The Transcription Factor TEAD1 Represses Smooth Muscle-specific Gene Expression by Abolishing Myocardin Function
The Transcription Factor TEAD1 Represses Smooth Muscle-specific Gene Expression by Abolishing Myocardin Function
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DOI：
10.1074/jbc.m113.515817
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发表时间：
2014-02-07
影响因子：
4.8
通讯作者：
Zhou, Jiliang
中科院分区：
文献类型：
--
作者：
Liu, Fang;Wang, Xiaobo;Zhou, Jiliang
背景：TEAD1在平滑肌特异性基因表达中的功能尚不清楚。结果：TEAD1在动脉损伤后被诱导，通过破坏心肌素功能抑制平滑肌特异性基因的表达。结论：TEAD1是一种新的平滑肌收缩基因表达抑制因子。意义：本研究为TEAD1在平滑肌细胞中促进表型转换提供了新的证据。TEAD（转录增强子激活子结构域）蛋白共享一个进化上保守的dna结合TEA结构域，该结构域与MCAT顺式调控元件结合。先前的研究表明，TEAD蛋白参与调节平滑肌-肌动蛋白的表达。然而，TEAD蛋白是否在调节血管平滑肌细胞中其他基因的表达中发挥更广泛的作用仍不确定。在这项研究中，我们发现TEAD1的表达在平滑肌细胞表型调节过程中被显著诱导，并与平滑肌特异性基因表达呈负相关。我们进一步证明TEAD1在抑制平滑肌特异性基因（包括平滑肌肌动蛋白）的表达中发挥了新的作用，通过废除心肌素（平滑肌分化的关键介质）的促生功能。在机制上，我们发现TEAD1与心肌素竞争结合血清反应因子（SRF），导致心肌素和SRF相互作用中断，从而减弱平滑肌特异性基因的表达。这项研究首次证明TEAD1是一种新的平滑肌特异性基因表达的一般抑制因子，通过干扰心肌素与SRF的结合。
Background: The function of TEAD1 in the expression of smooth muscle-specific genes is unknown. Results: TEAD1 is induced after arterial injury and suppresses the expression of smooth muscle-specific genes by abolishing myocardin function. Conclusion: TEAD1 is a novel repressor for smooth muscle contractile gene expression. Significance: This study provides novel evidence that TEAD1 is critical for promoting phenotypic switching in smooth muscle cells.The TEAD (transcriptional enhancer activator domain) proteins share an evolutionarily conserved DNA-binding TEA domain, which binds to the MCAT cis-acting regulatory element. Previous studies have shown that TEAD proteins are involved in regulating the expression of smooth muscle -actin. However, it remains undetermined whether TEAD proteins play a broader role in regulating expression of other genes in vascular smooth muscle cells. In this study, we show that the expression of TEAD1 is significantly induced during smooth muscle cell phenotypic modulation and negatively correlates with smooth muscle-specific gene expression. We further demonstrate that TEAD1 plays a novel role in suppressing expression of smooth muscle-specific genes, including smooth muscle -actin, by abolishing the promyogenic function of myocardin, a key mediator of smooth muscle differentiation. Mechanistically, we found that TEAD1 competes with myocardin for binding to serum response factor (SRF), resulting in disruption of myocardin and SRF interactions and thereby attenuating expression of smooth muscle-specific genes. This study provides the first evidence demonstrating that TEAD1 is a novel general repressor of smooth muscle-specific gene expression through interfering with myocardin binding to SRF.