p53 Regulation: a family affair

Abstract

The p53 protein averts tumor formation by preventing the proliferation of damaged cells. The presence of functional p53 is critical for efficient and proper cellular responses to a variety of stress conditions. Interestingly, p63 and p73, which are the homologous ancestors of p53, retain a broader set of activities than their progeny, particularly during early embryonic development. The link of these homologues to cancer and their effect on p53 tumor suppression is only beginning to be unravelled. The tight regulation of p53 is governed by the Mdm2 E3 ligase, but also by at least two other E3 ligases. Recent findings suggest fine-tuning of p53 regulation through changes in the ratio of p53 and Mdm2. This regulation of p53 is modulated by the Mdm2 homologue, Mdmx. Genetic studies reveal the critical role Mdmx plays in p53 regulation, although the mode of action is yet to be fully explored. The relief of p53 from this tight regulation is imperative in order for it to respond to stress signals. An intriguing player in this process is the prolyl isomerase Pin1, which induces a conformational change in p53, and more recently identified, also in p73, in response to DNA damage. This complex network of regulation emerges as a family affair. This wealth of knowledge has been translated into the development of novel anti-cancer strategies based on the p53 status in the cancer cell.