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  • The EMBO Journal (2002) 21, 5635 - 5644
  • doi:10.1093/emboj/cdf591

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

Jeong A. Han2, Jong-Il Kim1, Pat P. Ongusaha1, Daniel H. Hwang3, Leslie R. Ballou4, Alka Mahale5, Stuart A. Aaronson5 and Sam W. Lee1

  1. Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
  2. Present address: Department of Biochemistry and Molecular Biology, Kangwon National University College of Medicine, Chuncheon, South Korea
  3. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA
  4. Department of Veterans Affairs Medical Center, Department of Medicine, University of Tennessee, Memphis, TN 38163, USA
  5. Derald H.Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029, USA

Correspondence to:

Sam W. Lee, E-mail: slee2@caregroup.harvard.edu

Received 14 August 2002; Accepted 18 September 2002; Revised 17 September 2002

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 p53right arrowHB-EGFright arrowRas/Raf/MAPKright arrowCox-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.

  • Keywords:

    • apoptosis,
    • cell survival,
    • Cox-2,
    • MAPK,
    • p53