Switching on p53: an essential role for protein phosphorylation?

Abstract

The p53 tumour suppressor protein coordinates widespread changes in gene expression in response to a range of stress stimuli. p53 is regulated primarily through ubiquitylation and protein turnover mediated by its transcriptional target, MDM2. Induction and activation of p53 is achieved largely through uncoupling the p53/ MDM2 interaction, with various stress stimuli employing different but overlapping mechanisms to achieve this. p53 undergoes a range of post-translational modifications including multi-site phosphorylation, acetylation, methylation and ubiquitylation. DNA damage pathways in particular engender a large number of phosphorylation events, both in p53 itself and in regulatory partners including MDM2 and MDM4; these modifications mediate both the induction of p53 and stimulation of its activity. Surprisingly, other p53-activating stimuli do not promote multi-site phosphorylation. Moreover, simply uncoupling p53 and MDM2 pharmacologically can induce a robust p53 response. Various lines of evidence propose that activation of p53 via the DNA damage pathways is dispensable for p53-mediated tumour suppression and, by implication, that phosphorylation is not required. In contrast to this view, however, emerging evidence from animal models indicates that phosphorylation may indeed impact on tumour suppression, albeit in a possibly selective manner. Here we review the role of phosphorylation in regulating the p53 response in comparison to mechanisms employed by other stress signalling pathways. We consider its effects on biological outcome and reflect on issues that have yet to be addressed.