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.
Li
Gangyong
G
Department of Human Genetics, Box 0618, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618, USA.
Heaton
Joanne H
JH
Gelehrter
Thomas D
TD
D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D051548:Histone Acetyltransferases; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D005938:Glucocorticoids; D006727:Hormone Antagonists; D008024:Ligands; D051958:Nuclear Receptor Coactivator 2; D017395:Plasminogen Activator Inhibitor 1; D011965:Receptors, Glucocorticoid; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015735:Mifepristone; D003907:Dexamethasone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1