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

eLife

Julia I-Ju Leu¹  William J Quinn²  Qin Liu²  Subhasree Basu³  Maureen E Murphy³  Kathryn E Wellen⁴  Che-Pei Kung⁴  Joseph A Baur⁵  Thibaut Barnoud⁶  Keerthana Gnanapradeepan⁶  Joyce V Lee⁶  Madeline Good⁶  Zachary T Schug⁶  Donna L George⁶  Rexford Ahima⁷ 

[1] Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States;Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States;Department of Genetics, 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;Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins University School of Medicine, Baltimore, United States;Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, United States;Washington University in St. Louis, St Louis, United States;

关键词: mTOR;    p53;    Pro47Ser;    Rheb;    GAPDH;    metabolism;   

DOI  :  10.7554/eLife.55994

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown