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.
Elife. 2020 Nov 10;9:e55994. doi: 10.7554/eLife.55994.
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 , 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.
p53 的 Pro47Ser 变异体（S47）存在于非洲裔人群中，与人类和小鼠的癌症风险增加有关。由于半胱氨酸进口器的抑制作用受损，与野生型 p53 的细胞相比，S47 细胞显示出增加的谷胱甘肽（GSH）积累。我们表明，含有 S47 变异体的小鼠显示出增加的 mTOR 活性和氧化代谢，以及更大的大小，提高代谢效率和优越的适应性迹象。从机制上讲，我们表明，mTOR 及其正调节剂 Rheb 在 S47 细胞中显示出增加的关联；这是由于 S47 细胞中 GAPDH 的氧化还原状态改变，抑制了其结合和隔离 Rheb 的能力。降低谷胱甘肽的化合物可使 S47 细胞中的 GAPDH-Rheb 复合物和 mTOR 活性正常化。这项研究揭示了 p53 对 mTOR 的一种新的调控层，并提出了这种变异体可能在早期非洲被选择的可能性。
