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ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2 (avian))

Identity

Other namesEts2
Ets-2
LOC114
ETS2IT1
HGNC (Hugo) ETS2
LocusID (NCBI) 2114
Location 21q22.2
Location_base_pair Starts at 40177231 and ends at 40196878 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Chr 12: 39099101 - 39118749 on the direct strand

DNA/RNA

 
  Exon-Intron structure of human ETS2.
Description Ets-2 is a functioning gene comprising 10 exons and spanning 19.6 kb of genomic DNA. It encodes three mRNA transcripts: 4.7 kb, 3.6 kb and 2.7 kb, respectively (Watson et al., 1988). This suggests the existence of three functionally distinct proteins, potentially translated from these transcripts.
Transcription Structural analysis of the Ets2 promoter has revealed the absence of TATA and CAAT boxes, thus allowing transcription initiation from multiple start sites (Papas et al., 1990a). The first Intron of Ets2 also contains transcriptional initiation sequences, facilitating transcription. These sequences may compensate for the absence of TATA and CAAT sites within the promoter (Begue et al., 1997). The three RNA transcripts are thought to arise from alternative splicing by a number of different promoter polyadenylation signals (Watson et al., 1990). All Ets genes, including Ets2, are characterised by a region of conserved sequence known as the Ets domain (GGAA/T). This comprises an 85 amino acid region which forms the winged helix-turn-helix DNA binding domain (Watson et al., 1990).

Protein

 
  Schematic representation of the Ets2 protein. The pointed domain, the transactivation domain and the Ets DNA binding domain are all shown.
Description 1-469 amino acids
Pointed domain: 87-170 amino acids
DNA binding domain: 363-443 amino acids.
The Ets2 protein consists of 469 amino acids, a pointed domain, a transactivation domain and the Ets DNA binding domain (Watson et al., 1988). The protein is thought to exist in two forms: a 52 kDa, thought to be the full length protein (Watson et al., 1988) and a 54 kDa protein, believed to be a phosphorylated protein (Ma et al.,1996). The Ets2 protein is phosphorylated by Ca2+- dependent mitogenic signaling (Fisher et al., 1989; Fujiwara et al., 1990).
Expression Ets2 has previously been shown to play a role in cell proliferation and differentiation (Kilpatrick et al., 1999). Early studies demonstrated that overexpression of Ets2 results in cellular transformation and proliferation in vitro (Seth et al.,1989). Furthermore, transfection of non-tumourigenic cell lines with Ets2 results in increased cell adhesion and enhanced invasiveness. Increased Ets2 expression has been observed in breast (Buggy et al., 2006; Galang et al., 2004), prostate (Foos et al., 2000; Turner et al., 2007b), esophageal (Li et al., 2003) and hepatocellular (Liao et al., 1996) carcinomas.
Localisation The Ets2 protein is located in the nucleus.
Function Ets-2 has a number of important functions defined in mammalian systems. Ets genes are thought to act as positive or negative regulators of gene expression involved in various biological processes (Papas et al., 1989; Sapi et al., 1998). Ets-2 is thought to be involved in the regulation of cell proliferation and differentiation in certain cell types (Kilpatrick et al., 1999). In T-cells, Ets-2 expression is induced upon mitogenic stimulation (Bhat et al., 1987). It has been demonstrated that Ets-2 overexpression in myeloid progenitor cells stimulates the development of mature macrophages (Aperlo et al., 1996). Yamamoto et al., showed that deleting the Ets-2 gene in mice resulted in growth retardation and often embryonic death (Yamamoto et al.,1998). This may be due to a disruption in the transcriptional regulation of the epidermal growth factor and transforming growth factor-BETA.
Ets-2 expression has long been associated with Down's Syndrome. In 1990, Papas et al., identified and mapped two members of the Ets family of transcription factors - Ets-2 and Erg to the portion of chromosome 21 believed to be involved in Down's Syndrome (Papas et al., 1990 b). The Ets-2 gene is found in three copies in partial trisomies associated with the syndrome phenotype (Sacchi et al., 1988).
In the liver, Ets-2 expression has been associated with hepatic cell regeneration and also with the development of hepatocellular carcinoma (Bhat et al., 1996; Liao et al., 1996). Ets-2 expression has also been found in 30 % of rheumatoid arthritis patients (Sun et al., 2001). Ets-2 expression was reported in the synovial cells, suggesting an intrinsic activation mechanism of this immediate early gene in the disease process (Dooley et al., 1996).
A distinct role for Ets-2 in malignant transformation has been established. Seth et al., demonstrated that Ets-2 expression in NIH3T3 cells stimulates growth in the absence of serum growth factors (Seth et al., 1989). This group also showed that cell lines producing high levels of Ets-2 were capable of proliferating in the absence of serum. The Ets-2 transformed cells also exhibited anchorage-independent cell growth in agar suspension and tumourigenesis in nude mice. This study provides the first evidence of the transforming ability and mitogenic activity of Ets-2. Similar findings have been obtained by Sapi et al., using BT20 breast carcinoma cells (Sapi et al., 1998). Using these cells, colony formation was abolished following transfection with a dominant negative construct of Ets-2. Induction of Ets-2 has also been shown to be necessary for thyroid cell transformation (Sapi et al., 1998).

