P53: Guardian of the metabolome

Abstract

The p53 tumor suppressor protein is critically important for the maintenance of genetic integrity and is thought to accomplish this, following cellular perturbation, by the regulation of transcription of genes whose protein products execute cell cycle arrest, senescence, or apoptotic programs. However, new evidence links p53 to homeostatic and stress-induced regulation of metabolic processes, including glycolysis, glutaminolysis, oxidative phosphorylation, fatty acid oxidation, nucleotide biosynthesis, and maintenance of the levels of reactive oxygen species. These functions suggest a role for p53 in the control of cellular proliferation and protection against DNA damage of normally growing cells reacting to the changes in nutrient availability and intracellular redox status. Better understanding of the connection between p53 and metabolic pathways could lead to a fuller picture of the metabolic control of normal cellular growth and further elucidate the mechanism of oncogenic transformation. The notion things that are good in moderation will sometimes kill you when in excess aptly describes the activity of the p53 tumor suppressor protein. On the one hand, p53 is able to support damage free proliferation, yet at high levels it is able to induce apoptosis and cell death. Tumor suppressive functions of p53 are stimulated by any number of cellular stresses and have been the center of countless investigations. Nevertheless, the lack of apparent major physiological defects in p53 null mice has implied that p53 is dispensable for the protection of cellular homeostasis (Vousden, Prives, Cell 137(3):413-431, 2009). Despite this, mounting evidence supports a function for p53 in the maintenance of optimal cellular proliferation. The role of p53 in the promotion of cellular survival and homeostasis, although appearing to contradict its ability to induce cell cycle arrest or apoptosis, is likely to be a preventative mechanism that reduces the probability of damage and assures long-term viability (Olovnikov et al., Semin Cancer Biol 19(1):32-41, 2009; Gottlieb, Vousden, Cold Spring Harb Perspect Biol 2(4):a001040). A closer examination of the involvement of p53 in cellular respiration, growth, and a number of other metabolic pathways has reshaped our view of p53 activity in unstressed cells and provided more clarity to the metabolic changes associated with tumorigenic transformation.