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J. Biol. Chem., Vol. 280, Issue 51, 42067-42077, December 23, 2005

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The Smad6-Histone Deacetylase 3 Complex Silences the Transcriptional Activity of the Glucocorticoid Receptor

POTENTIAL CLINICAL IMPLICATIONS^*

Takamasa Ichijo, Antonis Voutetakis¶, Ana P. Cotrim, Nisan Bhattachryya||, Makiko Fujii**, George P. Chrousos¶, and Tomoshige Kino1

From the Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, Gene Therapy and Therapeutics Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, ^||Growth and Development Section, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ^**Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, and ^¶First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece

Glucocorticoids play pivotal roles in the maintenance of homeostasis but, when dysregulated, may also have deleterious effects. Smad6, one of the transforming growth factor (TGF) family downstream transcription factors, interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its Mad homology 2 domain and suppresses GR-mediated transcriptional activity in vitro. Adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo, preventing dexamethasone-induced elevation of blood glucose levels and hepatic mRNA expression of phosphoenolpyruvate carboxykinase, a well known rate-limiting enzyme of liver gluconeogenesis. Smad6 suppresses GR-induced transactivation by attracting histone deacetylase 3 to DNA-bound GR and by antagonizing acetylation of histone H3 and H4 induced by p160 histone acetyltransferase. These results indicate that Smad6 regulates glucocorticoid actions as a corepressor of the GR. From our results and known cross-talks between glucocorticoids and TGF family molecules, it appears that the anti-glucocorticoid actions of Smad6 may contribute to the neuroprotective, anticatabolic and pro-wound healing properties of the TGF family of proteins.

Received for publication, August 24, 2005 , and in revised form, October 20, 2005.

^* This study was supported in part by NICHD, National Institutes of Health (Bethesda, MD). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, Bldg. 10, Clinical Research Center, Rm. 1-3140, 10 Center Dr. MSC 1109, Bethesda, MD 20892-1109. Tel.: 301-496-6417; Fax: 301-402-0884; E-mail: kinot{at}mail.nih.gov.

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