p53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced apoptosis

Jeong A. Han, Jong Il Kim, Pat P. Ongusaha, Daniel H. Hwang, Leslie R. Ballou, Alka Mahale, Stuart A. Aaronson, Sam W. Lee

Research output: Contribution to journalArticle

172 Scopus citations

Abstract

The identification of transcriptional targets of the tumor suppressor p53 is crucial in understanding mechanisms by which it affects cellular outcomes. Through expression array analysis, we identified cyclooxygenase 2 (Cox-2), whose expression was inducible by wild-type p53 and DNA damage. We also found that p53-induced Cox-2 expression results from p53-mediated activation of the Ras/Raf/MAPK cascade, as demonstrated by suppression of Cox-2 induction in response to p53 by dominant-negative Ras or Raf1 mutants. Furthermore, heparin-binding epidermal growth factor-like growth factor (HB-EGF), a p53 downstream target gene, induced Cox-2 expression, implying that Cox-2 is an ultimate effector in the p53→HB-EGF→Ras/Raf/MAPK→Cox-2 pathway. p53-induced apoptosis was enhanced greatly in Cox-2 knock-out cells as compared with wild-type cells, suggesting that Cox-2 has an abrogating effect on p53-induced apoptosis. Also, a selective Cox-2 inhibitor, NS-398, significantly enhanced genotoxic stress-induced apoptosis in several types of p53+/+ normal human cells, through a caspase-dependent pathway. Together, these results demonstrate that Cox-2 is induced by p53-mediated activation of the Ras/Raf/ERK cascade, counteracting p53-mediated apoptosis. This anti-apoptosis effect may be a mechanism to abate cellular stresses associated with p53 induction.

Original languageEnglish (US)
Pages (from-to)5635-5644
Number of pages10
JournalEMBO Journal
Volume21
Issue number21
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

Keywords

  • Apoptosis
  • Cell survival
  • Cox-2
  • MAPK
  • p53

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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    Han, J. A., Kim, J. I., Ongusaha, P. P., Hwang, D. H., Ballou, L. R., Mahale, A., Aaronson, S. A., & Lee, S. W. (2002). p53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced apoptosis. EMBO Journal, 21(21), 5635-5644. https://doi.org/10.1093/emboj/cdf591