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Influence of induced reactive oxygen species in p53-mediated cell fate decisions.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2003 Dec; Vol. 23 (23), pp. 8576-85. - Publication Year :
- 2003
-
Abstract
- The p53 tumor suppressor gene can induce either apoptosis or a permanent growth arrest (also termed senescence) phenotype in response to cellular stresses. We show that the increase in intracellular reactive oxygen species (ROS) associated with the magnitude of p53 protein expression correlated with the induction of either senescence or apoptosis in both normal and cancer cells. ROS inhibitors ameliorated both p53-dependent cell fates, implicating ROS accumulation as an effector in each case. The absence of Bax or PUMA strongly inhibited both p53-induced apoptosis and ROS increase, indicating an important role these p53 targets affecting mitochondrial function genes in p53-mediated ROS accumulation. Moreover, physiological p53 levels in combination with an exogenous ROS source were able to convert a p53 senescence response into apoptosis. All of these findings establish a critical role of ROS accumulation and mitochondrial function in p53-dependent cell fates and show that other ROS inducers can collaborate with p53 to influence these fate decisions. Thus, our studies imply that therapeutic agents that generate ROS are more likely to be toxic for normal cells than p53-negative tumor cells and provide a rationale for identifying therapeutic agents that do not complement p53 in ROS generation to ameliorate the cytotoxic side effects in normal cells.
- Subjects :
- Apoptosis Regulatory Proteins
Base Sequence
Cell Line
Cell Line, Tumor
DNA genetics
Humans
Male
Mitochondria metabolism
Oxidative Stress
Phenotype
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
bcl-2-Associated X Protein
Apoptosis genetics
Apoptosis physiology
Cellular Senescence genetics
Cellular Senescence physiology
Genes, p53
Proto-Oncogene Proteins c-bcl-2
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 23
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 14612402
- Full Text :
- https://doi.org/10.1128/MCB.23.23.8576-8585.2003