p53 and stress in the ER

The p53 tumor suppressor is one of the central players in the response of cells to various forms of stress. Clearly, the main form of stress that activates p53 is genotoxic stress in the form of DNA double-strand breaks (DSBs) or stalled DNA replication forks (Kastan et al. 1991; Vogelstein et al. 2000). If left unchecked by p53, genotoxic stress can lead to loss of genomic integrity and cancer development, as exemplified by the phenotype of mice lacking the p53 gene and the high frequency of p53 gene inactivation in human cancer (Hollstein et al. 1991; Donehower et al. 1992). Given these consequences, it is not surprising that p53 has potent effects in the cells in which it is activated, including apoptosis and irreversible senescence (Yonish-Rouach et al. 1991; Serrano et al. 1997).

The ability of p53 to induce apoptosis and senescence clearly needs to be tightly regulated. Hyperactivation of p53 could compromise organism survival, if too many cells were driven to undergo apoptosis or permanent senescence, as illustrated by the premature aging phenotype of mice expressing a mutant p53 gene that leads to increased p53 activity (Tyner et al. 2002). Accordingly, there are several mechanisms to control p53 activity. Functionally, one of the most important such mechanisms involves the ubiquitin ligase Mdm2, which participates with p53 in a negative feedback loop: p53 activates transcription of the mdm2 gene, whose protein product then targets p53 for ubiquitin-dependent degradation (Wu et al. 1993; Honda et al. 1997). Thus, any increase in p53 activity is accompanied by increased p53 degradation. This and other mechanisms to control p53 activity can, of course, be overcome by genotoxic stress.

Genotoxic stress can activate p53 through several pathways that typically involve posttranslational modifications of the N or C terminus of p53 …