of

RET.

Detection

RT-PCR, Southern blot, and FISH (see Zu et al., 2006

for detailed methods).

Fusion Protein

The RET/NCOA4 fusion protein is also referred to as

PTC3. Chimeric protein consisting of the tyrosine

kinase domain of RET fused downstream of the

homodimerization domain of NCOA4. Constitutive

dimerization of fusion proteins results in continuous

downstream signalling through canonical cell growth

and proliferation pathways, promoting oncogenesis.

Description

Fusion protein consists of amino acids 1-238 of

NCOA4 and 712-C-terminus of RET. The N-terminal

region donated by NCOA4 contains a

homodimerization domain that results in constitutive

dimerization and activation of the RET kinase domain

in the C-terminal region of the molecule. Constitutive

activation increases signalling through a number of

downstream signalling pathways involved in cell

proliferation and survival, promoting oncogenesis.

Expression / Localisation

Cytoplasm.

Oncogenesis

RET/NCOA4 fusion proteins have been implicated

in the oncogenesis of papillary thyroid carcinoma.

To be noted Although RET/NCOA4 fusion proteins are known to

play a role in initiating papillary thyroid carcinoma,

they can also occur as a late mutational event. As with

all tumours, care must be taken in attributing

oncogenesis to a single genetic event.

References Santoro M, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 1994 Feb;9(2):509-16

Makani S, Kim W, Gaba AR. Struma Ovarii with a focus of papillary thyroid cancer: a case report and review of the literature. Gynecol Oncol. 2004 Sep;94(3):835-9

Elisei R, Romei C, Castagna MG, Lisi S, Vivaldi A, Faviana P, Marinò M, Ceccarelli C, Pacini F, Pinchera A. RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration. Thyroid. 2005 Dec;15(12):1355-61

Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J Clin Endocrinol Metab. 2006 Sep;91(9):3603-10

Boutross-Tadross O, Saleh R, Asa SL. Follicular variant papillary thyroid carcinoma arising in struma ovarii. Endocr Pathol. 2007 Fall;18(3):182-6

Yassa L, Sadow P, Marqusee E. Malignant struma ovarii. Nat Clin Pract Endocrinol Metab. 2008 Aug;4(8):469-72

Richardson DS, Gujral TS, Peng S, Asa SL, Mulligan LM. Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins. Cancer Res. 2009 Jun 1;69(11):4861-9


Richardson DS, Mulligan LM. Ovary: inv(10)(q11q11) in ovarian germ cell tumors. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):804-805.

Case Report Section Paper co-edited with the European LeukemiaNet




Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Elvira D Rodrigues Pereira Velloso, Carolina Kassab, Silvia Helena A Figueira, Denise Tiemi

Noguchi, Eliana Carla Armelin Benites, Cristóvão L P Mangueira, Fábio Morato de Oliveira

Clinical Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (EDRPV, CK, SHAF, CLPM);

Instituto de Clinicas Pediatricas Bolivar Risso - GRENDACC, Sao Paulo, Brazil (DTN, ECAB);

Cytogenetics and Onco-Hematology, FMRP USP, Brazil (FMDO)


Online updated version : http://AtlasGeneticsOncology.org/Reports/dic0709RodriguesID100043.html DOI: 10.4267/2042/44836


Clinics

Age and sex

13 years old female patient.

Previous history

No preleukemia. No previous malignancy. No inborn

condition of note.

Organomegaly

Hepatomegaly, splenomegaly, enlarged lymph nodes,

no central nervous system involvement.

Blood

WBC: 28.5X 109/l

HB: 6.6g/dl

Platelets: 110X 109/l

Blasts: 64%

Bone marrow: 72.4% of lymphoid blast cells.

Cyto-Pathology Classification

Cytology

ALL-L1

Immunophenotype

Blast cells positivity for: CD 34, HLA, CD10, CD19,

CD22 and cCD79a.

Rearranged Ig Tcr

Not done.

Pathology

Not done.

