First Author | Li G | Year | 2006 |
Journal | Mol Endocrinol | Volume | 20 |
Issue | 5 | Pages | 1025-34 |
PubMed ID | 16423881 | Mgi Jnum | J:108328 |
Mgi Id | MGI:3623699 | Doi | 10.1210/me.2005-0145 |
Citation | Li G, et al. (2006) Role of steroid receptor coactivators in glucocorticoid and transforming growth factor beta regulation of plasminogen activator inhibitor gene expression. Mol Endocrinol 20(5):1025-34 |
abstractText | 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. |