Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
Menée à l'aide de modèles murins présentant des mutations de sites d'acétylation du gène p53, cette étude montre que la fonction de suppression de tumeurs demeure active en l'absence des mécanismes d'apoptose, de sénescence et d'arrêt du cycle cellulaire habituellement induits par p53
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. Although p53K117R/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 metabolism 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 spontaneous tumorigenesis. º K120 acetylation of p53 is essential for p53-mediated apoptosis º The p533KR/3KR mutant is deficient in cell-cycle arrest, senescence, and apoptosis º This mutant nonetheless retains tumor suppression activity º Unconventional p53 function is critical for suppression of spontaneous tumorigenesis Abolishing the ability of p53 to promote cell-cycle arrest, senescence, and apoptosis surprisingly does not disrupt its ability to suppress tumor formation. Instead, evidence suggests that p53's regulation of glucose metabolism and ROS levels are critical for its tumor suppression activity.
Cell , résumé, 2011