Implicated in

Entity Human malignancies
Note A growing number of human malignancies have been associated with Ets2 overexpression. Early studies have demonstrated overexpression of Ets2 results in cellular transformation (Seth et al., 1989). Ets2 has been shown to act as both a negative and positive regulator of gene expression in biological processes, including metastasis, angiogenesis, tissue remodeling and apoptosis (Papas et al., 1990a).
  
Entity Breast Cancer
Disease Deregulation of Ets2 has been shown in human breast cancer (Turner et al., 2007a). Buggy et al., showed that both Ets2 mRNA and protein are overexpressed in human breast cancer compared with normal breast tissue (Buggy et al., 2006). Multiple studies in animal models and cell lines suggest that Ets2 is causally involved in breast cancer formation and progression (Buggy et al., 2006; Watabe et al., 1998). Transfection of the non-tumourigenic immortalized MCF-12A breast cancer cells with Ets2 resulted in serum growth factor independent proliferation, growth in soft agar and enhanced invasiveness (Sapi et al., 1998). In addition, Ets2 plays an important regulatory role in controlling expression of the breast tumour promoting protein, parathyroid hormone-related protein (Lindemann et al., 2003).
  
Entity Esophageal Carcinoma
Disease Overexpression of Ets2 has been observed in human esophageal carcinoma (Li et al., 2003). Compared with normal tissue expression of both Ets2 mRNA and protein are upregulated in tumour tissue, suggesting a role in the pathology of esophageal carcinoma.
  
Entity Prostate Cancer
Disease Increased expression of Ets2 has been shown in human prostate cancer (Foos et al., 2000; Turner et al., 2007b). Inhibition of Ets2 by antisense oligonucleotides or dominant negative constructs reduces anchorage-independent growth of prostate cancer cells, significantly reduces the ability of cells to form colonies in soft agar and reduces tumour formation in nude mice. Furthermore, Ets2 has been associated with the transcriptional upregulation of uPA and matrix metalloproteinase's (Man et al., 2003; Trojanowska, 2000), which are associated with prognosis in prostate cancer.
  

