Redox Control and Interplay Between p53 Isoforms: Roles in the Regulation of Basal p53 Levels, Cell Fate, and Senescence

The p53 tumor suppressor protein has achieved stardom in molecular oncology owing to frequent inactivation in a large range of cancers. Known as a factor activated by multiple forms of stress and causing a broad suppressive response to DNA damage, its regulation and functions in basal (non-stress) conditions has received relatively little attention. We summarize recent findings highlighting roles of p53 in physiological processes such as stem cell maintenance, development, aging and senescence, and regulation of basal oxidative cell metabolism. We suggest that these properties are regulated through two integrated biochemical systems: the redox-sensing capacity of the p53 protein (due to its structural features and its regulation by redox factors such as thioredoxin, metallothioneins, or the redox-repair enzyme APE1/ref-1), and the expression of p53 as multiple isoforms with antagonist effects. We propose that interactions between p53 and its isoforms Delta 40p53 or Delta 133p53 play critical roles in intracellular signaling by reactive oxygen species. We also discuss evidence that p53 controls energy production by repressing glycolysis and enhancing mitochondrial oxidative metabolism. Together, these mechanisms suggest that p53 acts not only as a "guardian of the genome'' against DNA damage but also as a finely-tuned regulator of redox-dependent physiological processes. Antioxid. Redox Signal. 15, 1655-1667.