title: CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation.
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.
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Yongna
authors.initials: Y
authors.lastname: Fan
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mingpeng
authors.initials: M
authors.lastname: She
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
mesh_terms: 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
chemical_list: 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