TY - JOUR TI - Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser AU - Gnanapradeepan, Keerthana AU - Leu, Julia I-Ju AU - Basu, Subhasree AU - Barnoud, Thibaut AU - Good, Madeline AU - Lee, Joyce V AU - Quinn, William J AU - Kung, Che-Pei AU - Ahima, Rexford AU - Baur, Joseph A AU - Wellen, Kathryn E AU - Liu, Qin AU - Schug, Zachary T AU - George, Donna L AU - Murphy, Maureen E A2 - Ojala, Päivi M A2 - Finley, Lydia WS A2 - DeNicola, Gina VL - 9 PY - 2020 DA - 2020/11/10 SP - e55994 C1 - eLife 2020;9:e55994 DO - 10.7554/eLife.55994 UR - https://doi.org/10.7554/eLife.55994 AB - 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. KW - mTOR KW - p53 KW - Pro47Ser KW - Rheb KW - GAPDH KW - metabolism JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -