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Gene Review

ETV4  -  ets variant 4

Homo sapiens

Synonyms: Adenovirus E1A enhancer-binding protein, E1A-F, E1AF, ETS translocation variant 4, PEA3, ...
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Disease relevance of ETV4

  • The ETV4 protein was localised to nuclei of spermatogonia and revealed an intense staining in seminoma cells [1].
  • In the present study, we determined the genomic breakpoint and characterized the chimeric transcript of the EWSR1-ETV4 fusion gene in two t(17;22) Ewing sarcomas [2].
  • E1AF expression was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumor-node-metastasis stage and recurrence [3].
  • E1AF mRNA was detected in 43 (47.8%) of the 90 colorectal tumors [4].
  • E1AF mRNA expression was detected in 64% of the 100 gastric cancer tissues, but was undetectable or only faintly detected in adjacent non-tumor tissues [3].

High impact information on ETV4

  • Target-Induced Transcriptional Control of Dendritic Patterning and Connectivity in Motor Neurons by the ETS Gene Pea3 [5].
  • In this issue, find that this retrograde GDNF-Pea3 signal controls dendrite patterning and assembly of a sensory-motor reflex circuit [6].
  • Glial-derived neurotrophic factor (GDNF), secreted by skeletal muscle, triggers expression of the ETS transcription factor Pea3 in a subset of motor neurons in the spinal cord [6].
  • We have identified that the DNA-binding protein PEA3, which is encoded by a previously isolated gene of the ets family, specifically targeted a DNA sequence on the HER-2/neu promoter and downregulated the promoter activity [7].
  • Expression of PEA3 resulted in preferential inhibition of cell growth and tumor development of HER-2/neu-overexpressing cancer cells [7].

Chemical compound and disease context of ETV4


Biological context of ETV4


Anatomical context of ETV4


Associations of ETV4 with chemical compounds

  • A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element [20].
  • We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells [9].
  • Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity [21].
  • In addition, ETV4 protein levels were diminished after loss of testicular luminal fluid factors [18].
  • The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase [22].

Physical interactions of ETV4

  • Using EMSA analysis we also observed that the EGF stimulated increase in PEA3 transcription factors led to increased binding to specific ETS sites within the MMP-7 promoter [17].
  • Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells [11].
  • Here, we have identified the LIM domain protein LPP as a novel coregulatory binding partner for PEA3 [23].
  • Basic calcium phosphate crystals induce matrix metalloproteinase-1 through the Ras/mitogen-activated protein kinase/c-Fos/AP-1/metalloproteinase 1 pathway. Involvement of transcription factor binding sites AP-1 and PEA-3 [24].
  • Of the oligonucleotides tested, EMSA revealed that TGF-beta treated OA chondrocyte proteins bound only to the AP-1 and PEA-3 [25].

Enzymatic interactions of ETV4


Regulatory relationships of ETV4

  • Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation [27].
  • Since E1A-F is known to activate matrix metalloproteinase genes, the chimera gene may possibly be involved in tumor progression and could be a novel tumor marker for Ewing's sarcoma/PNET [14].
  • Western blot analysis of nuclear extracts from EGF stimulated cells demonstrated that there was an increase in PEA3 protein when compared to non-treated cells [17].
  • BACKGROUND: Recently, PEA3 has been reported to suppress HER-2/neu overexpression by promoter activity and thereby inhibit tumorigenesis of breast cancer both in vitro and in vivo [28].
  • On the other hand, E1AF upregulates p21waf1/cip1 to induce cell cycle arrest when cells are exposed to stress [29].

