P53 and Cell Death

Abstract

The p53 transcription factor emerges not only as the most important tumour suppressor, but also as an intriguing scientific puzzle characterized by immense functional complexity. P53‐mediated apoptosis is a well‐established tumour suppression mechanism forming a critical barrier to tumourigenesis. Intense research into the mechanism of p53‐induced apoptosis revealed an involvement of p53 in the extrinsic and intrinsic cell death pathways, reactive oxygen species signalling and antisurvival responses. Notably, p53 exerts its effects by various direct and indirect mechanisms engaging transcriptional activation or repression of target genes as well as transcriptional independent modes of action. Importantly, more than 20 years of intense research has paved the way for a rational design of selective anticancer therapies aimed at restoration of p53 functionality in cancer cells. Key concepts: Apoptosis (programmed cell death) is a fundamental cellular process during development, maintenance of tissue homeostasis, and in cellular response to stress. P53 function is compromised in most cancer cases either by direct mutations (50%) or by indirect mechanisms P53 is a transcriptional factor that binds to specific target DNA sequences to either transcriptionally activate or repress genes. P53 activates multiple apoptotic signalling pathways (extrinsic and intrinsic) thereby promoting an efficient apoptotic response. The majority of pro‐apoptotic activities of p53 are mediated through the induction of specific apoptotic target genes, e.g. Bax , Puma and Noxa. P53 also contributes in the mitochondrial outer membrane permeabilization due to its relocalization to mitochondra and interaction with Bcl‐2‐family members. Harnessing p53 for cancer therapy is a promising strategy to combat cancer by reactivating pro‐apoptotic function in neoplastic cells.