External links

Nomenclature
HGNC (Hugo)ETS2   3489
Cards
AtlasETS2ID40503ch21q22
Entrez_Gene (NCBI)ETS2  2114  v-ets avian erythroblastosis virus E26 oncogene homolog 2
GeneCards (Weizmann)ETS2
Ensembl (Hinxton)ENSG00000157557 [Gene_View]  chr21:40177231-40196878 [Contig_View]  ETS2 [Vega]
ICGC DataPortalENSG00000157557
cBioPortalETS2
AceView (NCBI)ETS2
Genatlas (Paris)ETS2
WikiGenes2114
SOURCE (Princeton)NM_001256295 NM_005239
Genomic and cartography
GoldenPath (UCSC)ETS2  -  21q22.2   chr21:40177231-40196878 +  21q22.3   [Description]    (hg19-Feb_2009)
EnsemblETS2 - 21q22.3 [CytoView]
Mapping of homologs : NCBIETS2 [Mapview]
OMIM164740   
Gene and transcription
Genbank (Entrez)AA452482 AK000535 AK096841 AK315563 AV661268
RefSeq transcript (Entrez)NM_001256295 NM_005239
RefSeq genomic (Entrez)AC_000153 NC_000021 NC_018932 NT_011512 NW_001838708 NW_004929426
Consensus coding sequences : CCDS (NCBI)ETS2
Cluster EST : UnigeneHs.644231 [ NCBI ]
CGAP (NCI)Hs.644231
Alternative Splicing : Fast-db (Paris)GSHG0019485
Alternative Splicing GalleryENSG00000157557
Gene ExpressionETS2 [ NCBI-GEO ]     ETS2 [ SEEK ]   ETS2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP15036 (Uniprot)
NextProtP15036  [Medical]
With graphics : InterProP15036
Splice isoforms : SwissVarP15036 (Swissvar)
Domaine pattern : Prosite (Expaxy)ETS_DOMAIN_1 (PS00345)    ETS_DOMAIN_2 (PS00346)    ETS_DOMAIN_3 (PS50061)    PNT (PS51433)   
Domains : Interpro (EBI)Ets_dom [organisation]   Pointed_dom [organisation]   SAM/pointed [organisation]   Transform_prot_C-ets [organisation]   Transform_prot_C-ets-2 [organisation]   WHTH_DNA-bd_dom [organisation]  
Related proteins : CluSTrP15036
Domain families : Pfam (Sanger)Ets (PF00178)    SAM_PNT (PF02198)   
Domain families : Pfam (NCBI)pfam00178    pfam02198   
Domain families : Smart (EMBL)ETS (SM00413)  SAM_PNT (SM00251)  
DMDM Disease mutations2114
Blocks (Seattle)P15036
PDB (SRS)4BQA    4MHV   
PDB (PDBSum)4BQA    4MHV   
PDB (IMB)4BQA    4MHV   
PDB (RSDB)4BQA    4MHV   
Human Protein AtlasENSG00000157557 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP15036
HPRD01263
IPIIPI00009756   IPI00791092   IPI00790435   
Protein Interaction databases
DIP (DOE-UCLA)P15036
IntAct (EBI)P15036
FunCoupENSG00000157557
BioGRIDETS2
InParanoidP15036
Interologous Interaction database P15036
IntegromeDBETS2
STRING (EMBL)ETS2
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  sequence-specific DNA binding RNA polymerase II transcription factor activity  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription  skeletal system development  DNA binding  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  nucleoplasm  regulation of transcription from RNA polymerase II promoter  transcription from RNA polymerase II promoter  cell differentiation  glucocorticoid receptor binding  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  sequence-specific DNA binding RNA polymerase II transcription factor activity  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription  skeletal system development  DNA binding  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  nucleoplasm  regulation of transcription from RNA polymerase II promoter  transcription from RNA polymerase II promoter  cell differentiation  glucocorticoid receptor binding  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  
Pathways : BIOCARTAKeratinocyte Differentiation [Genes]    METS affect on Macrophage Differentiation [Genes]   
Pathways : KEGGRas signaling pathway    Dorso-ventral axis formation    HTLV-I infection   
Protein Interaction DatabaseETS2
Wikipedia pathwaysETS2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ETS2
snp3D : Map Gene to Disease2114
SNP (GeneSNP Utah)ETS2
SNP : HGBaseETS2
Genetic variants : HAPMAPETS2
Exome VariantETS2
1000_GenomesETS2 
ICGC programENSG00000157557 
Somatic Mutations in Cancer : COSMICETS2 
CONAN: Copy Number AnalysisETS2 
Mutations and Diseases : HGMDETS2
Genomic VariantsETS2  ETS2 [DGVbeta]
dbVarETS2
ClinVarETS2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM164740   
MedgenETS2
GENETestsETS2
Disease Genetic AssociationETS2
Huge Navigator ETS2 [HugePedia]  ETS2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneETS2
Homology/Alignments : Family Browser (UCSC)ETS2
Phylogenetic Trees/Animal Genes : TreeFamETS2
Chemical/Protein Interactions : CTD2114
Chemical/Pharm GKB GenePA27903
Clinical trialETS2
Cancer Resource (Charite)ENSG00000157557
Other databases
Probes
Litterature
PubMed97 Pubmed reference(s) in Entrez
CoreMineETS2
iHOPETS2
OncoSearchETS2

