title: Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3.
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.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-0618, USA.
authors.forename: C Z
authors.initials: CZ
authors.lastname: Song
authors.forename: X
authors.initials: X
authors.lastname: Tian
authors.forename: T D
authors.initials: TD
authors.lastname: Gelehrter
mesh_terms: D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D017395:Plasminogen Activator Inhibitor 1; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D008156:Luciferases