p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Abstract

The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.

Keywords: cancer; cell death; epigenetics; metabolism.

Figure 1

p53-mediated DNA damage response. p53 post-translational modifications determine its stabilization and activation. Downstream transcriptional targets include p21, PUMA, and Noxa, which control cell progression (p21) and cytochrome-C release/apoptosis (PUMA and Noxa). This canonical p53-mediated signalling cascade has for very long been considered the primary mechanism by which p53 prevents tumorigenesis. More recent evidence questions this dogmatic paradigm.

Figure 2

p53 control of cellular metabolism. p53 exerts a stringent control of the cellular metabolism at different level, including efficiency of glycolic pathway, mitochondrial respiration and lipid anabolism/catabolism. p53 directly controls human Tigar and GLUTs (transcriptionally) and G6PD (by protein-interaction), thus influencing the efficiency of the glycolytic flux and the related anabolic pathways. p53 exerts a control of the mitochondrial activity by influencing PDK2 and SCO2 expression. Finally, maturation of SREBP2 and the consequent activation of the cholesterol biosynthesis and fatty acids beta-oxidation are also regulated by p53 activity.

Figure 3

Dual effect of p53 on autophagy. Multiple mechanisms have implicated p53 in the regulation of autophagy with both repressing and promoting effects. Regulation of DRAM, Ulk1, Atg7, and Isg20L1 results in promotion of autophagy, whereas repression of PINK1 results in promotion of mitophagy. Effect on AMPK/mTOR pathway negatively influences autophagy and similar effect has been ascribed to cytoplasmic functions of p53.

Figure 4

p53 regulates ferroptosis. Iron-dependent lipid peroxidation, more recently named ferroptosis, has been also implicated in the tumor suppression capabilities of p53. Regulation of System Xc⁻ antiport appears to mediate p53 triggered promotion of ferroptotic cell death. Alternative mechanisms implicate p53 in promoting, but also preventing ferroptosis. This include the control of p21 and SAT1 expression. The relevance of this cell death modality for p53 mediate tumor suppression opens to novel intriguing perspectives.