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Gene Review

ETS2  -  v-ets avian erythroblastosis virus E26...

Homo sapiens

Synonyms: Protein C-ets-2
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Disease relevance of ETS2

  • ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiological features of Down syndrome (DS) [1].
  • These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2 [2].
  • Because chromosomal translocations have been associated with different human leukemias, studies addressing the possible association with the ETS1 (11q23) or ETS2 (21q22.3) loci are reviewed [3].
  • The organization of the PEA3 with the AP1-like motif in the ETS2 promoter resembles the oncogene-responsive unit previously identified in the polyoma virus enhancer region [4].
  • By using astrocytomas of different grades as a source of astrocytes, we demonstrate the presence of ETS1 and ETS2 messenger RNAs and proteins [5].

Psychiatry related information on ETS2

  • Recently, a microduplication on chromosome 21 including ETS2 locus was described in karyotypically 'normal' Down's syndrome and suspected in Alzheimer's disease; when testing Alzheimer's disease-affected brain cortex sections, no obvious difference was observed with the technique used [5].

High impact information on ETS2

  • The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11) [6].
  • Ets2 is located on human chromosome 21 (ref. 8) and is overexpressed in Down's syndrome (trisomy 21) [7].
  • Expression of Ets2, a proto-oncogene and transcription factor, occurs in a variety of cell types [7].
  • Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators [8].
  • Because Ets2 is localized in the nucleus of macrophages and binds to DNA in vitro, the kinetics of its expression suggest a role for Ets2 in the transduction within the nucleus of specific signals received at the cell membrane and involved in securing the survival and/or the development of functional competence of these cells [8].

Biological context of ETS2

  • We have previously shown that ETS transcription factors, regulate cell growth and differentiation, and ETS1 and ETS2 are able to transcriptionally regulate wt p53 gene expression [9].
  • Both the N-terminal region, comprising the transactivation domain, and the C-terminal region of ETS2 associated with ERG and, interestingly, the interaction of ERG through the transactivation domain of ETS2 was DNA-independent [10].
  • ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction [11].
  • In vitro studies have linked the up regulation of ERG expression with stromal cell independence in erythroleukemic clones and shown that the ERG related genes ETS1 and ETS2 have a mitogenic and transforming activity when overexpressed in NIH3T3 cells [12].
  • The coding regions of all of the ETS2 RNA species are the same length and, thus, should contain the same open reading frame [13].

Anatomical context of ETS2

  • ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line, A549 [14].
  • Our results show that resting T cells express high levels of ETS1 mRNA and protein, while expression of ETS2 is undetectable [15].
  • Previously, we have shown that the overexpression of ETS1 and ETS2 genes effects transformation of NIH 3T3 cells and specific transformants produce high levels of the ETS proteins [16].
  • Indeed we report for the first time that the ETS2 overexpression transgenic mouse develops a smaller thymus and lymphocyte abnormalities similar to that observed in DS [1].
  • In an effort to contribute to the construction of a transcriptional map of the DS CHD region we have performed direct cDNA selection using a YAC contig that maps between ETS2 and D21S15 and cDNAs synthesised from fetal heart structures [17].

Associations of ETS2 with chemical compounds


Physical interactions of ETS2

  • Our data shows that T/T homozygotes have a lower t/n-TRFLR, but a stronger TA expression, suggesting that the studied Ets2 binding site is a positive regulator of hTERT gene [22].
  • The Pointed domain has been implicated in protein-protein interactions and we find that Ets2 requires an intact Pointed domain to bind Cdk10 [23].
  • Progressive truncation of reporter constructs indicated that the site of PKA/Ets2 responsiveness lay in a region of the promoter between -126 and -67, which lacks a cAMP response element but contains the functional Ets2-binding site and an activator protein 1 (AP1) site [24].

Regulatory relationships of ETS2


Other interactions of ETS2

  • Results of transient transfection assays with A549 cells indicated that ETS2 had a strong positive effect on GM-CSF promoter activity [14].
  • These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2 [26].
  • Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells [27].
  • ERF (ETS2 Repressor Factor) is a novel member of the ets family of genes, which was isolated by virtue of its interaction with the ets binding site (EBS) within the ETS2 promoter [28].
  • Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells [29].

