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HGNC Approved Gene Symbol: ETV4
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:43,527,846-43,546,340 (from NCBI)
Higashino et al. (1993) cloned a cDNA for a protein that binds to the adenovirus E1A enhancer by screening a HeLa cell expression library with an oligomer for the E1AF DNA sequence. The cDNA encodes a 462-amino acid protein that showed sequence similarity within the ETS domain, a region required for sequence-specific DNA binding by members of the ETS oncogene family. E1AF is about 94% identical to the mouse PEA3 protein (polyomavirus enhancer activator-3). Northern blot analysis detected a 2.5-kb mRNA in HeLa cells whose levels increased during the early phase of adenovirus infection.
Higashino et al. (1995) showed that E1AF can activate the promoters of various matrix metalloproteinases, genes whose expression is associated with tumor cell invasion and metastasis, by 10 to 20 fold.
Vitari et al. (2011) identified COP1 (608067) as a tumor suppressor that negatively regulates ETV1 (600541), ETV4, and ETV5 (601600). ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wildtype ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN (601728) enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. Vitari et al. (2011) concluded that their findings identified COP1 as a tumor suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.
Isobe et al. (1995) used Southern blot analysis of DNA from hybrid cell panels to map the ETV4 gene to chromosome 17. For regional localization to 17q12-q21, they used hybrids retaining well-defined portions of chromosome 17. For refined localization to 17q21, they used fluorescence in situ hybridization.
ETV4/EWS Fusion Gene
Kaneko et al. (1996) identified a somatic t(17;22)(q12;q12) translocation in a MIC2 (CD99; 313470) antigen-positive undifferentiated sarcoma of infancy. On Southern blot analysis, EWS (133450) and E1AF cDNA probes hybridized to the same rearranged band, indicating that an EWS-E1AF fusion gene was formed in the tumor. Further Southern blot analysis showed that the breakpoint was in the region upstream to the ETS domain of the E1AF gene. Kaneko et al. (1996) concluded that the RNA binding domain of EWS may have been replaced by the DNA binding domain of E1AF in the EWS-E1AF fusion protein as in other fusion proteins previously characterized in various forms of Ewing sarcoma (612219).
Urano et al. (1996) identified a chimeric gene between the transactivation domain of EWS and E1AF in an extraskeletal Ewing sarcoma.
In the Ewing sarcoma tumors described by Kaneko et al. (1996) and Urano et al. (1996), Ishida et al. (1998) determined that the chimeric transcript represented an in-frame fusion between the 5-prime terminal region of EWSR1 and the 3-prime end of ETV4. The chimeric transcript could thus serve as a template for expression of a protein composed of the N-terminal portion of EWSR1 fused to the DNA-binding domain of ETV4. Long PCR and sequence analysis of genomic DNA revealed that either exon 8 or intron 7 of EWSR1 was fused to the same intron of ETV4 in both tumors. The 159-bp Alu-like sequence was repeated in the breakpoint region of the ETV4 gene, suggesting a mechanism of EWSR1-ETV4 gene fusion.
Lu et al. (2009) found that Etv4 and Etv5 (601600) are expressed at the ureteric bud tip and that they are among a set of genes upregulated by Gdnf (600837)-Ret (164761) signaling during mouse kidney development. Knockout of Etv5 was embryonic lethal prior to kidney development; however, both Etv4 -/- embryos and Etv4 +/- Etv5 +/- compound heterozygotes appeared grossly normal but occasionally showed renal agenesis, and Etv4 -/- Etv5 +/- newborn mice showed hypoplastic or missing kidneys. Lu et al. (2009) identified several genes whose expression in the ureteric bud depended on Etv4 and Etv5, including Cxcr4 (162643), Myb (189990), Met (164860), and Mmp14 (600754). The authors concluded that ETV4 and ETV5 play a role in branching morphogenesis in the developing kidney.
Higashino, F., Yoshida, K., Fujinaga, Y., Kamio, K., Fujinaga, K. Isolation of a cDNA encoding the adenovirus E1A enhancer binding protein: a new human member of the ets oncogene family. Nucleic Acids. Res. 21: 547-553, 1993. [PubMed: 8441666] [Full Text: https://doi.org/10.1093/nar/21.3.547]
Higashino, F., Yoshida, K., Noumi, T., Seiki, M., Fujinaga, K. Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters. Oncogene 10: 1461-1463, 1995. [PubMed: 7731700]
Ishida, S., Yoshida, K., Kaneko, Y., Tanaka, Y., Sasaki, Y., Urano, F., Umezawa, A., Hata, J., Fujinaga, K. The genomic breakpoint and chimeric transcripts in the EWSR1-ETV4/E1AF gene fusion in Ewing sarcoma. Cytogenet. Cell Genet. 82: 278-283, 1998. [PubMed: 9858836] [Full Text: https://doi.org/10.1159/000015119]
Isobe, M., Yamagishi, F., Yoshida, K., Higashino, F., Fujinaga, K. Assignment of the ets-related transcription factor E1A-F gene (ETV4) to human chromosome region 17q21. Genomics 28: 357-359, 1995. [PubMed: 8530053] [Full Text: https://doi.org/10.1006/geno.1995.1158]
Kaneko, Y., Yoshida, K., Handa, M., Toyoda, Y., Nishihira, H., Tanaka, Y., Sasaki, Y., Ishida, S., Higashino, F., Fujinaga, K. Fusion of an ETS-family gene, E1AF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. Genes Chromosomes Cancer 15: 115-121, 1996. [PubMed: 8834175] [Full Text: https://doi.org/10.1002/(SICI)1098-2264(199602)15:2<115::AID-GCC6>3.0.CO;2-6]
Lu, B. C., Cebrian, C., Chi, X., Kuure, S., Kuo, R., Bates, C. M., Arber, S., Hassell, J., MacNeil, L., Hoshi, M., Jain, S., Asai, N., Takahashi, M., Schmidt-Ott, K. M., Barasch, J., D'Agati, V., Costantini, F. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature Genet. 41: 1295-1302, 2009. Note: Erratum: Nature Genet. 42: 361 only, 2010. [PubMed: 19898483] [Full Text: https://doi.org/10.1038/ng.476]
Urano, F., Umezawa, A., Hong, W., Kikuchi, H., Hata, J. A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma. Biochem. Biophys. Res. Commun. 219: 608-612, 1996. [PubMed: 8605035] [Full Text: https://doi.org/10.1006/bbrc.1996.0281]
Vitari, A. C., Leong, K. G., Newton, K., Yee, C., O'Rourke, K., Liu, J., Phu, L., Vij, R., Ferrando, R., Couto, S. S., Mohan, S., Pandita, A., Hongo, J.-A., Arnott, D., Wertz, I. E., Gao, W.-Q., French, D. M., Dixit, V. M. COP1 is a tumour suppressor that causes degradation of ETS transcription factors. Nature 474: 403-406, 2011. [PubMed: 21572435] [Full Text: https://doi.org/10.1038/nature10005]