Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3.

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.
Mesh Terms:
Animals, COS Cells, DNA-Binding Proteins, Dexamethasone, Genes, Reporter, Glucocorticoids, Humans, Luciferases, Plasmids, Plasminogen Activator Inhibitor 1, Precipitin Tests, Protein Binding, Receptors, Glucocorticoid, Recombinant Fusion Proteins, Signal Transduction, Smad3 Protein, Trans-Activators, Transcriptional Activation, Transfection, Transforming Growth Factor beta, Tumor Cells, Cultured
Proc. Natl. Acad. Sci. U.S.A.
Date: Oct. 12, 1999
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