Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser

Keerthana Gnanapradeepan; Julia I.Ju Leu; Subhasree Basu; Thibaut Barnoud; Madeline Good; Joyce V. Lee; William J. Quinn; Che Pei Kung; Rexford Ahima; Joseph A. Baur; Kathryn E. Wellen; Qin Liu; Zachary T. Schug; Donna L. George; Maureen E. Murphy

doi:10.7554/eLife.55994

Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser

Keerthana Gnanapradeepan, Julia I.Ju Leu, Subhasree Basu, Thibaut Barnoud, Madeline Good, Joyce V. Lee, William J. Quinn, Che Pei Kung, Rexford Ahima, Joseph A. Baur, Kathryn E. Wellen, Qin Liu, Zachary T. Schug, Donna L. George, Maureen E. Murphy

School of Medicine

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e55994
Pages (from-to)	1-25
Number of pages	25
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.55994
State	Published - Oct 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

Access to Document

10.7554/eLife.55994

Cite this

Gnanapradeepan, K., Leu, J. I. J., Basu, S., Barnoud, T., Good, M., Lee, J. V., Quinn, W. J., Kung, C. P., Ahima, R., Baur, J. A., Wellen, K. E., Liu, Q., Schug, Z. T., George, D. L., & Murphy, M. E. (2020). Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser. eLife, 9, 1-25. Article e55994. https://doi.org/10.7554/eLife.55994

Gnanapradeepan, K, Leu, JIJ, Basu, S, Barnoud, T, Good, M, Lee, JV, Quinn, WJ, Kung, CP, Ahima, R, Baur, JA, Wellen, KE, Liu, Q, Schug, ZT, George, DL & Murphy, ME 2020, 'Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser', eLife, vol. 9, e55994, pp. 1-25. https://doi.org/10.7554/eLife.55994

@article{dcd66389e0c240feb832f06a57b00e3c,

title = "Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser",

abstract = "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.",

author = "Keerthana Gnanapradeepan and Leu, {Julia I.Ju} and Subhasree Basu and Thibaut Barnoud and Madeline Good and Lee, {Joyce V.} and Quinn, {William J.} and Kung, {Che Pei} and Rexford Ahima and Baur, {Joseph A.} and Wellen, {Kathryn E.} and Qin Liu and Schug, {Zachary T.} and George, {Donna L.} and Murphy, {Maureen E.}",

note = "Funding Information: This work was supported by R01 CA102184 (MEM), R01 CA139319 (DLG and MEM), R01 CA238611 (MEM), P01 CA114046 (DLG and MEM), T32 CA009071, F32 CA220972 and K99 CA241367 (TB), R01 CA174761 (KEW), R01 AG043483 and DK098656 (JAB) and the Rodent Metabolic Phenotyping Core (P30-DK19525), and DP2-CA249951 (ZTS). RSA is partly supported by a Bloomberg Distinguished Professorship. The authors acknowledge the Histotechnology, Laboratory Animal and Imaging facilities at the Wistar Institute. The authors are grateful to Allie Lipshutz and Lindsey Schweitzer for expert technical help, and Matthew Jennis for the mouse weight data. Publisher Copyright: {\textcopyright} Gnanapradeepan et al.",

year = "2020",

month = oct,

doi = "10.7554/eLife.55994",

language = "English (US)",

volume = "9",

pages = "1--25",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - 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.

N1 - Funding Information: This work was supported by R01 CA102184 (MEM), R01 CA139319 (DLG and MEM), R01 CA238611 (MEM), P01 CA114046 (DLG and MEM), T32 CA009071, F32 CA220972 and K99 CA241367 (TB), R01 CA174761 (KEW), R01 AG043483 and DK098656 (JAB) and the Rodent Metabolic Phenotyping Core (P30-DK19525), and DP2-CA249951 (ZTS). RSA is partly supported by a Bloomberg Distinguished Professorship. The authors acknowledge the Histotechnology, Laboratory Animal and Imaging facilities at the Wistar Institute. The authors are grateful to Allie Lipshutz and Lindsey Schweitzer for expert technical help, and Matthew Jennis for the mouse weight data. Publisher Copyright: © Gnanapradeepan et al.

PY - 2020/10

Y1 - 2020/10

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85096030906&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85096030906&partnerID=8YFLogxK

U2 - 10.7554/eLife.55994

DO - 10.7554/eLife.55994

M3 - Article

C2 - 33170774

AN - SCOPUS:85096030906

SN - 2050-084X

VL - 9

SP - 1

EP - 25

JO - eLife

JF - eLife

M1 - e55994

ER -

Increased mtor activity and metabolic efficiency in mouse and human cells containing the african-centric tumor-predisposing p53 variant pro47ser

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this