Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

ETS1 (v-ets erythroblastosis virus E26 oncogene homolog 1 (avian))

Written2010-01Andreas Lindstrot, Berit Langer, Nicolas Wernert
Institute of Pathology, Molecular Pathology Department, University of Bonn, Sigmund-Freud-Str 25, 53127 Bonn, Germany

(Note : for Links provided by Atlas : click)


Other aliasETS-1
LocusID (NCBI) 2113
Atlas_Id 40502
Location 11q24.3  [Link to chromosome band 11q24]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ETS1 (11q24.3) / CPED1 (7q31.31)ETS1 (11q24.3) / EWSR1 (22q12.2)ETS1 (11q24.3) / NEGR1 (1p31.1)
EWSR1 (22q12.2) / ETS1 (11q24.3)NECAP1 (12p13.31) / ETS1 (11q24.3)NEGR1 (1p31.1) / ETS1 (11q24.3)


Note Ets-1 is a 63 kb large gene with 8 exons located on chromosome 11q24.3.
Several splice variants are known:
- full length including exons 1-8 (p51) (Macleod et al., 1992),
- without exon 7 (p42) (Koizumi et al., 1990; Jorcyk et al., 1991),
- without exon 4 (Jorcyk et al., 1991),
- without exon 4 and 7 (Jorcyk et al., 1991),
- without exon 6 (Rothhammer et al., 2004),
- without exon 3 to 6 (p27) (Laitem et al., 2009).
The full length protein p51 and the splice variants p42 and p27 have been investigated in functional terms (Laitem et al., 2009). The other splice variants have only been shown to exist without describing their functions. The full length (p51) is important for angiogenesis, vasculogenesis as well as T- and B-cell formation. In the presence of calcium the p42-form cannot be phosphorylated. Under these conditions its self-inhibitory function is disturbed (Lionneton, 2003). The p42-form can bind stronger to the target DNA than the full length protein (Fisher et al., 1994). The p27-form has a double inactivating function. On the one hand it can bind to the Ets-binding site of the DNA without activating the transcription of the target gene. On the other hand it can actively delocalize the p51 form out of the nucleus through a mechanism not yet known (Laitem et al., 2009).
The promoter region of Ets-1 lacks the TATA-box and CAAT-box, but has six GC rich consensus sequences, which are recognized by SP1, two consensus sequences detected by AP1 and one consensus sequence, which can be recognized by AP2 (Jorcyk et al., 1991).
  Intron/exon arrangement of Ets-1. It is noteworthy, that the first intron is over 30 kb long, half of the length of the whole Ets-1 gene.


Description The human Ets-1 protein consists of 441 amino acids.
Several functional domains have been characterized:
- The pointed domain comprises the amino acids 54 to 135. This domain consists of five alpha-helices, forming a globular structure (Slubsky et al., 1998).
- The second domain between amino acids 130 and 242 is the transactivating domain, necessary for activation of transcription (Gegonne et al., 1992).
- The third domain, called the exon VII domain, spans the amino acids 243 to 331. It contains two regulatory domains. The C-terminal of this domain includes a self-inhibitory domain, which inhibits the interaction between Ets-1 and its partner proteins (Petersen et al., 1995). In the presence of DNA the inhibitory domain is cleaved (Petersen et al., 1995). The N-terminal part of the exon VII domain is driven by a calcium-dependent phosphorylation. After phosphorylation the binding of Ets-1 to the specific DNA-region is disturbed (Rabault and Ghysdael, 1994).
- The fourth domain connected to the Exon VII domain is the ETS-domain. It includes amino acids 331 to 415. This domain contains three alpha-helices and four beta-strands and builds a helix-turn-helix motive (Werner et al., 1995; Werner et al., 1997).
All members of the Ets-transcription factor-family contain the ETS-domain which consists of approximately 80 amino acids with four tryptophan repeats (Walsylyk et al., 1993). The ETS-domain binds to double-stranded DNA of target genes containing a GGAA/T core motive and different flanking regions (Sharrocks, 2001; Dittmer, 2003; Karim et al., 1990; Oikawa and Yamada, 2003). The sequences flanking the GGAA/T core as well as binding of further proteins to Ets-1 determine the DNA-binding specificity (Walsylyk et al., 1993). Among these proteins are different transcription factors including members of the Ets-family (Lelièvre et al., 2000). The expression of Ets-family members is controlled by different proteins like angiogenic factors (e.g. VEGF, TNF-alpha, TGF-beta and fibroblast growth factor 2). The activity of the Ets-family members can be induced or repressed by several kinases (e.g. MAP kinases and tyrosine kinases) (Lelièvre et al., 2000).
Localisation Ets-1 protein is normally located in the nucleus. ETS1 mRNA and protein can also be detected in the cytoplasm of endothelial cells during angiogenesis (including tumor vascularization), in different tumor cells as well as in fibroblasts of the tumor stroma (Valter et al., 1999; Mylona et al., 2006; Takai et al., 2000; Takai et al., 2002; Wernert et al., 1994; Behrens et al., 2003). The de-localization of Ets-1 out of the nucleus into the cytoplasm could be mediated by the p27-form of the Ets-1 protein (Laitem et al., 2009).
Function Ets-1 can transactivate or transrepress many target genes depending upon interaction partners of Ets-1 such as CREB binding protein (Hamzaoui et al., 2007). About 200 target genes of Ets-family members are known. They can be grouped according to their functions into genes involved in viruses, transcription, transformation, protein degradation, cell cycle regulation, apoptosis, cell signaling, growth and other processes (Sementchenko et al., 2000).
Among target genes of Ets-1 are those encoding several matrix metalloproteases (MMP-2, MMP-3, MMP-4 and MMP-9), TIMPs and uPA. Ets-1 is among the first genes up-regulated during chicken embryogenesis (Vandenbunder et al., 1989). It is particularly expressed in mesoderm, the neural crest as well as during haematopoiesis and blood vessel formation (Vandenbunder et al., 1989; Lincoln II and Bove, 2005). Ets-1 is also upregulated in lungs and kidneys, which undergo a branching remodeling (Raffetseder et al., 2004; Kola et al., 1993; Maroulakou and Bowe, 2000).
In adults Ets-1 is important for the maturation of B and T cells (Bories et al., 1995) and is highly expressed during wound healing and tumor angiogenesis (Wernert et al., 1992; Maroulakou and Bowe, 2000).
Ets-1 is also implicated in angiogenesis under normal and other pathological conditions, such as the menstrual cycle (Fujimoto et al., 2003), granulation tissue formation and inflammatory angiogenesis during rheumatoid arthritis (Wernert et al., 1992; Wernert et al., 2004). Ets-1 is not implicated in the formation of lymphoid vessels (Wernert et al., 2003).
Another function of Ets-1 is the regulation of apoptosis (Teruyama et al., 2001) by regulating genes encoding Bax, Bcl-2, Caspase-1 and Fas ligand (Nagarajan et al., 2009).
Homology Ets-1 is very similar to Ets-2 and found in several different animals (Laudet et al., 1999). Animals without Ets-1 have a higher Ets-2 expression level. The sequence of DNA and protein differs by only 15% (DNA) and 5% (protein) between human and chicken (Watson et al., 1988).
Two different transcription initiation sites exist in birds and reptiles leading to the expression of p68 and p54 (Mcleod et al., 1992).

Implicated in

Entity Tumors
Note In tumors Ets-1 has also been shown to be implicated in proliferation, migration and invasion of neoplastic cells such as melanoma and Hela cells (Rothhammer et al., 2003; Turner et al., 2007; Hahne et al., 2005).
In-vivo high Ets-1 expression can already be found in early phases of tumor development (Behrens et al., 2001; Behrens et al., 2003). Fibroblasts of the tumour stroma express Ets-1 during tumor invasion (Wernert et al., 1994).
Entity Prostate cancer
Note Ets-1 is strongly upregulated in prostate cancer cells (Alipov et al., 2005). A positive correlation between ETS-1 expression and Gleason score of prostate cancers has been demonstrated (Alipov et al., 2004).
Entity Breast cancer
Note In breast cancer Ets-1 is a marker of poor prognosis (Lincoln II and Bove, 2005).
Entity Lung cancer
Note Ets-1 expression in lung cancer is more often found in males and in squamous cell carcinomas than in women and in adenocarcinomas. In adenocarcinomas Ets-1 expression correlates with tumour size and poor prognosis (Yamaguchi, et al., 2007).
Entity Colon cancer
Note In colon cancer Ets-1 expression is directly related to malignancy with no expression in normal tissues and highest expression levels in adenocarcinomas with lymph node metastasis. Thus Ets-1 could be used as a prognosis-marker in colon cancer (Ito et al., 2002).
Entity Pancreatic cancer
Note In normal pancreatic tissue, Ets-1 expression is found to be weak in contrast to well differentiated carcinoma, in which Ets-1 is strongly expressed. The level of Ets-1 is downregulated again in poorly differentiated adenocarcinoma (Ito et al., 1998). Ets-1 has no effect upon tumor size, prognosis or TNM stage of pancreatic cancer (Ito et al., 1998).
Entity Rheumatoid arthritis
Note In rheumatoid arthritis Ets-1 is upregulated in synovial fibroblasts by TNF-alpha and IL-1, both mayor cytokines in inflammation. Ets-1 may affect the regulation of destructive metalloproteases (Redlich et al., 2001). Ets-1 is also considered responsible for the development of new blood vessels in rheumatoid tissues (Redlich et al., 2001; Wernert et al., 2002).


Overexpression of Ets-1 proto-oncogene in latent and clinical prostatic carcinomas.
Alipov G, Nakayama T, Ito M, Kawai K, Naito S, Nakashima M, Niino D, Sekine I.
Histopathology. 2005 Feb;46(2):202-8.
PMID 15693893
Stromal expression of invasion-promoting, matrix-degrading proteases MMP-1 and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers.
Behrens P, Mathiak M, Mangold E, Kirdorf S, Wellmann A, Fogt F, Rothe M, Florin A, Wernert N.
Int J Cancer. 2003 Nov 1;107(2):183-8.
PMID 12949792
The Ets-1 transcription factor is up-regulated together with MMP 1 and MMP 9 in the stroma of pre-invasive breast cancer.
Behrens P, Rothe M, Wellmann A, Krischler J, Wernert N.
J Pathol. 2001 May;194(1):43-50.
PMID 11329140
Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.
Bories JC, Willerford DM, Grevin D, Davidson L, Camus A, Martin P, Stehelin D, Alt FW.
Nature. 1995 Oct 19;377(6550):635-8.
PMID 7566176
The biology of the Ets1 proto-oncogene.
Dittmer J.
Mol Cancer. 2003 Aug 20;2:29. (REVIEW)
PMID 12971829
Real-time DNA binding measurements of the ETS1 recombinant oncoproteins reveal significant kinetic differences between the p42 and p51 isoforms.
Fisher RJ, Fivash M, Casas-Finet J, Erickson JW, Kondoh A, Bladen SV, Fisher C, Watson DK, Papas T.
Protein Sci. 1994 Feb;3(2):257-66.
PMID 8003962
Expression of ETS-1 related to angiogenesis in uterine endometrium during the menstrual cycle.
Fujimoto J, Aoki I, Toyoki H, Khatun S, Sato E, Tamaya T.
J Biomed Sci. 2003 May-Jun;10(3):320-7.
PMID 12711859
Analysis of the DNA binding and transcriptional activation properties of the Ets1 oncoprotein.
Gegonne A, Punyammalee B, Rabault B, Bosselut R, Seneca S, Crabeel M, Ghysdael J.
New Biol. 1992 May;4(5):512-9.
PMID 1515415
The transcription factor ETS-1: its role in tumour development and strategies for its inhibition.
Hahne JC, Okuducu AF, Sahin A, Fafeur V, Kiriakidis S, Wernert N.
Mini Rev Med Chem. 2008 Oct;8(11):1095-105. (REVIEW)
PMID 18855726
PTHrP P3 promoter activity in breast cancer cell lines: role of Ets1 and CBP (CREB binding protein).
Hamzaoui H, Rizk-Rabin M, Gordon J, Offutt C, Bertherat J, Bouizar Z.
Mol Cell Endocrinol. 2007 Mar 30;268(1-2):75-84. Epub 2007 Feb 1.
PMID 17321669
Expression of the ets-1 proto-oncogene in human pancreatic carcinoma.
Ito T, Nakayama T, Ito M, Naito S, Kanematsu T, Sekine I.
Mod Pathol. 1998 Feb;11(2):209-15.
PMID 9504693
Expression of ets-1 and ets-2 in colonic neoplasms.
Ito Y, Takeda T, Okada M, Matsuura N.
Anticancer Res. 2002 May-Jun;22(3):1581-4.
PMID 12168840
The human ETS1 gene: genomic structure, promoter characterization and alternative splicing.
Jorcyk CL, Watson DK, Mavrothalassitis GJ, Papas TS.
Oncogene. 1991 Apr;6(4):523-32.
PMID 2030910
The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence.
Karim FD, Urness LD, Thummel CS, Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA, Gunther CV, Nye JA, et al.,
Genes Dev. 1990 Sep;4(9):1451-3.
PMID 2253872
Isoforms of the human ets-1 protein: generation by alternative splicing and differential phosphorylation.
Koizumi S, Fisher RJ, Fujiwara S, Jorcyk C, Bhat NK, Seth A, Papas TS.
Oncogene. 1990 May;5(5):675-81.
PMID 2189104
The Ets1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation.
Kola I, Brookes S, Green AR, Garber R, Tymms M, Papas TS, Seth A.
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7588-92.
PMID 7689222
Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51.
Laitem C, Leprivier G, Choul-Li S, Begue A, Monte D, Larsimont D, Dumont P, Duterque-Coquillaud M, Aumercier M.
Oncogene. 2009 May 21;28(20):2087-99. Epub 2009 Apr 20.
PMID 19377509
Molecular phylogeny of the ETS gene family.
Laudet V, Hanni C, Stehelin D, Duterque-Coquillaud M.
Oncogene. 1999 Feb 11;18(6):1351-9.
PMID 10022817
The Ets family contains transcriptional activators and repressors involved in angiogenesis.
Lelievre E, Lionneton F, Soncin F, Vandenbunder B.
Int J Biochem Cell Biol. 2001 Apr;33(4):391-407. (REVIEW)
PMID 11312108
Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor.
Lionneton F, Lelievre E, Baillat D, Stehelin D, Soncin F.
Oncogene. 2003 Dec 11;22(57):9156-64.
PMID 14668797
The ets gene family.
Macleod K, Leprince D, Stehelin D.
Trends Biochem Sci. 1992 Jul;17(7):251-6. (REVIEW)
PMID 1502727
Expression and function of Ets transcription factors in mammalian development: a regulatory network.
Maroulakou IG, Bowe DB.
Oncogene. 2000 Dec 18;19(55):6432-42. (REVIEW)
PMID 11175359
Study of the topographic distribution of ets-1 protein expression in invasive breast carcinomas in relation to tumor phenotype.
Mylona EE, Alexandrou PT, Giannopoulou IA, Rafailidis PI, Markaki S, Keramopoulos A, Nakopoulou LL.
Cancer Detect Prev. 2006;30(2):111-7. Epub 2006 May 2.
PMID 16632244
Molecular biology of the Ets family of transcription factors.
Oikawa T, Yamada T.
Gene. 2003 Jan 16;303:11-34. (REVIEW)
PMID 12559563
Modulation of transcription factor Ets-1 DNA binding: DNA-induced unfolding of an alpha helix.
Petersen JM, Skalicky JJ, Donaldson LW, McIntosh LP, Alber T, Graves BJ.
Science. 1995 Sep 29;269(5232):1866-9.
PMID 7569926
Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity.
Rabault B, Ghysdael J.
J Biol Chem. 1994 Nov 11;269(45):28143-51.
PMID 7961750
Overexpression of transcription factor Ets-1 in rheumatoid arthritis synovial membrane: regulation of expression and activation by interleukin-1 and tumor necrosis factor alpha.
Redlich K, Kiener HP, Schett G, Tohidast-Akrad M, Selzer E, Radda I, Stummvoll GH, Steiner CW, Groger M, Bitzan P, Zenz P, Smolen JS, Steiner G.
Arthritis Rheum. 2001 Feb;44(2):266-74.
PMID 11229456
The effect of mechanical force on mRNA levels of collagenase, collagen type I, and tissue inhibitors of metalloproteinases in gingivae of dogs.
Redlich M, Reichenberg E, Harari D, Zaks B, Shoshan S, Palmon A.
J Dent Res. 2001 Dec;80(12):2080-4.
PMID 11808766
The Ets-1 transcription factor is involved in the development and invasion of malignant melanoma.
Rothhammer T, Hahne JC, Florin A, Poser I, Soncin F, Wernert N, Bosserhoff AK.
Cell Mol Life Sci. 2004 Jan;61(1):118-28.
PMID 14704859
Ets target genes: past, present and future.
Sementchenko VI, Watson DK.
Oncogene. 2000 Dec 18;19(55):6533-48. (REVIEW)
PMID 11175369
The ETS-domain transcription factor family.
Sharrocks AD.
Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37. (REVIEW)
PMID 11715049
Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site.
Slupsky CM, Gentile LN, Donaldson LW, Mackereth CD, Seidel JJ, Graves BJ, McIntosh LP.
Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12129-34.
PMID 9770451
