Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser.

Keerthana Gnanapradeepan,Qin Liu,Maureen E Murphy,Thibaut Barnoud,Che-Pei Kung,Joyce V Lee,Julia I-Ju Leu,Joseph A Baur,Zachary T Schug,Madeline Good,William J Quinn,Rexford Ahima,Kathryn E Wellen,Subhasree Basu,Donna L George

doi:10.7554/elife.55994

Abstract

The Pro47Ser variant of p53 (S47) exists in African-descent populations and is associated with increased cancer risk in humans and mice. Due to impaired repression of the cystine importer Slc7a11, S47 cells show increased glutathione (GSH) accumulation compared to cells with wild -type p53. We show that mice containing the S47 variant display increased mTOR activity and oxidative metabolism, as well as larger size, improved metabolic efficiency, and signs of superior fitness. Mechanistically, we show that mTOR and its positive regulator Rheb display increased association in S47 cells; this is due to an altered redox state of GAPDH in S47 cells that inhibits its ability to bind and sequester Rheb. Compounds that decrease glutathione normalize GAPDH-Rheb complexes and mTOR activity in S47 cells. This study reveals a novel layer of regulation of mTOR by p53, and raises the possibility that this variant may have been selected for in early Africa.

Highlights

The p53 tumor suppressor protein serves as a master regulator of the cellular response to intrinsic and extrinsic stress
We report that mouse and human S47 cells show a significant increase in mTOR activity, due in part to increased mTOR-Rheb binding in S47 cells
We report that cells and mice with the S47 variant of p53 have increased mTOR activity and evidence for increased metabolic efficiency

Summary

Introduction

The p53 tumor suppressor protein serves as a master regulator of the cellular response to intrinsic and extrinsic stress. Mutations in the TP53 gene occur in more than 50% of human cancers, and this gene is well known as the most frequently mutated gene in cancer (Hollstein et al, 1991). P53 works to suppress uncontrolled cellular growth and proliferation through various pathways including apoptosis, senescence, cell cycle arrest, and ferroptosis (Stockwell et al, 2017; Vousden and Prives, 2009). A role for p53 in the control of metabolism has emerged. The metabolic functions of p53 include the regulation of mitochondrial function, autophagy, cellular redox

Methods

Results

Conclusion