Discussion of some 'knowns' and some 'unknowns' about the tumour suppressor p53

Abstract

Activation of the tumour suppressor p53 upon cellular stress can induce a number of different cellular processes. The diverse actions of these processes are critical for the protective function of p53 in preventing the development of cancer. However, it is still not fully understood which process(es) activated by p53 is/are critical for tumour suppression and how this might differ depending on the type of cells undergoing neoplastic transformation and the nature of the drivers of oncogenesis. Moreover, it is not clear why upon activation of p53 some cells undergo cell cycle arrest and senescence whereas others die by apoptosis. Here we discuss some of the cellular processes that are crucial for p53-mediated tumour suppression and the factors that could impact cell fate upon p53 activation. Finally, we describe therapies aimed either at activating wild-type p53 or at changing the behaviour of mutant p53 to unleash tumour growth suppressive processes for therapeutic benefit in malignant disease.

Keywords: cell cycle arrest/senescence; cell death; p53; tumour suppression.

Figure 1

Cellular processes that are impacted by p53 activation, listing some important genes that regulate these pathways. Diverse stresses activate p53 via a number of upstream signalling pathways that are not depicted here. Upon activation, p53 impacts several cellular processes through direct (bold) and/or indirect (underlined) regulation of target genes. Genes that are induced by p53 are shown in black, whereas genes that are repressed by p53 are in blue. The processes activated by p53 that are postulated to contribute to its ability to suppress tumour development include apoptosis, cell cycle arrest, cellular senescence, DNA repair, regulation of cellular metabolism, autophagy, and ferroptotic cell death.

Figure 2

p53 regulation of the apoptotic cell death pathways. Cell death regulators encoded by direct p53 target genes and transcriptionally induced are outlined in a solid red box; those encoded by indirect p53 target genes and induced are outlined in a dashed red box; those encoded by indirect p53 target genes and repressed are outlined in a dashed blue box; other cell death regulators (not controlled by p53) are outlined in grey.