p53: Multiple Facets of a Rubik's Cube

Abstract

The p53 tumor suppressor has been studied for decades, and still there are many questions left unanswered. In this review, we first describe the current understanding of the wild-type p53 functions that determine cell survival or death, and regulation of the protein, with a particular focus on the negative regulators, the murine double minute family of proteins. We also summarize tissue-, stress-, and age-specific p53 activities and the potential underlying mechanisms. Among all p53 gene alterations identified in human cancers, p53 missense mutations predominate, suggesting an inherent biological advantage. Numerous gain-of-function activities of mutant p53 in different model systems and contexts have been identified. The emerging theme is that mutant p53, which retains a potent transcriptional activation domain, also retains the ability to modify gene transcription, albeit indirectly. Lastly, because mutant p53 stability is necessary for its gain of function, we summarize the mechanisms through which mutant p53 is specifically stabilized. A deeper understanding of the multiple pathways that impinge upon wild-type and mutant p53 activities and how these, in turn, regulate cell behavior will help identify vulnerabilities and therapeutic opportunities.

Keywords: age specificity; gain of function; missense mutation; p53 stabilization; stress specificity; tissue specificity.

Figure 1

p53 is activated in response to various stresses. In different contexts, the activation of p53 can either keep the cells alive (the survival pathway) or kill the cells (the death pathway).

Figure 2

Mdm2 and Mdm4 are potent inhibitors of the p53 tumor suppressor. Loss of either or disruption of the interaction between the two results in embryo lethal phenotypes (red). Mutation of the RING domain of Mdm2 alone is viable. In response to Mdm2 loss or radiation in the adult mouse, p53 activates numerous genes (see the section titled Tissue- and Stress-Specific p53 Activity). Major genes with important tissue-specific roles are listed (labeled in green when activated by radiation), as identified in studies discussed in this review.