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Molecular and Cellular Biology, December 2003, p. 8576-8585, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8576-8585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Influence of Induced Reactive Oxygen Species in p53-Mediated Cell Fate Decisions

Salvador Macip,1 Makoto Igarashi,1 Petra Berggren,1 Jian Yu,2 Sam W. Lee,3 and Stuart A. Aaronson1*

Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029,1 University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213,2 Cancer Biology Program, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 021153

Received 22 January 2003/ Returned for modification 26 February 2003/ Accepted 22 August 2003

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.

* Corresponding author. Mailing address: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Pl., Box 1130, New York, NY 10029. Phone: (212) 659-5400. Fax: (212) 987-2240. E-mail: Stuart.Aaronson{at}mssm.edu.

Molecular and Cellular Biology, December 2003, p. 8576-8585, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8576-8585.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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