Published Online
on May 20, 2002

A more recent version of this article appeared on June 11, 2002

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Submitted on January 16, 2002
Revised on March 28, 2002
Accepted on March 28, 2002

Obligatory Role of Cyclic Adenosine Monophosphate Response Element in Cyclooxygenase-2 Promoter Induction and Feedback Regulation by Inflammatory Mediators

Karsten Schroer PhD, Ying Zhu PhD, Michael A. Saunders PhD, Wu-Guo Deng PhD, Xiao-Ming Xu PhD, Jutta Meyer-Kirchrath PhD, and Kenneth K. Wu MD, PhD^*

From the Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology (Y.Z., M.S., W.-G.D., X.-M.X., K.K.W.), University of Texas Health Science Center, Houston, Tex; and Institut für Pharmakologie und Klinische Pharmakologie (K.S., J.M.-K.), Heinrich-Heine-Universtät Düsseldorf, Düsseldorf, Germany.

^* To whom correspondence should be addressed. E-mail: Kenneth.K.Wu{at}uth.tmc.edu.

Background—Cyclooxygenase-2 (COX-2) plays a key role in human inflammatory disorders such as vascular inflammation. COX-2 promoter activity is induced by proinflammatory mediators, but the role of cyclic adenosine monophosphate response element (CRE) in promoter stimulation remains unclear.

Methods and Results—Transient transfection of a 0.9-kb COX-2 promoter fragment bearing CRE mutation abrogated COX-2 promoter activity induced by proinflammatory mediators in human endothelial cells and fibroblasts. Dual mutations of CRE and an upstream CCAAT/enhancer binding protein (C/EBP) site did not have an additional effect. Binding of CREB-2, ATF-2, USF-2, and c-Jun transactivators to a wild-type and CRE-mutated oligonucleotide was analyzed by a novel DNA-binding assay. CREB-2 and ATF-2 in nuclear extracts of unstimulated endothelial cells bound to CRE, whereas USF-2 and c-Jun or c-Fos bound to non-CRE sites. CREB-2 and c-Fos binding was increased by phorbol 12-myristate 13-acetate but not tumor necrosis factor-. The binding assay and chromatin immunoprecipitation revealed binding of P300 coactivator to the COX-2 promoter region.

Conclusions—CRE plays an obligatory role in COX-2 promoter activation by diverse stimuli. CREB-2 and ATF-2 bound to CRE serve as an anchor for P300 interaction with upstream transactivators and downstream transcription machinery.

Key words: prostaglandins • interleukins • endothelium

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