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

Abstract

The Pro47Ser variant of p53 exists in African-descent populations, and is associated with increased cancer risk in humans and mice. This variant, hereafter S47, shows altered regulation of the cystine importer Slc7a11, and S47 cells possess increased cysteine and glutathione (GSH) accumulation compared to cells with wild type p53. In this study we show that mice containing the S47 variant have increased mTOR activity, increased oxidative metabolism, larger size, and improved metabolic efficiency. Mechanistically, we show that there is increased association between mTOR and its positive regulator Rheb in S47 cells, due to altered redox state of GAPDH, which normally binds and sequesters Rheb. Compounds that decrease glutathione in S47 cells normalize GAPDH-Rheb complex formation and mTOR activity. The enhanced metabolic efficiency may have been selected for in early Africa, making the S47 variant one of a growing number of cancer-predisposing genetic variants that possesses other positive, potentially selectable attributes.