Metabolic regulation of oxygen and redox homeostasis by p53: Lessons from evolutionary biology?

The genetic links between p53 and metabolic processes such as oxidative phosphorylation are being studied with increasing interest given that cellular metabolism seems to play an important role in tumorigenesis. This review focuses on how p53 regulation of various metabolic genes may influence redox homeostasis, as the genome is constantly susceptible to oxidative damage, a consequence of living in an aerobic environment. Because p53-like genetic sequences are also found in life forms that may not necessarily benefit from tumor suppression, an evolutionary introduction is given in an attempt to understand why p53 might regulate a basic cellular activity such as metabolism. The presented epidemiologic and experimental data suggest that one reason may be for the homeostatic regulation of oxygen, the essential substrate for reactive oxygen species generation.

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► Human and animal data suggest that oxygen promotes tumorigenesis.
► Oxygen consumption by mitochondrial respiration affects redox homeostasis.
► p53 has both pro-oxidant and antioxidant activities via multiple pathways.
► p53 regulates mitochondrial respiration as part of its antioxidant function.