Airing Out an Antioxidant Role for the Tumor Suppressor p53

Abstract

The tumor suppressor p53 exerts its activity by preventing DNA-damaged cells from dividing until either the chromosomal repair is effected or the cell undergoes apoptosis. Reactive oxygen species (ROS) are enhanced through the action of p53-mediated transcription of apoptosis-promoting genes; however, p53 also can promote the expression of many antioxidant genes that prevent apoptosis. New research indicates that in low cellular stress, low concentrations of p53 induce the expression of antioxidant genes, whereas in severe cellular stress, high concentrations of p53 promote the expression of genes that contribute to ROS formation and p53-mediated apoptosis. p53-depleted cells injected into athymic mice increased significantly in tumor volume, whereas injected p53(+/+) cells did not grow to the same degree. Interestingly, administration of the antioxidant compound N-acetylcysteine (NAC) inhibited the growth of tumor volume in p53-depleted injected cells, and NAC supplementation of p53(-/-) mice from birth greatly decreased the number of karyotype abnormalities and tumors formed in these mice by six months of age. Thus, under normal (or low stress) conditions, p53 appears to have an antioxidant role that protects cells from oxidative DNA damage and although this effect might depend on the concentration of p53, other cellular factors likely participate in a cell's final fate.

Lack of p53 Decreases Basal Oxidative Stress Levels in the Brain Through Upregulation of Thioredoxin-1, Biliverdin Reductase-A, Manganese Superoxide Dismutase, and Nuclear Factor Kappa-B

“…Model of p53 leading to reactive oxygen species/reactive nitrogen species (ROS/RNS) in the brain. Physiological levels of p53 (black thin arrows) serve to contain ROS and RNS at nontoxic levels through the transactivation of genes encoding for proteins with antioxidant activity such as glutathione peroxidase-1 (GPX-1) (56,60,64). Furthermore, basal levels (black thin arrows) of p53 are required to balance energy metabolism among mitochondrial respiration, glycolysis, and the pentose phosphate shunt, with mitochondrial respiration that is the major source of ROS production (42).…”

p53 Orchestrates the PGC-1α-Mediated Antioxidant Response Upon Mild Redox and Metabolic Imbalance

“…More recent discoveries reveal new and opposite functions for p53 in the regulation of various aspects of cellular metabolism, senescence, and apoptosis (7,13,36,46). Among the genes that are directly modulated by p53, antioxidants, mitochondrial, and glycolytic genes are included (16,17,36,42). Another important key modulator of cellular metabolism is nuclear factor (erythroid-derived 2)-like2 (NFE2L2 or NRF2), a bZIP transcription factor controlling the expression of genes coding for detoxifying and antioxidant enzymes, thus maintaining ROS homeostasis (10).…”

Redox Regulation of Cell Survival

“…Loss of p53 function contributes to the development of many types of human cancer (284). A number of studies suggest that p53 plays an important role in controlling cell fate through regulation of cellular ROS level (28,69,300). a. P53 serves as an antioxidant to maintain redox homeostasis and normal cell survival.…”