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J. Biol. Chem., Vol. 282, Issue 9, 5973-5983, March 2, 2007

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Regulation of Pancreas Duodenum Homeobox-1 Expression by Early Growth Response-1^*

From the Laboratory of Molecular Endocrinology and Diabetes Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114

The homeodomain transcription factor pancreas duodenum homeobox-1 (PDX-1) is a key regulator of pancreatic -cell development, function, and survival. Deficits in PDX-1 expression result in insulin deficiency and hyperglycemia. We previously found that the glucose-responsive transcription factor early growth response-1 (Egr-1) activates the insulin promoter in part by increasing expression levels of PDX-1. We now report that Egr-1 binds and activates multiple regulatory sites within the pdx-1 promoter. We identified consensus Egr-1 recognition sequences within proximal and distal regions of the mouse pdx-1 promoter and demonstrated specific binding of Egr-1 by chromatin immunoprecipitation and electrophoretic mobility shift assays. Overexpression of Egr-1 increased transcriptional activation of the –4500 proximal pdx-1 promoter and of the highly conserved regulatory Areas I, II, and III. Mutagenesis of a specific Egr-1 binding site within Area III substantially decreased Egr-1-mediated activation. Egr-1 increased the transcriptional activation of Areas I and II, despite the absence of Egr-1 recognition sequences within this promoter segment, suggesting that Egr-1 also can regulate the pdx-1 promoter indirectly. Egr-1 increased, and a dominant-negative Egr-1 mutant repressed, the transcriptional activation of distal pdx-1 promoter sequences. Mutagenesis of a specific Egr-1 binding site within regulatory Area IV reduced basal and Egr-1-mediated transcriptional activation. Our data indicate that Egr-1 regulates expression of PDX-1 in pancreatic -cells by both direct and indirect activation of the pdx-1 promoter. We propose that Egr-1 expression levels may act as a sensor in pancreatic -cells to translate extracellular signals into changes in PDX-1 expression levels and pancreatic -cell function.

Received for publication, August 1, 2006 , and in revised form, November 27, 2006.

^* This work was supported by a pilot and feasibility award (to K. E.), Boston Area Diabetes and Endocrinology Research Center Grant P30DK057521, which is supported by the National Institutes of Health, and by a Career Development Award from the American Diabetes Association (to M. K. T.). 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: Laboratory of Molecular Endocrinology and Diabetes Unit, Massachusetts General Hospital, Thier 340, 50 Blossom St., Boston, MA 02114. Tel.: 617-726-6342; Fax: 617-726-6954; E-mail: mthomas1{at}partners.org.

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