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J. Biol. Chem., Vol. 280, Issue 46, 38438-38444, November 18, 2005

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Interactions between Areas I and II Direct pdx-1 Expression Specifically to Islet Cell Types of the Mature and Developing Pancreas^*

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

PDX-1 regulates transcription of genes involved in islet cell function and pancreas development. Islet-specific expression is controlled by 5'-flanking sequences from base pair (bp) -2917 to -1918 in transgenic experiments, which encompasses both conserved (i.e. Area I (bp -2761/-2457), Area II (bp -2153/-1923)) and non-conserved pdx-1 sequences. However, only an Area II-driven transgene is independently active in vivo, albeit in only a fraction of islet PDX-1-producing cells. Our objective was to identify the sequences within the -2917/-1918-bp region that act in conjunction with Area II to allow comprehensive expression in islet PDX-1⁺ cells. In cell line-based transfection assays, only Area I effectively potentiated Area II activity. Both Area I and Area II functioned in an orientation-independent manner, whereas synergistic, enhancer-like activation was uniquely found with duplicated Area II. Chimeras of Area II and the generally active SV40 enhancer or the cell-specific insulin enhancer suggested that islet cell-enriched activators were necessary for Area I activation, because Area II-mediated stimulation was reduced by the SV40 enhancer and activated by the insulin enhancer. Several conserved sites within Area I were important in Area I/Area II activation, with binding at bp -2614/-2609 specifically controlled by Nkx2.2, an insulin gene regulator that is required for terminal cell differentiation. The ability of Area I to modulate Area II activation was also observed in vivo, as an Area I/Area II-driven transgene recapitulated the endogenous pdx-1 expression pattern in developing and adult islet cells. These results suggest that Area II is a central pdx-1 control region, whose islet cell activity is uniquely modified by Area I regulatory factors.

Received for publication, August 4, 2005

^* This work was supported by National Institutes of Health Grants RO1 DK-50203 (to R. S.), Training Grant 5T32 CA09385-18 (to J. C. V. V.), and Juvenile Diabetes Research Foundation Postdoctoral 3-2003-579 (to I. A.). The transgenic mice were developed with the assistance of Transgenic/ES Cell Shared Resource Grants CA68485 and DK20593 and by 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.

¹ Current address: National Center for Toxicogenomics, National Institutes of Health, NIEHS, Research Triangle Park, NC 27709.

² 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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