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

2010-01-01   Andreas Lindstrot , Berit Langer , Nicolas Wernert 

Institute of Pathology, Molecular Pathology Department, University of Bonn, Sigmund-Freud-Str 25, 53127 Bonn, Germany





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).
Atlas Image
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.



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).


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).


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).


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 name
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 name
Prostate cancer
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 name
Breast cancer
In breast cancer Ets-1 is a marker of poor prognosis (Lincoln II and Bove, 2005).
Entity name
Lung cancer
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 name
Colon cancer
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 name
Pancreatic cancer
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).
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Rheumatoid arthritis
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).


Pubmed IDLast YearTitleAuthors
156938932005Overexpression of Ets-1 proto-oncogene in latent and clinical prostatic carcinomas.Alipov G et al
129497922003Stromal 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 et al
113291402001The Ets-1 transcription factor is up-regulated together with MMP 1 and MMP 9 in the stroma of pre-invasive breast cancer.Behrens P et al
75661761995Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene.Bories JC et al
129718292003The biology of the Ets1 proto-oncogene.Dittmer J et al
80039621994Real-time DNA binding measurements of the ETS1 recombinant oncoproteins reveal significant kinetic differences between the p42 and p51 isoforms.Fisher RJ et al
127118592003Expression of ETS-1 related to angiogenesis in uterine endometrium during the menstrual cycle.Fujimoto J et al
15154151992Analysis of the DNA binding and transcriptional activation properties of the Ets1 oncoprotein.Gegonne A et al
188557262008The transcription factor ETS-1: its role in tumour development and strategies for its inhibition.Hahne JC et al
173216692007PTHrP P3 promoter activity in breast cancer cell lines: role of Ets1 and CBP (CREB binding protein).Hamzaoui H et al
95046931998Expression of the ets-1 proto-oncogene in human pancreatic carcinoma.Ito T et al
121688402002Expression of ets-1 and ets-2 in colonic neoplasms.Ito Y et al
20309101991The human ETS1 gene: genomic structure, promoter characterization and alternative splicing.Jorcyk CL et al
22538721990The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence.Karim FD et al
21891041990Isoforms of the human ets-1 protein: generation by alternative splicing and differential phosphorylation.Koizumi S et al
76892221993The 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 et al
193775092009Ets-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 et al
100228171999Molecular phylogeny of the ETS gene family.Laudet V et al
113121082001The Ets family contains transcriptional activators and repressors involved in angiogenesis.Lelièvre E et al
146687972003Characterization and functional analysis of the p42Ets-1 variant of the mouse Ets-1 transcription factor.Lionneton F et al
15027271992The ets gene family.Macleod K et al
111753592000Expression and function of Ets transcription factors in mammalian development: a regulatory network.Maroulakou IG et al
166322442006Study of the topographic distribution of ets-1 protein expression in invasive breast carcinomas in relation to tumor phenotype.Mylona EE et al
125595632003Molecular biology of the Ets family of transcription factors.Oikawa T et al
75699261995Modulation of transcription factor Ets-1 DNA binding: DNA-induced unfolding of an alpha helix.Petersen JM et al
79617501994Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity.Rabault B et al
112294562001Overexpression 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 et al
118087662001The effect of mechanical force on mRNA levels of collagenase, collagen type I, and tissue inhibitors of metalloproteinases in gingivae of dogs.Redlich M et al
147048592004The Ets-1 transcription factor is involved in the development and invasion of malignant melanoma.Rothhammer T et al
111753692000Ets target genes: past, present and future.Sementchenko VI et al
117150492001The ETS-domain transcription factor family.Sharrocks AD et al
97704511998Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site.Slupsky CM et al
118366352002c-Ets1 is a promising marker in epithelial ovarian cancer.Takai N et al
114240912001Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells.Teruyama K et al
176613552007Defining ETS transcription regulatory networks and their contribution to breast cancer progression.Turner DP et al
105540421999Expression 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 et al
24836811989Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo.Vandenbunder B et al
84255531993The Ets family of transcription factors.Wasylyk B et al
28471451988Mammalian ets-1 and ets-2 genes encode highly conserved proteins.Watson DK et al
94602391997Correction of the NMR structure of the ETS1/DNA complex.Werner MH et al
79232161994Stromal expression of c-Ets1 transcription factor correlates with tumor invasion.Wernert N et al
119767352002The Ets 1 transcription factor is upregulated during inflammatory angiogenesis in rheumatoid arthritis.Wernert N et al
128985912003Ets 1 is expressed in capillary blood vessels but not in lymphatics.Wernert N et al
13705941992c-ets1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans.Wernert N et al
177859522007Ets-1 proto-oncogene as a potential predictor for poor prognosis of lung adenocarcinoma.Yamaguchi E et al
95287931998A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions.Yang C et al

Other Information

Locus ID:

NCBI: 2113
MIM: 164720
HGNC: 3488
Ensembl: ENSG00000134954


dbSNP: 2113
ClinVar: 2113
TCGA: ENSG00000134954


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Dorso-ventral axis formationKEGGko04320
Renal cell carcinomaKEGGko05211
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
Dorso-ventral axis formationKEGGhsa04320
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Ras signaling pathwayKEGGhsa04014
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
198381932009Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.332
176715022007Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer.328
201691772010Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.143
201691772010Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.143
214446772011miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer.115
200197982009DNA specificity determinants associate with distinct transcription factor functions.110
185387352008The role of SPINK1 in ETS rearrangement-negative prostate cancers.108
196573772009ETS gene fusions in prostate cancer.101
177214412007New androgen receptor genomic targets show an interaction with the ETS1 transcription factor.97
210814892011miR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells.91


Andreas Lindstrot ; Berit Langer ; Nicolas Wernert

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

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: