The p53 Pathway and Metabolism: The Tree That Hides the Forest

SIMPLE SUMMARY: The p53 pathway is a major tumor suppressor pathway that prevents the propagation of abnormal cells by regulating DNA repair, cell cycle progression, cell death, or senescence. The multiple cellular processes regulated by p53 were more recently extended to the control of metabolism, and many studies support the notion that perturbations of p53-associated metabolic activities are linked to cancer development. Converging lines of evidence support the notion that, in addition to p53, other key components of this molecular cascade are also important regulators of metabolism. Here, we illustrate the underestimated complexity of the metabolic network controlled by the p53 pathway and show how its perturbation contributes to human diseases including cancer, aging, and metabolic diseases. ABSTRACT: The p53 pathway is functionally inactivated in most, if not all, human cancers. The p53 protein is a central effector of numerous stress-related molecular cascades. p53 controls a safeguard mechanism that prevents accumulation of abnormal cells and their transformation by regulating DNA repair, cell cycle progression, cell death, or senescence. The multiple cellular processes regulated by p53 were more recently extended to the control of metabolism and many studies support the notion that perturbations of p53-associated metabolic activities are linked to cancer development, as well as to other pathophysiological conditions including aging, type II diabetes, and liver disease. Although much less documented than p53 metabolic activities, converging lines of evidence indicate that other key components of this tumor suppressor pathway are also involved in cellular metabolism through p53-dependent as well as p53-independent mechanisms. Thus, at least from a metabolic standpoint, the p53 pathway must be considered as a non-linear pathway, but the complex metabolic network controlled by these p53 regulators and the mechanisms by which their activities are coordinated with p53 metabolic functions remain poorly understood. In this review, we highlight some of the metabolic pathways controlled by several central components of the p53 pathway and their role in tissue homeostasis, metabolic diseases, and cancer.