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PNAS 96 (21): 11776-11781

Copyright © 1999 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

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

Chao-Zhong Song*, Xin Tian*, and Thomas D. Gelehrter*,{dagger},{ddagger}

Departments of *Human Genetics and {dagger}Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0618

Accepted for publication August 10, 1999.

Received for publication April 30, 1999.

Abstract: The transforming growth factor-β (TGF-β) 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-β transcriptional activation of the type-1 plasminogen activator inhibitor (PAI-1) gene in a ligand-dependent manner. Similarly, GR represses TGF-β activation of the TGF-β 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-β signaling pathways.

{ddagger} To whom reprint requests should be addressed. E-mail: tdgum{at}umich.edu.

Communicated by Keith R. Yamamoto, University of California, San Francisco, CA

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