Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators

被引:73
作者
Schroer, K
Zhu, Y
Saunders, MA
Deng, WG
Xu, XM
Meyer-Kirchrath, J
Wu, KK
机构
[1] Univ Texas, Sch Med, Div Hematol, Hlth Sci Ctr, Houston, TX 77030 USA
[2] Univ Texas, Hlth Sci Ctr, Vasc Biol Res Ctr, Inst Mol Med, Houston, TX 77030 USA
[3] Univ Dusseldorf, Inst Pharmakol & Klin Pharmakol, D-4000 Dusseldorf, Germany
关键词
prostaglandins; interleukins; endothelium;
D O I
10.1161/01.CIR.0000018127.10968.34
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-a. 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.
引用
收藏
页码:2760 / 2765
页数:6
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