Nutrient restriction is a potent means of extending lifespan and postponing disease, including cancer, in many animal species. However, little is known about the signaling pathways that coordinate the animal response to nutritional restriction and maintain metabolic homeostasis. The p53 tumor suppressor has been shown to regulate energy metabolism through regulation of glucose transport, glycolysis, oxidative phosphorylation, glutamine hydrolysis, fatty acid oxidation, mTOR signaling and autophagy. Despite this, a direct role for p53 in signaling nutritional restriction stress and maintaining metabolic homeostasis has yet to be established, in part due to the absence of model organisms that are suitable to p53 nutrient response analysis. We have recently identified the ribosomal protein (RP)-Mdm2-p53 pathway as an anti-cancer signaling pathway safeguarding oncogenic c-Myc induced superfluous ribosomal biosynthesis. Here we utilize a mouse model containing single point mutation (C305F) in the Mdm2, which results in its impaired binding to ribosomal proteins, to investigate the impact of energy status on both the rates of ribosome biogenesis and p53 function. We show that this mutation, although does not cause phenotypical changes to mice fed a standard diet, has led to a profound inability of mice to respond to dietary restriction. We establish a nutrient stress-response signaling pathway in which ribosomal proteins mediate activation of p53 through their interaction with Mdm2, and postulate how changes in nutrient availability may induce the RP-Mdm2-p53 signaling pathway to modulate p53-dependent metabolic regulation that could ultimately determine disease and survival.

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