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

Marina Lasa, Kamal R. Mahtani, Andrew Finch, Gary Brewer, Jeremy Saklatvala, Andrew R. Clark

Research output: Contribution to journalArticlepeer-review

364 Scopus citations

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 β-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 β-globin-Cox-2 transcripts. The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as β-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 (US)
Pages (from-to)4265-4274
Number of pages10
JournalMolecular and cellular biology
Volume20
Issue number12
DOIs
StatePublished - Jun 2000

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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