Homeostatic functions of the p53 tumor suppressor: Regulation of energy metabolism and antioxidant defense

Abstract

The p53 tumor suppressor plays pivotal role in the organism by supervising strict compliance of individual cells to needs of the whole organisms. It has been widely accepted that p53 acts in response to stresses and abnormalities in cell physiology by mobilizing the repair processes or by removing the diseased cells through initiating the cell death programs. Recent studies, however, indicate that even under normal physiological conditions certain activities of p53 participate in homeostatic regulation of metabolic processes and that these activities are important for prevention of cancer. These novel functions of p53 help to align metabolic processes with the proliferation and energy status, to maintain optimal mode of glucose metabolism and to boost the energy efficient mitochondrial respiration in response to ATP deficiency. Additional activities of p53 in non-stressed cells tune up the antioxidant defense mechanisms reducing the probability of mutations caused by DNA oxidation under conditions of daily stresses. The deficiency in the p53-mediated regulation of glycolysis and mitochondrial respiration greatly accounts for the deficient respiration of the predominance of aerobic glycolysis in cancer cells (the Warburg effect), while the deficiency in the p53-modulated antioxidant defense mechanisms contributes to mutagenesis and additionally boosts the carcinogenesis process.

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

“…By contrast, lack of p53 in Hep3B cells manifested more apparent autophagic parameters, such as LC3 lipidation, redistribution of LC3 in cytoplasmic puncta, accumulation of autophagosomes, and depletion of p62/ SQSTM1 during reperfusion. It has been reported that p53-null cells are insensitive to metabolic stress with a higher intracellular ATP level (37). Our results provide additional evidence to support the possibility that p53 null cells are better equipped with more active autophagy to survive metabolic stress.…”

Cancer as a Metabolic Disease

“…The cancer mutator phenotype was invoked to explain the large number of somatic mutations found in cancer, but mutations in the p53 caretaker gene are not expressed in all cancers nor does p53 deletion produce cancer in mice suggesting a more complicated involvement of this and other genome guardians in carcinogenesis [7,[101][102][103][104]. While numerous genetic abnormalities have been described in most human cancers, no specific mutation is reliably diagnostic for any specific type of tumor [7,17,105].…”

“…For example, impaired mitochondrial function can induce abnormalities in p53 activation, while abnormalities in p53 expression and regulation can further impair mitochondrial function [85,103,113,116,[140][141][142][143]. The function of the pRB tumor suppressor protein, which controls the cell cycle, is also sensitive to ROS production through the redox state of the cell [144].…”

TP53 Gene Polymorphisms in Cancer Risk: The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities

“…(Chumakov, 2007;Green and Kroemer, 2009;McCarthy, 2011;Olovnikov et al, 2009;Vousden and Prives, 2009;Vousden and Ryan, 2009). p53 protein is encoded by the TP53 gene (OMIM no.…”