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HGNC Approved Gene Symbol: ETV1
Cytogenetic location: 7p21.2 Genomic coordinates (GRCh38): 7:13,891,229-13,991,425 (from NCBI)
Jeon et al. (1995) identified the ETV1 gene, the human homolog of the mouse Er81 gene, in a variant Ewing sarcoma (612219) translocation (7;22) which fused the EWS gene (133450) to ETV1.
Coutte et al. (1999) demonstrated that the truncated isoform (ETV1-beta) and the full-length isoform (ETV1-alpha) bind similarly specific DNA ETS-binding sites. Comparison of expression of the alpha and beta forms in the same tissues, such as adrenal or bladder, showed no clear-cut differences.
Flames and Hobert (2009) demonstrated that a simple cis regulatory element, the dopamine (DA) motif, controls the expression of all dopamine pathway genes in all dopaminergic cell types in C. elegans. The DA motif is activated by the ETS transcription factor AST-1. Loss of ast-1 results in the failure of all distinct dopaminergic neuronal subtypes to terminally differentiate. Ectopic expression of ast-1 is sufficient to activate the dopamine pathway in some cellular contexts. Vertebrate dopamine pathway genes also contain phylogenetically conserved DA motifs that can be activated by the mouse ETS transcription factor Etv1, and a specific class of dopamine neurons fails to differentiate in mice lacking Etv1. Moreover, ectopic Etv1 expression induces dopaminergic fate marker expression in neuronal primary cultures. Mouse Etv1 can also functionally substitute for ast-1 in C. elegans. The human DA motif appears to be GGGATGTA. Flames and Hobert (2009) concluded that their studies revealed a simple and apparently conserved regulatory logic of dopamine neuron terminal differentiation and may provide new entry points into the diagnosis or therapy of conditions in which dopamine neurons are defective.
Chi et al. (2010) demonstrated that ETV1 is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT (164920)-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in gastrointestinal stromal tumors (GISTs; see 606764) and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation.
Vitari et al. (2011) identified COP1 (608067) as a tumor suppressor that negatively regulates ETV1, ETV4 (600711), 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.
In mice, Oka et al. (2015) identified 2 distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. The authors showed that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV1, evokes intense drinking behavior, even in fully water-satiated animals. The light-induced response, which is highly specific for water, is both immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT (616440), drastically suppresses drinking, even in water-craving thirsty animals. Oka et al. (2015) concluded that these results revealed an innate brain circuit that can turn an animal's water-drinking behavior on and off and that probably functions as a center for thirst control in the mammalian brain.
Dehorter et al. (2015) demonstrated that a network activity dynamically modulates the properties of fast-spiking interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of fast-spiking basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Dehorter et al. (2015) concluded that interneuron properties are malleable in the adult cortex, at least to a certain extent.
Both the human ETV1 gene and the mouse Er81 gene contain 13 exons in more than 90 kb of genomic DNA (Coutte et al., 1999).
Jeon et al. (1995) localized the ETV1 gene to chromosome 7p22 by breakpoint analysis in the translocation t(7;22)(p22;q12) and by fluorescence in situ hybridization.
Jeon et al. (1995) found that identical EWS nucleotide sequences existed in most of the EWS-FLI1 and EWS-ERG chimeric transcripts and were fused to a portion of the ETV1 gene encoding an ETS domain with sequence-specific DNA-binding activity. These findings confirmed that the fusion of EWS to different ETS family members can result in a similar tumor phenotype.
Tomlins et al. (2005) used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG (165080) and ETV1, were identified as outliers in prostate cancer (see 176807). Tomlins et al. (2005) identified recurrent gene fusions of the 5-prime untranslated region of TMPRSS2 (602060) to ERG or ETV1 in prostate cancer tissues with outlier expression. By using FISH, Tomlins et al. (2005) demonstrated that 23 of 29 prostate cancer samples harbored rearrangements in ERG or ETV1. Cell line experiments suggested that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer.