Analytical, diagnostic and therapeutic context of ETS2


  1. ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Wolvetang, E.J., Wilson, T.J., Sanij, E., Busciglio, J., Hatzistavrou, T., Seth, A., Hertzog, P.J., Kola, I. Hum. Mol. Genet. (2003) [Pubmed]
  2. AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer. Furukawa, T., Kanai, N., Shiwaku, H.O., Soga, N., Uehara, A., Horii, A. Oncogene (2006) [Pubmed]
  3. Molecular analysis of the ets genes and their products. Watson, D.K., Ascione, R., Papas, T.S. Critical reviews in oncogenesis. (1990) [Pubmed]
  4. Positive and negative factors regulate the transcription of the ETS2 gene via an oncogene-responsive-like unit within the ETS2 promoter region. Mavrothalassitis, G.J., Papas, T.S. Cell Growth Differ. (1991) [Pubmed]
  5. Expression of ETS proto-oncogenes in astrocytes in human cortex. Amouyel, P., Gégonne, A., Delacourte, A., Défossez, A., Stéhelin, D. Brain Res. (1988) [Pubmed]
  6. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Ohtani, N., Zebedee, Z., Huot, T.J., Stinson, J.A., Sugimoto, M., Ohashi, Y., Sharrocks, A.D., Peters, G., Hara, E. Nature (2001) [Pubmed]
  7. Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice. Sumarsono, S.H., Wilson, T.J., Tymms, M.J., Venter, D.J., Corrick, C.M., Kola, R., Lahoud, M.H., Papas, T.S., Seth, A., Kola, I. Nature (1996) [Pubmed]
  8. Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators. Boulukos, K.E., Pognonec, P., Sariban, E., Bailly, M., Lagrou, C., Ghysdael, J. Genes Dev. (1990) [Pubmed]
  9. Regulation of the human stress response gene GADD153 expression: role of ETS1 and FLI-1 gene products. Seth, A., Giunta, S., Franceschil, C., Kola, I., Venanzoni, M.C. Cell Death Differ. (1999) [Pubmed]
  10. The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner. Basuyaux, J.P., Ferreira, E., Stéhelin, D., Butticè, G. J. Biol. Chem. (1997) [Pubmed]
  11. ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction. Venanzoni, M.C., Robinson, L.R., Hodge, D.R., Kola, I., Seth, A. Oncogene (1996) [Pubmed]
  12. Human ERG is a proto-oncogene with mitogenic and transforming activity. Hart, A.H., Corrick, C.M., Tymms, M.J., Hertzog, P.J., Kola, I. Oncogene (1995) [Pubmed]
  13. Molecular organization and differential polyadenylation sites of the human ETS2 gene. Watson, D.K., Mavrothalassitis, G.J., Jorcyk, C.L., Smyth, F.E., Papas, T.S. Oncogene (1990) [Pubmed]
  14. ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line, A549. Lu, Z., Kim, K.A., Suico, M.A., Uto, A., Seki, Y., Shuto, T., Isohama, Y., Miyata, T., Kai, H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Bhat, N.K., Thompson, C.B., Lindsten, T., June, C.H., Fujiwara, S., Koizumi, S., Fisher, R.J., Papas, T.S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  16. ETS target genes: identification of egr1 as a target by RNA differential display and whole genome PCR techniques. Robinson, L., Panayiotakis, A., Papas, T.S., Kola, I., Seth, A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  17. Identification and characterization of a new human cDNA from chromosome 21q22.3 encoding a basic nuclear protein. Egeo, A., Mazzocco, M., Sotgia, F., Arrigo, P., Oliva, R., Bergonòn, S., Nizetic, D., Rasore-Quartino, A., Scartezzini, P. Hum. Genet. (1998) [Pubmed]
  18. Conserved chromosomal positions of dual domains of the ets protooncogene in cats, mice, and humans. Watson, D.K., McWilliams-Smith, M.J., Kozak, C., Reeves, R., Gearhart, J., Nunn, M.F., Nash, W., Fowle, J.R., Duesberg, P., Papas, T.S. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  19. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Weng, L.P., Brown, J.L., Baker, K.M., Ostrowski, M.C., Eng, C. Hum. Mol. Genet. (2002) [Pubmed]
  20. Genetic instability of chromosome 3 in HPV-immortalized and tumorigenic human keratinocytes. Montgomery, K.D., Tedford, K.L., McDougall, J.K. Genes Chromosomes Cancer (1995) [Pubmed]
  21. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Yang, B.S., Hauser, C.A., Henkel, G., Colman, M.S., Van Beveren, C., Stacey, K.J., Hume, D.A., Maki, R.A., Ostrowski, M.C. Mol. Cell. Biol. (1996) [Pubmed]
  22. Ets2 binding site single nucleotide polymorphism at the hTERT gene promoter--effect on telomerase expression and telomere length maintenance in non-small cell lung cancer. Hsu, C.P., Hsu, N.Y., Lee, L.W., Ko, J.L. Eur. J. Cancer (2006) [Pubmed]
  23. Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Kasten, M., Giordano, A. Oncogene (2001) [Pubmed]
  24. Combinatorial roles of protein kinase A, Ets2, and 3',5'-cyclic-adenosine monophosphate response element-binding protein-binding protein/p300 in the transcriptional control of interferon-tau expression in a trophoblast cell line. Das, P., Ezashi, T., Gupta, R., Roberts, R.M. Mol. Endocrinol. (2008) [Pubmed]
  25. Characterization of monoclonal antibodies specific to the transcription factor ETS-2 protein. Sanij, E., Scott, B., Wilson, T., Xu, D., Hertzog, P., Wolvetang, E. Immunol. Lett. (2003) [Pubmed]
  26. Down syndrome congenital heart disease: a narrowed region and a candidate gene. Barlow, G.M., Chen, X.N., Shi, Z.Y., Lyons, G.E., Kurnit, D.M., Celle, L., Spinner, N.B., Zackai, E., Pettenati, M.J., Van Riper, A.J., Vekemans, M.J., Mjaatvedt, C.H., Korenberg, J.R. Genet. Med. (2001) [Pubmed]
  27. p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Phelps, M., Darley, M., Primrose, J.N., Blaydes, J.P. Cancer Res. (2003) [Pubmed]
  28. ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. Sgouras, D.N., Athanasiou, M.A., Beal, G.J., Fisher, R.J., Blair, D.G., Mavrothalassitis, G.J. EMBO J. (1995) [Pubmed]
  29. Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells. Kilpatrick, L.M., Kola, I., Salamonsen, L.A. Biol. Reprod. (1999) [Pubmed]
  30. Regulation of transcription of the human presenilin-1 gene by ets transcription factors and the p53 protooncogene. Pastorcic, M., Das, H.K. J. Biol. Chem. (2000) [Pubmed]
  31. Platelet derived growth factor induced tenascin-C transcription is phosphoinositide 3-kinase/Akt-dependent and mediated by Ets family transcription factors. Jinnin, M., Ihn, H., Asano, Y., Yamane, K., Trojanowska, M., Tamaki, K. J. Cell. Physiol. (2006) [Pubmed]
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