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Tumor Suppression in the Absence of p53-Mediated Cell-Cycle.pdf

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Tumor Suppression in the Absence of p53-Mediated Cell-Cycle

Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence Tongyuan Li,1 Ning Kon,1 Le Jiang,1 Minjia Tan,2 Thomas Ludwig,1 Yingming Zhao,2 Richard Baer,1 and Wei Gu1,* 1Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA 2Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA *Correspondence: wg8@columbia.edu DOI 10.1016/j.cell.2012.04.026SUMMARY Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation.Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of p53 acetylation sites. Althoughp53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early- onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to regulate energy metabo- lism and reactive oxygen species production. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset sponta- neous tumorigenesis.INTRODUCTION The p53 tumor suppressor regulates multiple signaling pathways triggered by diverse cellular stresses, including DNA damage, abnormal oncogenic events, loss of normal cell contacts, and hypoxia, as well as some normal cellular processes (Vousden and Prives, 2009; Feng and Levine, 2010). Although the molec- ular mechanis