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J. Biol. Chem., Vol. 279, Issue 34, 35403-35411, August 20, 2004

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Transcriptional Regulation of Cyclooxygenase-2 Gene in Pancreatic -Cells^*

Fan Yang and David Bleich

From the Susan and Leslie Gonda (Goldschmied) Diabetes & Genetic Research Center, Department of Diabetes, Endocrinology, & Metabolism, City of Hope National Medical Center, Duarte, California 91010

Prostaglandin E₂ (PGE₂) has been shown to negatively affect pancreatic -cell function, and its inducible synthesis is mediated in part by cycloxygenase-2 (COX-2). Regulation of basal and inducible COX-2 gene expression in pancreatic -cells is not fully understood. In this report, we used pancreatic -cells (RINm5F) to explore the molecular mechanisms regulating COX-2 promoter activity. Through deletion analysis of a –907/+70-bp 5' upstream region of the mouse COX-2 gene, we identified an inhibition domain (–804/–371) and an activation domain (–371/+70). The highest promoter activity was seen when the promoter was reduced to –371 bp. Several cis-acting elements were selected for site-directed mutations in the activation domain. We identified three sites that were essential for basal COX-2 promoter activity: 1) CCAAT/enhancer-binding protein (C/EBP), 2) aryl hydrocarbon receptor (AhR), and 3) cAMP response element-binding protein (CREB). Single mutation of each individual site inhibited 70–80% of basal COX-2 promoter activity. Double mutation of the AhR and CREB-binding sites showed synergy in repressing COX-2 promoter activity as did mutation of all three sites. We demonstrated that the transcription factors from RINm5F nuclear extracts specifically bound to oligonucleotides containing C/EBP, AhR, or CREB consensus sites. Forskolin, an activator of adenyl cyclase, increased COX-2 promoter activity via the CREB site. COX-2 promoter activity was also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR activator, through the AhR site. Both forskolin and 2,3,7,8-tetrachlorodibenzo-p-dioxin increased COX-2 mRNA in a dose-dependent manner. We consider these three transcriptional regulators of COX-2 expression to be potential targets for the prevention of -cell damage mediated by PGE₂.

Received for publication, April 12, 2004 , and in revised form, June 11, 2004.

^* 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 Diabetes, Endocrinology, & Metabolism, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010. Tel.: 626-256-4673, Ext. 68251; Fax: 626-301-8212; E-mail: dbleich{at}coh.org.

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