Abstract
The transforming growth factor-beta (TGF-beta) family of cytokines and glucocorticoids regulate diverse biological processes through modulating the expression of target genes. Here we report that glucocorticoid receptor (GR) represses TGF-beta transcriptional activation of the type-1 plasminogen activator inhibitor (PAI-1) gene in a ligand-dependent manner. Similarly, GR represses TGF-beta activation of the TGF-beta responsive sequence containing Smad3/4-binding sites. Using mammalian two-hybrid assays, we demonstrate that GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains. Finally, we show that GR interacts with Smad3 both in vitro and in vivo. These results suggest a molecular basis for the cross-regulation between glucocorticoid and TGF-beta signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Dexamethasone / pharmacology
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Genes, Reporter
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Glucocorticoids / pharmacology
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Humans
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Luciferases / metabolism
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Plasmids / metabolism
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Plasminogen Activator Inhibitor 1 / genetics*
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Plasminogen Activator Inhibitor 1 / metabolism
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Precipitin Tests
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Protein Binding
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Receptors, Glucocorticoid / genetics*
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Receptors, Glucocorticoid / metabolism
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Recombinant Fusion Proteins / metabolism
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Signal Transduction*
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Smad3 Protein
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcriptional Activation*
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Transfection
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / genetics*
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Glucocorticoids
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Plasminogen Activator Inhibitor 1
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Receptors, Glucocorticoid
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Recombinant Fusion Proteins
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SMAD3 protein, human
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Smad3 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Dexamethasone
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Luciferases