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

The transforming growth factor-beta (TGF-beta) family of cytokines and gluc ocorticoids regulate diverse biological processes through modulating the ex pression of target genes. Here we report that glucocorticoid receptor (GR) represses TGF-beta transcriptional activation of the type-1 plasminogen act ivator inhibitor (PAI-1) gene in a ligand-dependent manner. Similarly, CR r epresses TGF-beta activation of the TGF-beta responsive sequence containing Smad3/4-binding sites. Using mammalian two-hybrid assays, we demonstrate t hat CR inhibits transcriptional activation by both Smad3 and Smad4 C-termin al activation domains. Finally, we show that GR interacts with Smad3 both i n vitro and in vivo. These results suggest a molecular basis for the cross- regulation between glucocorticoid and TGF-beta signaling pathways.