c-Ets1 is a promising marker in epithelial ovarian cancer.
Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I.
Int J Mol Med. 2002 Mar;9(3):287-92.
PMID 11836635
Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells.
Teruyama K, Abe M, Nakano T, Iwasaka-Yagi C, Takahashi S, Yamada S, Sato Y.
J Cell Physiol. 2001 Aug;188(2):243-52.
PMID 11424091
Defining ETS transcription regulatory networks and their contribution to breast cancer progression.
Turner DP, Findlay VJ, Moussa O, Watson DK.
J Cell Biochem. 2007 Oct 15;102(3):549-59. (REVIEW)
PMID 17661355
Expression of the Ets-1 transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis.
Valter MM, Hugel A, Huang HJ, Cavenee WK, Wiestler OD, Pietsch T, Wernert N.
Cancer Res. 1999 Nov 1;59(21):5608-14.
PMID 10554042
Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo.
Vandenbunder B, Pardanaud L, Jaffredo T, Mirabel MA, Stehelin D.
Development. 1989 Oct;107(2):265-74.
PMID 2483681
The Ets family of transcription factors.
Wasylyk B, Hahn SL, Giovane A.
Eur J Biochem. 1993 Jan 15;211(1-2):7-18. (REVIEW)
PMID 8425553
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 Nov;85(21):7862-6.
PMID 2847145
Correction of the NMR structure of the ETS1/DNA complex.
Werner MH, Clore GM, Fisher CL, Fisher RJ, Trinh L, Shiloach J, Gronenborn AM.
J Biomol NMR. 1997 Dec;10(4):317-28.
PMID 9460239
Stromal expression of c-Ets1 transcription factor correlates with tumor invasion.
Wernert N, Gilles F, Fafeur V, Bouali F, Raes MB, Pyke C, Dupressoir T, Seitz G, Vandenbunder B, Stehelin D.
Cancer Res. 1994 Nov 1;54(21):5683-8.
PMID 7923216
The Ets 1 transcription factor is upregulated during inflammatory angiogenesis in rheumatoid arthritis.
Wernert N, Justen HP, Rothe M, Behrens P, Dreschers S, Neuhaus T, Florin A, Sachinidis A, Vetter H, Ko Y.
J Mol Med. 2002 Apr;80(4):258-66. Epub 2002 Jan 24.
PMID 11976735
Ets 1 is expressed in capillary blood vessels but not in lymphatics.
Wernert N, Okuducu AF, Pepper MS.
J Pathol. 2003 Aug;200(5):561-7.
PMID 12898591
c-ets1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans.
Wernert N, Raes MB, Lassalle P, Dehouck MP, Gosselin B, Vandenbunder B, Stehelin D.
Am J Pathol. 1992 Jan;140(1):119-27.
PMID 1370594
Ets-1 proto-oncogene as a potential predictor for poor prognosis of lung adenocarcinoma.
Yamaguchi E, Nakayama T, Nanashima A, Matsumoto K, Yasutake T, Sekine I, Nagayasu T.
Tohoku J Exp Med. 2007 Sep;213(1):41-50.
PMID 17785952
A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions.
Yang C, Shapiro LH, Rivera M, Kumar A, Brindle PK.
Mol Cell Biol. 1998 Apr;18(4):2218-29.
PMID 9528793


This paper should be referenced as such :
Lindstrot, A ; Langer, B ; Wernert, N
ETS1 (v-ets erythroblastosis virus E26 oncogene homolog 1 (avian))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):950-954.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  t(10;14)(q24;q11) TLX1/TRD::t(7;10)(q34;q24) TRB/HOX11
dup (11q) in myeloid malignancies
MLL amplification in leukemia

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  Lung: Translocations in Squamous Cell Carcinoma
t(1;11)(p31;q24) NEGR1/ETS1
t(1;11)(p31;q24) ETS1/NEGR1

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2113
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:35:38 CEST 2018

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us