Dying to Survive—The p53 Paradox

SIMPLE SUMMARY: p53 is best known for its tumour suppressive functions mediated through regulation of an extensive-gene regulatory network. Here we review progress in our understanding of the complex role that p53 plays in controlling expression of cell-death regulatory pathways; how paradoxically, this may be important for cellular and organismal survival in response to homeostatic stress; the potential impact on the response to p53 activating therapies; and the ways that this might be exploited in cancer types for which maintaining wild-type p53 is beneficial. ABSTRACT: The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.