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Role of Steroid Receptor Coactivators in Glucocorticoid and Transforming Growth Factor ß Regulation of Plasminogen Activator Inhibitor Gene Expression

Departments of Human Genetics (G.L., J.H.H., T.D.G.) and Internal Medicine (T.D.G.), University of Michigan Medical School, Ann Arbor, Michigan 48109-0618

Address all correspondence and requests for reprints to: Thomas D. Gelehrter, Department of Human Genetics, Box 0618, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618.E-mail: tdgum{at}umich.edu.

TGFß 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 TGFß 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 TGFß 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 TGFß-induced activation from the TGFß-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 TGFß-induced activation of the PAI-1 promoter.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   SRC-1  |  GRIP1

Ligands:   Dexamethasone  |  RU486

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