Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38

M Lasa, M Brook, J Saklatvala, A R Clark

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)771-80
Number of pages10
JournalMolecular and Cellular Biology
Volume21
Issue number3
DOIs
Publication statusPublished - Feb 2001

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

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