Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) constitutes a key event in atherosclerosis, neointimal hyperplasia, and the response to vascular injury. Estrogen receptor alpha (ERalpha) mediates the protective effects of estrogen in injured blood vessels and regulates ligand-dependent gene expression in vascular cells. However, the molecular mechanisms mediating ERalpha-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.
Li
Hui Joyce
HJ
Molecular Cardiology Research Institute, Department of Medicine, and Division of Cardiology, New England Medical Center Hospitals, Tufts University School of Medicine, Boston, MA 02111, USA.
Haque
Zaffar
Z
Lu
Qing
Q
Li
Li
L
Karas
Richard
R
Mendelsohn
Michael
M
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3; D011485:Protein Binding; D014018:Tissue Distribution; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D000099251:Myocardin
D047628:Estrogen Receptor alpha; D004967:Estrogens; D051548:Histone Acetyltransferases; D008024:Ligands; D009687:Nuclear Proteins; D056921:Nuclear Receptor Coactivator 3; D015534:Trans-Activators; D000099251:Myocardin; C538866:NCOA3 protein, human