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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.

Pubmed ID: 17360478

Authors

  • Li HJ
  • Haque Z
  • Lu Q
  • Li L
  • Karas R
  • Mendelsohn M

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 6, 2007

Associated Grants

None

Mesh Terms

  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Estrogen Receptor alpha
  • Estrogens
  • Gene Expression Regulation
  • Histone Acetyltransferases
  • Humans
  • Ligands
  • Muscle, Smooth, Vascular
  • Nuclear Proteins
  • Nuclear Receptor Coactivator 3
  • Protein Binding
  • Tissue Distribution
  • Trans-Activators
  • Transcription, Genetic