Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade

M Lasa, K R Mahtani, A Finch, G Brewer, J Saklatvala, A R Clark

Research output: Contribution to journalArticlepeer-review

Abstract

A tetracycline-regulated reporter system was used to investigate the regulation of cyclooxygenase 2 (Cox-2) mRNA stability by the mitogen-activated protein kinase (MAPK) p38 signaling cascade. The stable beta-globin mRNA was rendered unstable by insertion of the 2, 500-nucleotide Cox-2 3' untranslated region (3' UTR). The chimeric transcript was stabilized by a constitutively active form of MAPK kinase 6, an activator of p38. This stabilization was blocked by SB203580, an inhibitor of p38, and by two different dominant negative forms of MAPK-activated protein kinase 2 (MAPKAPK-2), a kinase lying downstream of p38. Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta-globin-Cox-2 transcripts. The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as beta-globin-Cox-2 transcripts were partially stabilized by phosphomimetic mutant forms of hsp27. A short (123-nucleotide) fragment of the Cox-2 3' UTR was necessary and sufficient for the regulation of mRNA stability by the p38 cascade and interacted with a HeLa protein immunologically related to AU-rich element/poly(U) binding factor 1.
Original languageEnglish
Pages (from-to)4265-74
Number of pages10
JournalMolecular and Cellular Biology
Volume20
Issue number12
DOIs
Publication statusPublished - Jun 2000

Keywords

  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • HeLa Cells
  • Humans
  • Tetracycline
  • Membrane Proteins
  • RNA, Messenger
  • Anti-Bacterial Agents
  • Base Sequence
  • MAP Kinase Signaling System
  • p38 Mitogen-Activated Protein Kinases
  • Isoenzymes
  • Molecular Sequence Data
  • Mitogen-Activated Protein Kinases
  • Signal Transduction

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