The coordinate regulation of the p53 and mTOR pathways in cells

TLDR

Cell growth and proliferation depend on coordinated nutrient/growth‑factor signals and stress responses, with mTOR as the central nutrient sensor and p53 as a key stress sensor; disruptions in this coordination can lead to cancer. p53 regulates mTOR through AMP‑activated kinase activation and requires the TSC1/TSC2 complex, both of which respond to cellular energy deprivation. The study demonstrates that p53 activation suppresses mTOR activity and its downstream targets such as autophagy, that glucose starvation both inhibits mTOR and transiently phosphorylates p53, and that these pathways cross‑talk to jointly regulate cell growth, proliferation, and death.

Abstract

Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.