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Molecular and Cellular Biology, May 2009, p. 2398-2408, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01737-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CHIP Represses Myocardin-Induced Smooth Muscle Cell Differentiation via Ubiquitin-Mediated Proteasomal Degradation

Ping Xie,^1, Yongna Fan,^1, Hua Zhang,¹ Yuan Zhang,¹ Mingpeng She,¹ Dongfeng Gu,² Cam Patterson,^3* and Huihua Li^1*

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, Beijing 100005, China,¹ Department of Evidence Based Medicine and Department of Population Genetics and Prevention, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China,² Division of Cardiology and Carolina Cardiovascular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7126³

Received 12 November 2008/ Returned for modification 22 December 2008/ Accepted 10 February 2009

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.

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* Corresponding author. Mailing address for Huihua Li: 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 100005, China. Phone and fax: 86-(10)6529-6494. E-mail: hhli1995{at}yahoo.com. Mailing address for Cam Patterson: Division of Cardiology and Carolina Cardiovascular Biology, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126. Phone: (919) 843-6477. Fax: (919) 966-1743. E-mail: cpatters{at}med.unc.edu

Published ahead of print on 23 February 2009.

P.X. and Y.F. contributed equally to this work.

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Molecular and Cellular Biology, May 2009, p. 2398-2408, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01737-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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