Electron microscopy

Not done.

Diagnosis

Common B (B-II) ALL at diagnosis.

Survival

Date of diagnosis: 02-2009

Treatment: Chemotherapy with BFM95 for

intermediate risk.

Complete remission: remission was obtained after the

first induction cycle.

Treatment related death: no

Relapse: no

Status: Alive. Last follow up: 04-2009

Survival: 1 month

Karyotype

Sample: Bone marrow

Culture time: 24h and 48 h without stimulating agents

Banding: GAW- band

Results:

45,XX,-7,+mar[11]/45,XX,dic(7;9)(p11;p11)[9]

/46,XX[4]

Karyotype at Relapse: not applied.

Other molecular cytogenetics technics:

Spectral Karyotyping (SKY) using SkyPaint ASR

(Applied Spectral Imaging). The marker seen in the

first clone was elucidated as a derivative chromosome 9

Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Rodrigues Pereira Velloso ED, et al.


(figure 3). The study confirm the der(7;9) seen in the

second clone (figure 4).

Other Molecular Studies

Technics: Not done.

Figure 1: G-banding karyotype showing the first clone with monosomy 7 and one marker (recognized as a der(9) after sky study).

Figure 2: Partial G- banding karyotypes showing the second clone with dic(7;9)(p11;p11).

Figure 3: Sky study showing the first clone with monosomy 7 and a der(9).

Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Rodrigues Pereira Velloso ED, et al.


Figure 4: Sky study showing the second clone with dic(7;9)(p11;p11).

Comments

The case presented here is, to our knowledge, the 19th

reported case of dic (7;9)(p11;p11) in acute

lymphoblastic leukemia. From the literature review, 10

patients were less than 15 years old, seven with FAB

L1 morphology, like our patient. She presented a

enlarged liver and spleen, as ten and six of the cases

reported in the studies, but without hyperleukocytosis,

which was common for ALL patients with

simultaneous dic(7;9) and t(9;22), present in 9 of 18

cases.

The prognostic significance of this abnormality remains

controversial. Russo et al. suggested that the deletion of

tumor suppressor genes located on 7p is associated with

an adverse prognostic factor in ALL.

Heerema et al. related that abnormalities in

chromosome 9p are associated with increased relapse

in children with ALL, probably because the

inactivation of the tumor suppressor genes CDKN2 and

CDKN1, mapped to 9p21-22. In the series of Pan et al.

(2006), the prognosis of the patients with dic(7;9) and

t(9;22) is worse than that of those with isolated

dic(7;9).

From the 18 cases, 11 have no data of survival, 4

achieved long term remission and 3 died. Our children

remain in clinical remission 45 days after induction

therapy with intermediate risk BFM 95 (Berlin-

Frankfurt-Munster) protocol.

References Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood. 1991 May 1;77(9):2016-22

Russo C, Carroll A, Kohler S, Borowitz M, Amylon M, Homans A, Kedar A, Shuster J, Land V, Crist W. Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1991 Mar 1;77(5):1050-6

Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC, Nachman JB, Steinherz PG, Hutchinson R, Gaynon PS, Arthur DC, Uckun FM. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group. Blood. 1999 Sep 1;94(5):1537-44

Pan J, Xue Y, Wu Y, Wang Y, Shen J. Dicentric (7;9)(p11;p11) is a rare but recurrent abnormality in acute lymphoblastic leukemia: a study of 7 cases. Cancer Genet Cytogenet. 2006 Sep;169(2):159-63

Smith A, Das P, O'Reilly J, Patsouris C, Campbell LJ. Three adults with acute lymphoblastic leukemia and dic(7;9)(p11.2;p11). Cancer Genet Cytogenet. 2006 Apr 1;166(1):86-8


Rodrigues Pereira Velloso ED, Kassab C, Figueira SHA, Noguchi DT, Armelin Benites EC, Mangueira CLP, de Oliveira FM. Dicentric dic(7;9)(p11;p11): a new case in childhood ALL. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):806-808.



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