Other interactions of ETV4


Analytical, diagnostic and therapeutic context of ETV4


  1. Gene signatures of testicular seminoma with emphasis on expression of ets variant gene 4. Gashaw, I., Grümmer, R., Klein-Hitpass, L., Dushaj, O., Bergmann, M., Brehm, R., Grobholz, R., Kliesch, S., Neuvians, T.P., Schmid, K.W., von Ostau, C., Winterhager, E. Cell. Mol. Life Sci. (2005) [Pubmed]
  2. The genomic breakpoint and chimeric transcripts in the EWSR1-ETV4/E1AF gene fusion in Ewing sarcoma. Ishida, S., Yoshida, K., Kaneko, Y., Tanaka, Y., Sasaki, Y., Urano, F., Umezawa, A., Hata, J., Fujinaga, K. Cytogenet. Cell Genet. (1998) [Pubmed]
  3. Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer. Yamamoto, H., Horiuchi, S., Adachi, Y., Taniguchi, H., Nosho, K., Min, Y., Imai, K. Carcinogenesis (2004) [Pubmed]
  4. Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis. Nosho, K., Yoshida, M., Yamamoto, H., Taniguchi, H., Adachi, Y., Mikami, M., Hinoda, Y., Imai, K. Carcinogenesis (2005) [Pubmed]
  5. Target-Induced Transcriptional Control of Dendritic Patterning and Connectivity in Motor Neurons by the ETS Gene Pea3. Vrieseling, E., Arber, S. Cell (2006) [Pubmed]
  6. Retrograde control of neural circuit formation. Deppmann, C.D., Ginty, D.D. Cell (2006) [Pubmed]
  7. The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Xing, X., Wang, S.C., Xia, W., Zou, Y., Shao, R., Kwong, K.Y., Yu, Z., Zhang, S., Miller, S., Huang, L., Hung, M.C. Nat. Med. (2000) [Pubmed]
  8. TMPRSS2:ERG Fusion by Translocation or Interstitial Deletion Is Highly Relevant in Androgen-Dependent Prostate Cancer, But Is Bypassed in Late-Stage Androgen Receptor-Negative Prostate Cancer. Hermans, K.G., van Marion, R., van Dekken, H., Jenster, G., van Weerden, W.M., Trapman, J. Cancer Res. (2006) [Pubmed]
  9. The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells. Fauquette, V., Perrais, M., Cerulis, S., Jonckheere, N., Ducourouble, M.P., Aubert, J.P., Pigny, P., Van Seuningen, I. Biochem. J. (2005) [Pubmed]
  10. LKB1/STK11 Suppresses Cyclooxygenase-2 Induction and Cellular Invasion through PEA3 in Lung Cancer. Upadhyay, S., Liu, C., Chatterjee, A., Hoque, M.O., Kim, M.S., Engles, J., Westra, W., Trink, B., Ratovitski, E., Sidransky, D. Cancer Res. (2006) [Pubmed]
  11. Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene. Menendez, J.A., Vellon, L., Lupu, R. Ann. Oncol. (2005) [Pubmed]
  12. Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? Davidson, B., Goldberg, I., Gotlieb, W.H., Kopolovic, J., Risberg, B., Ben-Baruch, G., Reich, R. Cancer Metastasis Rev. (2003) [Pubmed]
  13. E1A-F is overexpressed early in human colorectal neoplasia and associated with cyclooxygenase-2 and matrix metalloproteinase-7. Boedefeld, W.M., Soong, R., Weiss, H., Diasio, R.B., Urist, M.M., Bland, K.I., Heslin, M.J. Mol. Carcinog. (2005) [Pubmed]
  14. A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma. Urano, F., Umezawa, A., Hong, W., Kikuchi, H., Hata, J. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  15. Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression. Bièche, I., Tozlu, S., Girault, I., Onody, P., Driouch, K., Vidaud, M., Lidereau, R. Carcinogenesis (2004) [Pubmed]
  16. Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). Pendás, A.M., Balbín, M., Llano, E., Jiménez, M.G., López-Otín, C. Genomics (1997) [Pubmed]
  17. Epidermal growth factor upregulates matrix metalloproteinase-7 expression through activation of PEA3 transcription factors. Lynch, C.C., Crawford, H.C., Matrisian, L.M., McDonnell, S. Int. J. Oncol. (2004) [Pubmed]
  18. Putative regulation of expression of members of the Ets variant 4 transcription factor family and their downstream targets in the rat epididymis. Yang, L., Fox, S.A., Kirby, J.L., Troan, B.V., Hinton, B.T. Biol. Reprod. (2006) [Pubmed]
  19. Isolation of a cDNA encoding the adenovirus E1A enhancer binding protein: a new human member of the ets oncogene family. Higashino, F., Yoshida, K., Fujinaga, Y., Kamio, K., Fujinaga, K. Nucleic Acids Res. (1993) [Pubmed]
  20. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. Subbaramaiah, K., Norton, L., Gerald, W., Dannenberg, A.J. J. Biol. Chem. (2002) [Pubmed]
  21. Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). Menendez, J.A., Lupu, R. Current pharmaceutical biotechnology (2006) [Pubmed]
  22. The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase. O'Hagan, R.C., Hassell, J.A. Oncogene (1998) [Pubmed]
  23. The LIM domain protein LPP is a coactivator for the ETS domain transcription factor PEA3. Guo, B., Sallis, R.E., Greenall, A., Petit, M.M., Jansen, E., Young, L., Van de Ven, W.J., Sharrocks, A.D. Mol. Cell. Biol. (2006) [Pubmed]
  24. Basic calcium phosphate crystals induce matrix metalloproteinase-1 through the Ras/mitogen-activated protein kinase/c-Fos/AP-1/metalloproteinase 1 pathway. Involvement of transcription factor binding sites AP-1 and PEA-3. Sun, Y., Wenger, L., Brinckerhoff, C.E., Misra, R.R., Cheung, H.S. J. Biol. Chem. (2002) [Pubmed]
  25. Transforming growth factor-beta induced collagenase-3 production in human osteoarthritic chondrocytes is triggered by Smad proteins: cooperation between activator protein-1 and PEA-3 binding sites. Tardif, G., Reboul, P., Dupuis, M., Geng, C., Duval, N., Pelletier, J.P., Martel-Pelletier, J. J. Rheumatol. (2001) [Pubmed]
  26. PEA3 cooperates with c-Jun in regulation of HER2/neu transcription. Matsui, K., Sugimori, K., Motomura, H., Ejiri, N., Tsukada, K., Kitajima, I. Oncol. Rep. (2006) [Pubmed]
  27. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T. Hum. Mol. Genet. (2006) [Pubmed]
  28. Clinical significance of PEA3 in human breast cancer. Kinoshita, J., Kitamura, K., Tanaka, S., Sugimachi, K., Ishida, M., Saeki, H. Surgery (2002) [Pubmed]
  29. E1AF, an ets-oncogene family transcription factor. Shindoh, M., Higashino, F., Kohgo, T. Cancer Lett. (2004) [Pubmed]
  30. Elevated beta1,4-galactosyltransferase I in highly metastatic human lung cancer cells. Identification of E1AF as important transcription activator. Zhu, X., Jiang, J., Shen, H., Wang, H., Zong, H., Li, Z., Yang, Y., Niu, Z., Liu, W., Chen, X., Hu, Y., Gu, J. J. Biol. Chem. (2005) [Pubmed]
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