Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation

doi:10.1073/pnas.0611639104

Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation

*Molecular Cardiology Research Institute, Department of Medicine, and Division of Cardiology, New England Medical Center Hospitals, Tufts University School of Medicine, Boston, MA 02111;
^‡Centre for Clinical and Basic Research, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele, 00163 Rome, Italy; and
^†Department of Medicine, Wayne State University, 421 East Canfield Avenue, Detroit, MI 48201

Communicated by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, December 29, 2006 (received for review December 9, 2006)

Abstract

Abnormal proliferation of vascular smooth muscle cells (VSMCs) constitutes a key event in atherosclerosis, neointimal hyperplasia, and the response to vascular injury. Estrogen receptor α (ERα) mediates the protective effects of estrogen in injured blood vessels and regulates ligand-dependent gene expression in vascular cells. However, the molecular mechanisms mediating ERα-dependent VSMC gene expression and VSMC proliferation after vascular injury are not well defined. Here, we report that the ER coactivator steroid receptor coactivator 3 (SRC3) is also a coactivator for the major VSMC transcription factor myocardin, which is required for VSMC differentiation to the nonproliferative, contractile state. The N terminus of SRC3, which contains a basic helix-loop-helix/Per-ARNT-Sim protein–protein interaction domain, binds the C-terminal activation domain of myocardin and enhances myocardin-mediated transcriptional activation of VSMC-specific, CArG-containing promoters, including the VSMC-specific genes SM22 and myosin heavy chain. Suppression of endogenous SRC3 expression by specific small interfering RNA attenuates myocardin transcriptional activation in cultured cells. The SRC3–myocardin interaction identifies a site of convergence for nuclear hormone receptor-mediated and VSMC-specific gene regulation and suggests a possible mechanism for the vascular protective effects of estrogen on vascular injury.

Footnotes

^§To whom correspondence should be addressed. E-mail: mmendelsohn{at}tufts-nemc.org
Author contributions: H.J.L., Z.H., R.K., and M.M. designed research; H.J.L., Z.H., and Q.L. performed research; Q.L., L.L., and R.K. contributed new reagents/analytic tools; H.J.L., Z.H., R.K., and M.M. analyzed data; H.J.L. and M.M. wrote the paper; and M.M. directed all aspects of design and analysis of data.
The authors declare no conflict of interest.
Abbreviations:

SRC,

steroid receptor coactivator;

ER,

estrogen receptor;

VSMC,

vascular smooth muscle cell;

NHR,

nuclear hormone receptor;

CBP,

cAMP response element-binding protein binding protein;

TAD,

transactivation domain;

DBD,

DNA binding domain;

bHLH,

basic helix–loop–helix;

PAS,

Per-ARNT-Sim;

SRF,

serum response factor;

MRTF,

myocardin-related transcription factor.