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首页> 外文期刊>Molecular and Cellular Biology >Smooth Muscle-Specific Genes Are Differentially Sensitive to Inhibition by Elk-1
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Smooth Muscle-Specific Genes Are Differentially Sensitive to Inhibition by Elk-1

机译：平滑肌特定基因对Elk-1的抑制差异敏感。

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Understanding the mechanism of smooth muscle cell (SMC) differentiation will provide the foundation for elucidating SMC-related diseases, such as atherosclerosis, restenosis, and asthma. In the current study, overexpression of Elk-1 in SMCs down-regulated expression of several endogenous smooth muscle-restricted proteins, including telokin, SM22α, and smooth muscle α-actin. In contrast, down-regulation of endogenous Elk-1 in smooth muscle cells increased the expression of only telokin and SM22α, suggesting that smooth muscle-specific promoters are differentially sensitive to the inhibitory effects of Elk-1. Consistent with this, overexpression of the DNA binding domain of Elk-1, which acts as a dominant-negative protein by displacing endogenous Elk-1, enhanced the expression of telokin and SM22α without affecting expression of smooth muscle α-actin. Elk-1 suppressed the activity of smooth muscle-restricted promoters, including the telokin promoter that does not contain a consensus Elk-1 binding site, through its ability to block myocardin-induced activation of the promoters. Gel mobility shift and chromatin immunoprecipitation assays revealed that Elk-1 binds to a nonconsensus binding site in the telokin promoter and Elk-1 binding is dependent on serum response factor (SRF) binding to a nearby CArG box. Although overexpression of the SRF-binding B-box domain of Elk-1 is sufficient to repress the myocardin activation of the telokin promoter, this repression is not as complete as that seen with an Elk-1 fragment that includes the DNA binding domain. In addition, reporter gene assays demonstrate that an intact Elk-1 binding site in the telokin promoter is required for Elk-1 to maximally inhibit promoter activity. Together, these data suggest that the differential sensitivity of smooth muscle-specific genes to inhibition by Elk-1 may play a role in the complex changes in smooth muscle-specific protein expression that are observed under pathological conditions.
机译：了解平滑肌细胞（SMC）分化的机制将为阐明与SMC相关的疾病（例如动脉粥样硬化，再狭窄和哮喘）奠定基础。在当前的研究中，SMC中Elk-1的过表达下调了几种内源性平滑肌限制性蛋白的表达，包括telokin，SM22α和平滑肌α-肌动蛋白。相反，平滑肌细胞中内源性Elk-1的下调仅增加了telokin和SM22α的表达，表明平滑肌特异性启动子对Elk-1的抑制作用具有不同的敏感性。与此相一致的是，Elk-1的DNA结合结构域的过表达（通过取代内源性Elk-1成为显性阴性蛋白）增强了telokin和SM22α的表达，而不影响平滑肌α-actin的表达。 Elk-1具有阻断心肌诱导的启动子激活的能力，从而抑制了平滑肌限制性启动子的活性，包括不包含共有的Elk-1结合位点的telokin启动子。凝胶迁移率变化和染色质免疫沉淀试验表明，Elk-1结合到telokin启动子的非共有结合位点，而Elk-1结合则取决于与附近CArG盒结合的血清反应因子（SRF）。尽管Elk-1的SRF结合B-box结构域的过表达足以抑制telokin启动子的心肌激活，但这种抑制作用不如包含DNA结合域的Elk-1片段所见。此外，报告基因测定表明，Elk-1最大限度地抑制启动子活性需要在telokin启动子中完整的Elk-1结合位点。总之，这些数据表明，平滑肌特异性基因对Elk-1抑制的敏感性差异可能在病理条件下观察到的平滑肌特异性蛋白表达的复杂变化中起作用。

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