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J. Biol. Chem., Vol. 283, Issue 33, 22612-22619, August 15, 2008

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MafA and MafB Regulate Pdx1 Transcription through the Area II Control Region in Pancreatic β Cells^*

From the Department of Molecular Physiology and Biophysics, Vanderbilt Medical School, Nashville, Tennessee 37232

Pancreatic-duodenal homeobox factor-1 (Pdx1) is highly enriched in islet β cells and integral to proper cell development and adult function. Of the four conserved 5'-flanking sequence blocks that contribute to transcription in vivo, Area II (mouse base pairs -2153/-1923) represents the only mammalian specific control domain. Here we demonstrate that regulation of β-cell-enriched Pdx1 expression by the MafA and MafB transcription factors is exclusively through Area II. Thus, these factors were found to specifically activate through Area II in cell line transfection-based assays, and MafA, which is uniquely expressed in adult islet β cells was only bound to this region in quantitative chromatin immunoprecipitation studies. MafA and MafB are produced in β cells during development and were both bound to Area II at embryonic day 18.5. Expression of a transgene driven by Pdx1 Areas I and II was also severely compromised during insulin⁺ cell formation in MafB^-/- mice, consistent with the importance of this large Maf in β-cell production and Pdx1 expression. These findings illustrate the significance of large Maf proteins to Pdx1 expression in β cells, and in particular MafB during pancreatic development.

Received for publication, April 15, 2008 , and in revised form, June 2, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01 DK42502 & DK50203 (to R. S.) and 5T32 DK07563-20 METP postdoctoral training (to A. V.). This work was also supported in part by the American Diabetes Association (7-04-RA-116, to R. S.) and the Juvenile Diabetes Research Foundation (Advanced Postdoctoral 10-2006-5, to I. A.). Partial support was also provided to the Molecular Biology Core Laboratory by the Vanderbilt University Diabetes Research and Training Center (Public Health Service Grant P60 DK20593). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Tables S1 and S2.

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¹ Present address: Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology, Duke University Medical Center, Durham, NC.

² Present address: Department of Pathology, Vanderbilt Medical School, Nashville, TN.

³ Present address: Program for Developmental Biology & Stem Cell Research, University of Lund, Sweden.

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⁴ To whom correspondence should be addressed. Tel.: 615-322-7026; Fax: 615-322-7236; E-mail: Roland.Stein{at}Vanderbilt.edu.

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