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Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators.
- Source :
-
Circulation [Circulation] 2002 Jun 11; Vol. 105 (23), pp. 2760-5. - Publication Year :
- 2002
-
Abstract
- 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.<br />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-alpha. The binding assay and chromatin immunoprecipitation revealed binding of P300 coactivator to the COX-2 promoter region.<br />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.
- Subjects :
- Activating Transcription Factor 4
Cell Line, Transformed
Cells, Cultured
Chromatin metabolism
Cyclic AMP analogs & derivatives
Cyclic AMP metabolism
Cyclooxygenase 2
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Enzyme Induction
Humans
Interleukin-1 pharmacology
Membrane Proteins
Nuclear Proteins metabolism
Promoter Regions, Genetic
Prostaglandins pharmacology
Tetradecanoylphorbol Acetate pharmacology
Transcription Factors metabolism
Transcriptional Activation
Tumor Necrosis Factor-alpha pharmacology
Up-Regulation
Endothelium, Vascular enzymology
Inflammation Mediators pharmacology
Isoenzymes genetics
Prostaglandin-Endoperoxide Synthases genetics
Response Elements
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 105
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 12057991
- Full Text :
- https://doi.org/10.1161/01.cir.0000018127.10968.34