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

2020 ◽  
Author(s):  
Keerthana Gnanapradeepan ◽  
Julia I-Ju Leu ◽  
Subhasree Basu ◽  
Thibaut Barnoud ◽  
Madeline Good ◽  
...  
Keyword(s):  
Human Cells ◽  
Author Response ◽  
Metabolic Efficiency ◽  
Mtor Activity

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Keerthana Gnanapradeepan ◽  
Julia I-Ju Leu ◽  
Subhasree Basu ◽  
Thibaut Barnoud ◽  
Madeline Good ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Oxidative Metabolism ◽  
Redox State ◽  
African Descent ◽  
Human Cells ◽  
Metabolic Efficiency ◽  
Wild Type ◽  
Positive Regulator ◽  
Wild Type P53 ◽  
Mtor Activity

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.

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

2020 ◽  
Author(s):  
Keerthana Gnanapradeepan ◽  
Subhasree Basu ◽  
Thibaut Barnoud ◽  
Julia I-Ju Leu ◽  
Madeline Good ◽  
...  
Keyword(s):  
Complex Formation ◽  
Cancer Risk ◽  
Oxidative Metabolism ◽  
Genetic Variants ◽  
Redox State ◽  
Human Cells ◽  
Metabolic Efficiency ◽  
Wild Type ◽  
Altered Regulation ◽  
Mtor Activity

AbstractThe 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.

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2015 ◽  
Author(s):  
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Zeynep Yurtsever ◽  
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Keyword(s):  
Human Cells ◽  
Author Response ◽  
Chloride Currents

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Author(s):  
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2019 ◽  
Author(s):  
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...  
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scholarly journals Author response: STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells

2020 ◽  
Author(s):  
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...  
Keyword(s):  
Human Cells ◽  
Author Response ◽  
Oncogenic Transformation ◽  
Pp2a Activity

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2020 ◽  
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...  
Keyword(s):  
Sleeping Beauty ◽  
Human Cells ◽  
Author Response
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