CHIP Represses Myocardin-Induced Smooth Muscle Cell Differentiation via Ubiquitin-Mediated Proteasomal Degradation
CHIP Represses Myocardin-Induced Smooth Muscle Cell Differentiation via Ubiquitin-Mediated Proteasomal Degradation
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DOI：
10.1128/mcb.01737-08
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发表时间：
2009-02
影响因子：
5.3
通讯作者：
P. Xie;Yongna Fan;Hua Zhang;Y. Zhang;M. She;D. Gu;C. Patterson;Huihua Li
中科院分区：
文献类型：
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作者：
P. Xie;Yongna Fan;Hua Zhang;Y. Zhang;M. She;D. Gu;C. Patterson;Huihua Li
心肌素是血清反应因子（SRF）的共激活因子，在血管平滑肌细胞（SMC）分化过程中起着重要作用。然而，调节myocardin稳定性和活性的分子机制还没有很好地定义。在这里，我们表明，E3连接酶C末端的Hsc70相互作用蛋白（CHIP）抑制心肌依赖性SMC基因的表达和转录活性。CHIP在体内和体外与蛋白酶体相互作用并促进心肌蛋白泛素介导的降解。此外，通过CHIP的心肌蛋白泛素化需要其磷酸化。重要的是，CHIP过表达降低了心肌蛋白依赖性SMC收缩基因表达的水平，并减少了离体动脉收缩性。据我们所知，这些研究结果首次表明，CHIP促进的myocardin蛋白水解在SMC表型和血管张力的生理控制中起着关键作用，这可能对病理生理条件如动脉粥样硬化，高血压和阿尔茨海默病具有重要意义。
ABSTRACT Myocardin, a coactivator of serum response factor (SRF), plays a critical role in the differentiation of vascular smooth muscle cells (SMCs). However, the molecular mechanisms regulating myocardin stability and activity are not well defined. Here we show that the E3 ligase C terminus of Hsc70-interacting protein (CHIP) represses myocardin-dependent SMC gene expression and transcriptional activity. CHIP interacts with and promotes myocardin ubiquitin-mediated degradation by the proteasome in vivo and in vitro. Furthermore, myocardin ubiquitination by CHIP requires its phosphorylation. Importantly, CHIP overexpression reduces the level of myocardin-dependent SMC contractile gene expression and diminishes arterial contractility ex vivo. These findings for the first time, to our knowledge, demonstrate that CHIP-promoted proteolysis of myocardin plays a key role in the physiological control of SMC phenotype and vessel tone, which may have an important implication for pathophysiological conditions such as atherosclerosis, hypertension, and Alzheimer's disease.