Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Anti-Inflammatory Agents / pharmacology
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Base Sequence
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Cyclooxygenase 2
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Dactinomycin / pharmacology
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Dexamethasone / pharmacology*
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects
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Genes, Reporter / drug effects
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Globins / genetics
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HeLa Cells
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Humans
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Isoenzymes / genetics
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Membrane Proteins
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Mifepristone / pharmacology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Molecular Sequence Data
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Prostaglandin-Endoperoxide Synthases / genetics*
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RNA Stability / drug effects*
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism*
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Tetracycline / pharmacology
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p38 Mitogen-Activated Protein Kinases
Substances
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3' Untranslated Regions
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Isoenzymes
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Membrane Proteins
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RNA, Messenger
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Dactinomycin
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Mifepristone
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Dexamethasone
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Globins
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Tetracycline