From the Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912 and.
J Biol Chem. 2014 Feb 7;289(6):3308-16. doi: 10.1074/jbc.M113.515817. Epub 2013 Dec 16.
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 α-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 α-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.
TEAD（转录增强因子激活域）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 顺式作用调节元件结合。先前的研究表明，TEAD 蛋白参与调节平滑肌α-肌动蛋白的表达。然而，TEAD 蛋白是否在血管平滑肌细胞中更广泛地调节其他基因的表达仍未确定。在这项研究中，我们表明 TEAD1 的表达在平滑肌细胞表型调节过程中显著诱导，并与平滑肌特异性基因表达呈负相关。我们进一步证明，TEAD1 通过消除心肌调节素（平滑肌分化的关键介质）的促肌生成功能，在抑制平滑肌特异性基因表达中发挥新的作用，包括平滑肌α-肌动蛋白。从机制上讲，我们发现 TEAD1 与心肌调节素竞争结合血清反应因子（SRF），导致心肌调节素和 SRF 相互作用的破坏，从而减弱平滑肌特异性基因的表达。这项研究首次证明，TEAD1 通过干扰心肌调节素与 SRF 的结合，作为平滑肌特异性基因表达的新型通用抑制剂。