Tomlins et al. (2007) explored the mechanism of ETV1 outlier expression in human prostate tumors and prostate cancer cell lines. They identified previously unknown 5-prime fusion partners in prostate tumors with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3; 605097) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen repressed gene (C15ORF21; 611314), and a strongly expressed housekeeping gene (HNRNPA2B1; 600124). To study aberrant activation of ETV1, Tomlins et al. (2007) identified 2 prostate cancer cell lines that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-Mb prostate-specific region at 14q13.3-q21.1 in both cell lines, in one by cryptic insertion and in the other by balanced translocation. Because the common factor of these rearrangements is aberrant ETV1 overexpression, Tomlins et al. (2007) recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrated that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci.
Arber et al. (2000) generated mutant mice with 2 targeted alleles of the Er81 gene. In the first allele, the eleventh exon, which encodes part of the ETS DNA-binding domain, was deleted. In the second allele, an SV40 nuclear localization signal fused to lacZ was introduced in-frame with the ATG in the second exon. All mutant mice exhibited severe motor discoordination, yet the specification of motor neurons and induction of muscle spindles occurred normally. The motor defect in the Er81 mutants resulted from a failure of group Ia proprioceptive afferents to form a discrete termination zone in the ventral spinal cord. As a consequence, there was a dramatic reduction in the formation of direct connections between proprioceptive afferents and motor neurons. The authors concluded that ER81 therefore controls a late step in the establishment of functional sensory-motor circuitry in the developing spinal cord.
Arber, S., Ladle, D. R., Lin, J. H., Frank, E., Jessell, T. M. ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell 101: 485-498, 2000. [PubMed: 10850491] [Full Text: https://doi.org/10.1016/s0092-8674(00)80859-4]
Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., Sawyers, C. L. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 467: 849-853, 2010. [PubMed: 20927104] [Full Text: https://doi.org/10.1038/nature09409]
Coutte, L., Monte, D., Imai, K., Pouilly, L., Dewitte, F., Vidaud, M., Adamski, J., Baert, J.-L., de Launoit, Y. Characterization of the human and mouse ETV1/ER81 transcription factor genes: role of the two alternatively spliced isoforms in the human. Oncogene 18: 6278-6286, 1999. [PubMed: 10597226] [Full Text: https://doi.org/10.1038/sj.onc.1203020]
Dehorter, N., Ciceri, G., Bartolini, G., Lim, L., del Pino, I., Marin, O. Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch. Science 349: 1216-1220, 2015. [PubMed: 26359400] [Full Text: https://doi.org/10.1126/science.aab3415]
Flames, N., Hobert, O. Gene regulatory logic of dopamine neuron differentiation. Nature 458: 885-889, 2009. [PubMed: 19287374] [Full Text: https://doi.org/10.1038/nature07929]
Jeon, I.-S., Davis, J. N., Braun, B. S., Sublett, J. E., Roussel, M. F., Denny, C. T., Shapiro, D. N. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene 10: 1229-1234, 1995. [PubMed: 7700648]
Oka, Y., Ye, M., Zuker, C. S. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature 520: 349-352, 2015. [PubMed: 25624099] [Full Text: https://doi.org/10.1038/nature14108]
Tomlins, S. A., Laxman, B., Dhanasekaran, S. M., Helgeson, B. E., Cao, X., Morris, D. S., Menon, A., Jing, X., Cao, Q., Han, B., Yu, J., Wang, L., Montie, J. E., Rubin, M. A., Pienta, K. J., Roulston, D., Shah, R. B., Varambally, S., Mehra, R., Chinnaiyan, A. M. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448: 595-599, 2007. [PubMed: 17671502] [Full Text: https://doi.org/10.1038/nature06024]
Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X.-W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., Lee, C., Montie, J. E., Shah, R. B., Pienta, K. J., Rubin, M. A., Chinnaiyan, A. M. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644-648, 2005. [PubMed: 16254181] [Full Text: https://doi.org/10.1126/science.1117679]
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]