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The stability of cyclooxygenase 2 (Cox-2) mRNA is regulated positively by proinflammatory stimuli acting through mitogen-activated protein kinase (MAPK) p38 and negatively by anti-inflammatory glucocorticoids such as dexamethasone. A tetracycline-regulated reporter system was used to investigate mechanisms of regulation of Cox-2 mRNA stability. Dexamethasone was found to destabilize beta-globin-Cox-2 reporter mRNAs by inhibiting p38. This inhibition occurred at the level of p38 itself: stabilization of reporter mRNA by a kinase upstream of p38 was blocked by dexamethasone, while stabilization by a kinase downstream of p38 was insensitive to dexamethasone. Inhibition of p38 activity by dexamethasone was observed in a variety of cell types treated with different activating stimuli. Furthermore, inhibition of p38 was antagonized by the anti-glucocorticoid RU486 and was delayed and actinomycin D sensitive, suggesting that ongoing glucocorticoid receptor-dependent transcription is required.

Original publication

DOI

10.1128/MCB.21.3.771-780.2001

Type

Journal article

Journal

Mol Cell Biol

Publication Date

02/2001

Volume

21

Pages

771 - 780

Keywords

3' Untranslated Regions, Anti-Inflammatory Agents, Base Sequence, Cyclooxygenase 2, Dactinomycin, Dexamethasone, Enzyme Inhibitors, Gene Expression, Genes, Reporter, Globins, HeLa Cells, Humans, Isoenzymes, Membrane Proteins, Mifepristone, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Prostaglandin-Endoperoxide Synthases, RNA Stability, RNA, Messenger, Tetracycline, p38 Mitogen-Activated Protein Kinases