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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

Molecular and cellular biology

Publication Date

02/2001

Volume

21

Pages

771 - 780

Addresses

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London W6 8LH, United Kingdom.

Keywords

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