CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation.
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.
Xie
Ping
P
Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing, China.
Fan
Yongna
Y
Zhang
Hua
H
Zhang
Yuan
Y
She
Mingpeng
M
Gu
Dongfeng
D
Patterson
Cam
C
Li
Huihua
H
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099251:Myocardin
D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000099251:Myocardin; C540442:Stub1 protein, rat