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HGNC Approved Gene Symbol: ELK1
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:47,635,520-47,650,604 (from NCBI)
Rao et al. (1989) identified 2 new members of the ETS (164720, 164740) oncogene superfamily, ELK1 and ELK2. The ELK or related sequences appear to be transcriptionally active in testis and lung.
Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues. Serum response factor (SRF; 600589) activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin (606127), and ternary complex factors (TCFs) of the ETS-domain family, respectively. Wang et al. (2004) showed that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by ELK1, a TCF that acts as a myogenic repressor. The opposing influences of myocardin and ELK1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directed ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. Wang et al. (2004) concluded that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.
By coimmunoprecipitation, electron microscopy, and fractionation of adult rat brain, Barrett et al. (2006) found that Elk1 associated with the mitochondrial permeability transition pore complex, a structure involved in both apoptotic and necrotic cell death. The association of Elk1 with mitochondria increased following proapoptotic stimuli. Overexpression of Elk1 in primary neurons decreased cell viability, whereas small interfering RNA-mediated Elk1 knockdown increased cell viability. The decreased viability induced by Elk1 overexpression was blocked by an inhibitor of the permeability transition pore complex.
Using time-resolved nuclear magnetic resonance spectroscopy, Mylona et al. (2016) found that ERK2 (176948) phosphorylation proceeded at markedly different rates at 8 transcriptional activation domain (TAD) sites in vitro, which were classified as fast, intermediate, and slow. Mutagenesis experiments showed that phosphorylation of fast and intermediate sites promoted Mediator interaction and transcriptional activation, whereas modification of slow sites counteracted both functions, thereby limiting ELK1 output. Progressive ELK1 phosphorylation thus ensures a self-limiting response to ERK activation, which occurs independently of antagonizing phosphatase activity.
By analysis of somatic cell hybrids and in situ hybridization, Rao et al. (1989) mapped the ELK1 gene to Xp11.2 and the ELK2 gene to 14q32.3. The former is near the translocation breakpoint seen in t(X;18)(p11.2;q11.2), which is characteristic of synovial sarcoma; the latter is near the 14q32 breakpoint seen in ataxia-telangiectasia and other T-cell malignancies. Janz et al. (1994) used fluorescence in situ hybridization and a panel of tumor-derived somatic cell hybrids to assign the ELK1 gene to Xp11.4-p11.2, distal to the OATL1 region (311240). Tamai et al. (1995) used interspecific backcross analysis to map the Elk gene to the mouse X chromosome. Giovane et al. (1995) mapped ELK1 to human Xp11.2-p11.1 and to mouse XA1-A3 by in situ hybridization.
PSEUDOGENES
Yamauchi et al. (1999) found by sequence analysis that the ELK2 locus on 14q32.2 that was identified by Rao et al. (1989) is actually a processed pseudogene (ELK2P1) of ELK1.
Barrett, L. E., Van Bockstaele, E. J., Sul, J. Y., Takano, H., Haydon, P. G., Eberwine, J. H. Elk-1 associates with the mitochondrial permeability transition pore complex in neurons. Proc. Nat. Acad. Sci. 103: 5155-5160, 2006. [PubMed: 16549787] [Full Text: https://doi.org/10.1073/pnas.0510477103]
Giovane, A., Sobieszczuk, P., Mignon, C., Mattei, M.-G., Wasylyk, B. Locations of the ets subfamily members net, elk1, and sap1 (ELK3, ELK1, and ELK4) on three homologous regions of the mouse and human genomes. Genomics 29: 769-772, 1995. [PubMed: 8575773] [Full Text: https://doi.org/10.1006/geno.1995.9938]
Janz, M., Lehmann, U., Olde Weghuis, D., de Leeuw, B., Geurts van Kessel, A., Gilgenkrantz, S., Hipskind, R. A., Nordheim, A. Refined mapping of the human Ets-related gene Elk-1 to Xp11.2-p11.4, distal to the OATL1 region. Hum. Genet. 94: 442-444, 1994. [PubMed: 7927346] [Full Text: https://doi.org/10.1007/BF00201610]
Mylona, A., Theillet, F.-X., Foster, C., Cheng, T. M., Miralles, F., Bates, P. A., Selenko, P., Treisman, R. Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation. Science 354: 233-237, 2016. [PubMed: 27738173] [Full Text: https://doi.org/10.1126/science.aad1872]
Rao, V. N., Huebner, K., Isobe, M., ar-Rushdi, A., Croce, C. M., Reddy, E. S. P. Elk, tissue-specific ets-related genes on chromosomes X and 14 near translocation breakpoints. Science 244: 66-70, 1989. [PubMed: 2539641] [Full Text: https://doi.org/10.1126/science.2539641]
Tamai, Y., Taketo, M., Nozaki, M., Seldin, M. F. Mouse Elk oncogene maps to chromosome X and a novel Elk oncogene (Elk3) maps to chromosome 10. Genomics 26: 414-416, 1995. [PubMed: 7601474] [Full Text: https://doi.org/10.1016/0888-7543(95)80232-b]
Wang, Z., Wang, D.-Z., Hockemeyer, D., McAnally, J., Nordheim, A., Olson, E. N. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428: 185-189, 2004. [PubMed: 15014501] [Full Text: https://doi.org/10.1038/nature02382]
Yamauchi, T., Toko, M., Suga, M., Hatakeyama, T., Isobe, M. Structural organization of the human Elk1 gene and its processed pseudogene Elk2. DNA Res. 6: 21-27, 1999. [PubMed: 10231026] [Full Text: https://doi.org/10.1093/dnares/6.1.21]