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 (Brooks and Gu 2003; Xu 2003). The ATM protein kinase, which is activated in response to DNA DSBs, is a key player in p53 activation. ATM activates the Chk2 kinase, which in turn phosphorylates p53 on Ser 20, leading to dissociation of p53 from Mdm2 and increased p53 protein levels. A similar pathway is thought to operate in response to replication blocks, although in this case, ATR, an ATMrelated kinase, is activated, and p53 phosphorylation on Ser 20 is most likely mediated by both Chk2 and Chk1 (Abraham 2001; Iliakis et al. 2003). Modifications within the C terminus of p53 are numerous and regulate both the functional activity of p53 and its protein levels. Acetylation of several lysines, including Lys 373, Lys 381, and Lys 382, enhances the transcriptional activity of p53 and also stabilizes the p53 protein, because lysines that are acetylated cannot be ubiquitinated (Brooks and Gu 2003; Xu 2003). Dephosphorylation of Ser 376 is also observed in response to DNA DSBs (Waterman et al. 1998). This dephosphorylation is ATM-dependent and is apparently important for p53 to activate gene transcription and induce cell cycle arrest (Stavridi et al. 2001). Clearly, ATM, being a kinase, does not directly dephosphorylate p53 on Ser 376; however, the identity of the kinase(s) and phosphatase(s) that modify this residue are not known. Even though p53 probably originated during evolution to respond specifically to genotoxic stress (Nordstrom and Abrams 2000; Derry et al. 2001), cells are exposed to a multitude of stresses. Therefore, the question arises whether cells have developed mechanisms to ensure that p53 activation is restricted to conditions that threaten genomic integrity. Our understanding of the pathways leading to p53 activation suggests that the cells sense that genomic integrity is threatened by the presence of DNA DSBs or stalled replication forks (Abraham 2001; Iliakis et al. 2003). Certainly, stalling of replication forks due to DNA damage is a good indication of a threat to genomic integrity; however, stalling of replication forks due to reasons other than DNA damage or depleted nucleotides may not necessarily be indicative of a threat to genomic integrity. For example, heat shock will slow down most cellular processes, including DNA replication, but heat is not a genotoxic agent. From the perspective of the cell, it is probably not desirable to activate p53 in response to every agent that slows DNA replication, but how cells make these distinctions had not attracted a lot of attention. The manuscript by the group of A. Koromilas in this issue (Qu et al. 2004) addresses how a specific form of cellular stress inhibits p53 function. The authors examined cells in which an unfolded protein response (UPR) was induced specifically in the endoplasmic reticulum (ER). This type of stress, often referred to as ER stress, was found to inhibit p53, probably to help ensure that Corresponding author. EMAIL halazonetis@wistar.upenn. edu; FAX (215) 573-9271. Article and publication are at http://www.genesdev. org/cgi/doi/10.1101/ gad.1181704.