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Molecular and Cellular Biology, April 2003, p. 2425-2437, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2425-2437.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Myocardin Is a Critical Serum Response Factor Cofactor in the Transcriptional Program Regulating Smooth Muscle Cell Differentiation

Kevin L. Du,1 Hon S. Ip,2 Jian Li,1 Mary Chen,1 Frederic Dandre,3 William Yu,1 Min Min Lu,1 Gary K. Owens,3 and Michael S. Parmacek1*

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,1 Third Wave Technologies, Madison, Wisconsin 53719,2 Department of Molecular Physiology and Biophysics, University of Virginia, Charlottesville, Virginia 229083

Received 18 November 2002/ Accepted 4 January 2003

The SAP family transcription factor myocardin functionally synergizes with serum response factor (SRF) and plays an important role in cardiac development. To determine the function of myocardin in the smooth muscle cell (SMC) lineage, we mapped the pattern of myocardin gene expression and examined the molecular mechanisms underlying transcriptional activity of myocardin in SMCs and embryonic stem (ES) cells. The human and murine myocardin genes were expressed in vascular and visceral SMCs at levels equivalent to or exceeding those observed in the heart. During embryonic development, the myocardin gene was expressed abundantly in a precise, developmentally regulated pattern in SMCs. Forced expression of myocardin transactivated multiple SMC-specific transcriptional regulatory elements in non-SMCs. By contrast, myocardin-induced transactivation was not observed in SRF-/- ES cells but could be rescued by forced expression of SRF or the SRF DNA-binding domain. Furthermore, expression of a dominant-negative myocardin mutant protein or small-interfering-RNA-induced myocardin knockdown significantly reduced SM22{alpha} promoter activity in SMCs. Most importantly, forced expression of myocardin activated expression of the SM22{alpha}, smooth muscle {alpha}-actin, and calponin-h1 genes in undifferentiated mouse ES cells. Taken together, these data demonstrate that myocardin plays an important role in the SRF-dependent transcriptional program that regulates SMC development and differentiation.

* Corresponding author. Mailing address: Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, 9.123 Founders Pavilion, 3400 Spruce St., Philadelphia, PA 19104. Phone: (215) 662-3140. Fax: (215) 349-8017. E-mail: Michael.parmacek{at}uphs.upenn.edu.

Molecular and Cellular Biology, April 2003, p. 2425-2437, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2425-2437.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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