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J. Biol. Chem., Vol. 279, Issue 52, 54241-54247, December 24, 2004

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The Pancreatic Duodenal Homeobox-1 Protein (Pdx-1) Interacts with Histone Deacetylases Hdac-1 and Hdac-2 on Low Levels of Glucose^*

Amber L. Mosley and Sabire Özcan

From the Department of Molecular and Cellular Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536

We have previously demonstrated that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter. Furthermore, we have shown that the glucose-mediated hyperacetylation of histone H4 depends on the recruitment of the histone acetyltransferase p300 by the beta cell-specific transcription factor Pdx-1. In this study, we demonstrate that the histone deacetylases Hdac-1 and Hdac-2 are rapidly recruited to the insulin promoter in the mouse insulinoma cell line MIN6 when cells are switched from high to low glucose media. Moreover, we demonstrate that the beta cell-specific homeodomain protein Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. In vitro studies indicate that the interaction between Pdx-1 and Hdac-1 or Hdac-2 is direct and requires the C terminus of Pdx-1. Treatment of MIN6 cells with okadaic acid, which inhibits the activity of protein phosphatases, abolishes the interaction of Pdx-1 with Hdac-1 and Hdac-2 on low levels of glucose, suggesting the requirement of a dephosphorylation event for this interaction to occur. These data indicate that insulin gene expression is decreased on low levels of glucose by recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the transcription factor Pdx-1.

Received for publication, September 9, 2004 , and in revised form, October 12, 2004.

^* This work was supported by a grant from the American Diabetes Association (to S. Ö.) and by a predoctoral fellowship from the American Heart Association Ohio Valley Affiliate (to A. L. M.). 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.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, MN608 Lexington, KY 40536. Tel.: 859-257-4821; Fax: 859-323-1037; E-mail: sozcan{at}uky.edu.

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