Bibliography

Temporal and tissue-specific expression of mouse ets genes.
Bhat NK, Fisher RJ, Fujiwara S, Ascione R, Papas TS.
Proc Natl Acad Sci U S A 1987; 84(10): 3161-3165.
PMID 3472202
 
The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21).
Sacchi N, Cheng SV, Tanzi RE, Gusella JF, Drabkin HA, Patterson D, Haines JH, Papas TS.
Genomics 1988; 3(2): 110-116.
PMID 3267212
 
Mammalian ets-1 and ets-2 genes encode highly conserved proteins.
Watson DK, McWilliams MJ, Lapis P, Lautenberger JA, Schweinfest CW, Papas TS.
Proc Natl Acad Sci U S A 1988; 85(21): 7862-7866.
PMID 2847145
 
c-ets-2 and the mitogenic signal pathway.
Fisher RJ, Fujiwara S, Bhat NK, Schweinfest CW, Papas TS.
Haematol Blood Transfus 1989; 32: 441-448.
PMID 2516500
 
The ets family of genes: molecular biology and functional implications.
Papas TS, Fisher RJ, Bhat N, Fujiwara S, Watson DK, Lautenberger J, Seth A, Chen ZQ, Burdett L, Pribyl L, et al.
Curr Top Microbiol Immunol 1989; 149: 143-147.
PMID 2659278
 
c-ets-2 protooncogene has mitogenic and oncogenic activity.
Seth A, Watson DK, Blair DG, Papas TS.
Proc Natl Acad Sci U S A 1989; 86(20): 7833-7837.
PMID 2813360
 
Phosphorylation of the ETS-2 protein: regulation by the T-cell antigen receptor-CD3 complex.
Fujiwara S, Koizumi S, Fisher RJ, Bhat NK, Papas TS.
Mol Cell Biol 1990; 10(3): 1249-1253.
PMID 2137553
 
The ETS family of genes: structural analysis, gene products, and involvement in neoplasia and other pathologies.
Papas TS, Blair DG, Watson DK, Yuan CC, Ruscetti SK, Fujiwara S, Seth AK, Fisher RJ, Bhat NK, Mavrothalassitis G, et al.
Prog Clin Biol Res 1990a; 360: 137-168.
PMID 2247505
 
ETS family of genes in leukemia and Down syndrome.
Papas TS, Watson DK, Sacchi N, Fujiwara S, Seth AK, Fisher RJ, Bhat NK, Mavrothalassitis G, Koizumi S, Jorcyk CL, et al.
Am J Med Genet Suppl 1990b; 7: 251-261.
PMID 2149958
 
Molecular analysis of the ets genes and their products.
Watson DK, Ascione R, Papas TS.
Crit Rev Oncog 1990; 1(4): 409-436.
PMID 1964597
 
Constitutive c-ets2 expression in M1D+ myeloblast leukemic cells induces their differentiation to macrophages.
Aperlo C, Pognonec P, Stanley ER, Boulukos KE.
Mol Cell Biol 1996; 16(12): 6851-6858.
PMID 8943340
 
Pleiotropic functions of ETS-1.
Bhat N, Fischinger PJ, Seth A, Watson DK, Papas TS.
Int J Oncol. 1996; 8: 841-846.
 
Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis.
Dooley S, Herlitzka I, Hanselmann R, Ermis A, Henn W, Remberger K, Hopf T, Welter C.
Ann Rheum Dis 1996; 55(5): 298-304.
PMID 8660103
 
Expression of the c-jun, jun-B, ets-2 and liver regeneration factor-1 (LRF-1) genes during promotion and progression of rat liver carcinogenesis in the resistant hepatocyte model.
Liao DZ, Blanck A, Gustafsson JA, Hallstrom IP.
Cancer Lett 1996; 100(1-2): 215-221.
PMID 8620444
 
A novel ets-2-related nuclear factor is involved in transcriptional activation of the human interleukin-12 p40 gene promoter in response to interferon-gamma and LPS stimulation of monocytic cells.
Ma X, Gri G, Trinchieri G.
Ann N Y Acad Sci 1996; 795: 357-360.
PMID 8958954
 
Identification of a second promoter in the human c-ets-2 proto-oncogene.
Begue A, Crepieux P, Vu-Dac N, Hautefeuille A, Spruyt N, Laudet V, Stehelin D.
Gene Expr 1997; 6(6): 333-347
PMID 9495315
 
