Multiple stress signals activate mutant p53 in vivo
Menée sur un modème murin, cette étude analyse les rôles joués par différents signaux de stress dans la régulation d'une forme mutée du gène p53 et évalue leurs conséquences sur la formation et la survie des tumeurs
p53 levels are tightly regulated in normal cells, and thus the wild-type p53 protein is nearly undetectable until stimulated through a variety of stresses. In response to stress, p53 is released from its negative regulators, mainly Mdm2, allowing p53 to be stabilized to activate cell cycle arrest, senescence, and apoptosis programs. Many of the upstream signals that regulate wild type p53 are known; however, limited information for the regulation of mutant p53 exists. Previously, we demonstrated that wild-type and mutant p53R172H are regulated in a similar manner in the absence of Mdm2 or p16. Additionally, this stabilization of mutant p53 is responsible for the gain-of-function metastatic phenotype observed in the mouse. In this report, we examined the role of oncogenes, DNA damage, and reactive oxygen species, signals that stabilize wild type p53, on the stabilization of mutant p53 in vivo and the consequences of this expression on tumor formation and survival. These factors stabilized mutant p53 protein which often times contributed to exacerbated tumor phenotypes. These findings, coupled with the fact that patients carry p53 mutations without stabilization of p53, suggest that personalized therapeutic schemes may be needed for individual patients depending on their p53 status.