p53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced apoptosis
- 1 November 2002
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 21 (21), 5635-5644
- https://doi.org/10.1093/emboj/cdf591
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.Keywords
This publication has 64 references indexed in Scilit:
- Cyclooxygenase-2 Inducing Mcl-1-dependent Survival Mechanism in Human Lung Adenocarcinoma CL1.0 CellsPublished by Elsevier BV ,2001
- COX‐2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX‐2 inhibitor celecoxibThe FASEB Journal, 2001
- Enhanced Epidermal Growth Factor Receptor Signaling in MCF7 Breast Cancer Cells after Long-Term Culture in the Presence of the Pure Antiestrogen ICI 182,780 (Faslodex)Endocrinology, 2001
- Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase ActivityMolecular and Cellular Biology, 2000
- MAPK Mediation of Hypertonicity-stimulated Cyclooxygenase-2 Expression in Renal Medullary Collecting Duct CellsPublished by Elsevier BV ,2000
- Microtubule-interfering Agents Stimulate the Transcription of Cyclooxygenase-2Journal of Biological Chemistry, 2000
- Compensatory Prostaglandin E2 Biosynthesis in Cyclooxygenase 1 or 2 Null CellsThe Journal of Experimental Medicine, 1998
- Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver CellsPublished by Elsevier BV ,1997
- Induction of the growth inhibitor IGF-binding protein 3 by p53Nature, 1995
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993