Abstract
As a hallmark of tumor cells, metabolic alterations play a critical role in tumor development and could be targeted for tumor therapy. Tumor suppressor p53 plays a central role in tumor prevention. As a transcription factor, p53 mainly exerts its function in tumor suppression through its transcriptional regulation of its target genes to initiate various cellular responses. Cell cycle arrest, apoptosis and senescence are most well-understood functions of p53, and are traditionally accepted as the major mechanisms for p53 in tumor suppression. Recent studies have revealed a novel function of p53 in regulation of cellular metabolism. p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutamine metabolism, lipid metabolism, and antioxidant defense. Through the regulation of these metabolic processes, p53 maintains the homeostasis of cellular metabolism and redox balance in cells, which contributes significantly to the role of p53 as a tumor suppressor. Further understanding of the role and molecular mechanism of p53 in cellular metabolism could lead to the identification of novel targets and development of novel strategies for tumor therapy.
Highlights
Tumor suppressor p53 plays a central role in tumor prevention [1,2,3,4]. p53 is the most frequently-mutated gene in human tumors; DNA mutations in p53 occur in over 50% of all tumors and almost every type of tumor
Here we reviewed our current understanding of the role and mechanisms of p53 in maintaining the homeostasis of cellular energy metabolism and the redox balance in cells
Whereas cell-cycle arrest, apoptosis, and senescence are traditionally accepted as the major mechanisms by which p53 exerts its tumor suppressive function, these findings provide strong evidence that the functions of p53 in maintaining the homeostasis of cellular energy metabolism and the redox balance in cells contribute significantly to the role of p53 as a tumor suppressor
Summary
Tumor suppressor p53 plays a central role in tumor prevention [1,2,3,4]. p53 is the most frequently-mutated gene in human tumors; DNA mutations in p53 occur in over 50% of all tumors and almost every type of tumor. Through the regulation of many different p53 target genes and several different pathways, p53 promotes mitochondrial oxidative phosphorylation and inhibits aerobic glycolysis, leading to the negative regulation of the Warburg effect. Consistent with the function of p53 in regulating genes involved in antioxidant defense, p53 deficiency results in the elevation of intracellular ROS levels, which greatly increases DNA oxidation and the rate of mutagenesis in cells. These effects could be substantially reversed by ectopic expression of antioxidant p53 target Sestrins in p53 null cells or by the application of antioxidant Nacetylcysteine both in vitro and in vivo [18,19]. The activated p53 protein induces the expression of prooxidant genes, including PIG3, PIG6, FDXR, Bax, and Puma, all of which can further increase intracellular ROS levels and promote the p53-mediated apoptosis and senescence to maintain genomic integrity [81,82,83,84]
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