Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, United States; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Julia I-Ju Leu
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Subhasree Basu
Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, United States
Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, United States
Madeline Good
Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, United States
Joyce V Lee
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
William J Quinn
Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
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.