Ets-2 transdominant mutant abolishes anchorage-independent growth and macrophage colony-stimulating factor-stimulated invasion by BT20 breast carcinoma cells.
Sapi E, Flick MB, Rodov S, Kacinski BM.
Cancer Res 1998; 58(5): 1027-1033.
PMID 9500466
 
ETS2 function is required to maintain the transformed state of human prostate cancer cells.
Sementchenko VI, Schweinfest CW, Papas TS, Watson DK.
Oncogene 1998; 17(22): 2883-2888.
PMID 9879994
 
The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor.
Watabe T, Yoshida K, Shindoh M, Kaya M, Fujikawa K, Sato H, Seiki M, Ishii S, Fujinaga K.
Int J Cancer 1998; 77(1): 128-137.
PMID 9639404
 
Defective trophoblast function in mice with a targeted mutation of Ets2.
Yamamoto H, Flannery ML, Kupriyanov S, Pearce J, McKercher SR, Henkel GW, Maki RA, Werb Z, Oshima RG.
Genes Dev 1998; 12(9): 1315-1326.
PMID 9573048
 
Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells.
Kilpatrick LM, Kola I, Salamonsen LA.
Biol Reprod 1999; 61(1): 120-126.
PMID 10377039
 
Altered Ets transcription factor activity in prostate tumor cells inhibits anchorage-independent growth, survival, and invasiveness.
Foos G, Hauser CA.
Oncogene 2000; 19(48): 5507-5516.
PMID 11114728
 
Ets factors and regulation of the extracellular matrix.
Trojanowska M.
Oncogene 2000; 19(55): 6464-6471. (Review)
PMID 11175362
 
Messenger-RNA expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli.
Sun HB, Yokota H.
Bone 2001; 28(3): 303-309.
PMID 11248661
 
ETS proteins and MMPs: partners in invasion and metastasis.
Singh S, Barrett J, Sakata K, Tozer RG, Singh G.
Curr Drug Targets 2002; 3(5): 359-367.
PMID 12182227
 
Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells.
Lindemann RK, Braig M, Hauser CA, Nordheim A, Dittmer J.
Biochem J 2003; 372(Pt 3): 787-797.
PMID 12628005
 
Overexpression of ETS2 in human esophageal squamous cell carcinoma.
Li X, Lu JY, Zhao LQ, Wang XQ, Liu GL, Liu Z, Zhou CN, Wu M, Liu ZH.
World J Gastroenterol 2003; 9(2): 205-208.
PMID 12532432
 
Ets2-dependent stromal regulation of mouse mammary tumors.
Man AK, Young LJ, Tynan JA, Lesperance J, Egeblad M, Werb Z, Hauser CA, Muller WJ, Cardiff RD, Oshima RG.
Mol Cell Biol 2003; 23(23): 8614-8625.
PMID 14612405
 
Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors.
Galang CK, Muller WJ, Foos G, Oshima RG, Hauser CA.
J Biol Chem 2004; 279(12): 11281-1192.
PMID 14662758
 
Ets2 transcription factor in normal and neoplastic human breast tissue.
Buggy Y, Maguire TM, McDermott E, Hill AD, O'Higgins N, Duffy MJ.
Eur J Cancer 2006; 42(4): 485-491.
PMID 16380248
 
Defining ETS transcription regulatory networks and their contribution to breast cancer progression.
Turner DP, Findlay VJ, Moussa O, Watson DK.
J Cell Biochem 2007a; 102(3): 549-559.
PMID 17661355
 
Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer.
Turner DP, Moussa O, Sauane M, Fisher PB, Watson DK.
Cancer Res 2007b; 67(4): 1618-1625.
PMID 17308102
 
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Contributor(s)

Written07-2008Yvonne Buggy, Michael J Duffy
Drug Safety Research Unit, SO14 0 Southampton, UK (YB); UCD School of Medicine and Medical Science, University College Dublin, Ireland (MJD)

Citation

This paper should be referenced as such :
Buggy, Y ; Duffy, MJ
ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2 (avian))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(6):409-412.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/ETS2ID40503ch21q22.html

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indexed on : Fri Aug 8 11:17:35 CEST 2014

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