Role of steroid receptor coactivators in glucocorticoid and transforming growth factor beta regulation of plasminogen activator inhibitor gene expression.

TGFbeta is a major regulator of extracellular matrix deposition and a potent inducer of type-1 plasminogen activator inhibitor (PAI-1) gene expression. We have reported that liganded glucocorticoid receptor (GR) represses TGFbeta transactivation of PAI-1 in Hep3B human hepatoma cells and that it interacts functionally and physically with the C-terminal activation ...
domain of Smad3, a mediator of TGFbeta signaling. The ligand binding domain of GR is required for GR-mediated transrepression, but the GR DNA binding domain and activation function 1 domains are not. We report here that overexpression of steroid receptor coactivator-1 (SRC-1) and GR-interacting protein-1 (GRIP-1) enhanced repression by liganded GR, and by a GR mutant defective in repression. Surprisingly, SRC-1 and GRIP-1 also enhanced TGFbeta-induced activation from the TGFbeta-responsive sequence of the PAI-1 gene by a GR-independent mechanism. Coimmunoprecipitation and mammalian one-hybrid experiments demonstrated that SRC-1 and GRIP-1 interact physically with endogenous Smad3 and functionally with the C-terminal domain of Smad3 to directly enhance transcription. Thus, the GR coactivators, SRC-1 and GRIP-1, act as both corepressors of the glucocorticoid repression of PAI-1 gene transcription, and coactivators of TGFbeta-induced activation of the PAI-1 promoter.
Mesh Terms:
Cell Line, Tumor, Dexamethasone, Gene Expression, Gene Expression Regulation, Glucocorticoids, Histone Acetyltransferases, Hormone Antagonists, Humans, Ligands, Mifepristone, Mutation, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 2, Plasminogen Activator Inhibitor 1, Protein Structure, Tertiary, Receptors, Glucocorticoid, Smad3 Protein, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta
Mol. Endocrinol.
Date: May. 01, 2006
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