Increased MTOR Activity and Metabolic Efficiency in Mouse and Human Cells Containing the African-centric Tumor-predisposing P53 Variant Pro47Ser

Overview

Journal Elife

Specialty Biology

Date 2020 Nov 10

PMID 33170774

Citations 9

Authors

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

Affiliations

Soon will be listed here.

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 , 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.

Citing Articles

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Mason E, Menon S, Schneider B, Gaskill C, Dawson M, Moore C J Clin Invest. 2023; 133(24).

PMID: 37874650 PMC: 10721153. DOI: 10.1172/JCI171430.

The African-centric P47S Variant of Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.

Stieg D, Parris J, Yang T, Mirji G, Reiser S, Murali N Cancer Res Commun. 2023; 3(7):1200-1211.

PMID: 37441266 PMC: 10335007. DOI: 10.1158/2767-9764.CRC-23-0149.

Emerging insights into ethnic-specific TP53 germline variants.

Fischer N, Ma Y, Gariepy J J Natl Cancer Inst. 2023; 115(10):1145-1156.

PMID: 37352403 PMC: 10560603. DOI: 10.1093/jnci/djad106.

Association of Single Nucleotide Polymorphisms with Prostate Cancer in a Racially Diverse Cohort of Men.

Duncan A, Nousome D, Ricks R, Kuo H, Ravindranath L, Dobi A Biomedicines. 2023; 11(5).

PMID: 37239075 PMC: 10216554. DOI: 10.3390/biomedicines11051404.

Common activities and predictive gene signature identified for genetic hypomorphs of .

Leung J, Leu J, Indeglia A, Kannan T, Clarke N, Kirven N Proc Natl Acad Sci U S A. 2023; 120(7):e2212940120.

PMID: 36749725 PMC: 9962931. DOI: 10.1073/pnas.2212940120.

References

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

Lee M, Ha S, Kim J, Koh A, Lee C, Kim J . Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb. Mol Cell Biol. 2009; 29(14):3991-4001. PMC: 2704738. DOI: 10.1128/MCB.00165-09. View

Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M . Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001; 27(2):195-200. DOI: 10.1038/84839. View

Yoon M . mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass. Front Physiol. 2017; 8:788. PMC: 5650960. DOI: 10.3389/fphys.2017.00788. View

Vicens A, Posada D . Selective Pressures on Human Cancer Genes along the Evolution of Mammals. Genes (Basel). 2018; 9(12). PMC: 6316132. DOI: 10.3390/genes9120582. View

Goodman C . Role of mTORC1 in mechanically induced increases in translation and skeletal muscle mass. J Appl Physiol (1985). 2019; 127(2):581-590. DOI: 10.1152/japplphysiol.01011.2018. View

Murphy M, Liu S, Yao S, Huo D, Liu Q, Dolfi S . A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer. 2017; 3:5. PMC: 5445618. DOI: 10.1038/s41523-017-0007-9. View

Brandes N, Schmitt S, Jakob U . Thiol-based redox switches in eukaryotic proteins. Antioxid Redox Signal. 2008; 11(5):997-1014. PMC: 2787739. DOI: 10.1089/ars.2008.2285. View

Ye L, Widlund A, Sims C, Lamming D, Guan Y, Davis J . Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY). 2013; 5(7):539-50. PMC: 3765582. DOI: 10.18632/aging.100576. View

10.

Ye L, Varamini B, Lamming D, Sabatini D, Baur J . Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet. 2012; 3:177. PMC: 3438685. DOI: 10.3389/fgene.2012.00177. View

11.

Schieke S, Phillips D, McCoy Jr J, Aponte A, Shen R, Balaban R . The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006; 281(37):27643-52. DOI: 10.1074/jbc.M603536200. View

12.

Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J . Rheb binds and regulates the mTOR kinase. Curr Biol. 2005; 15(8):702-13. DOI: 10.1016/j.cub.2005.02.053. View

13.

Jennis M, Kung C, Basu S, Budina-Kolomets A, Leu J, Khaku S . An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 2016; 30(8):918-30. PMC: 4840298. DOI: 10.1101/gad.275891.115. View

14.

Kung C, Leu J, Basu S, Khaku S, Anokye-Danso F, Liu Q . The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction. Cell Rep. 2016; 14(10):2413-25. PMC: 4926645. DOI: 10.1016/j.celrep.2016.02.037. View

15.

Green N, Reisler E, Houk K . Quantitative evaluation of the lengths of homobifunctional protein cross-linking reagents used as molecular rulers. Protein Sci. 2001; 10(7):1293-304. PMC: 2374107. DOI: 10.1110/ps.51201. View

16.

Hasty P, Sharp Z, Curiel T, Campisi J . mTORC1 and p53: clash of the gods?. Cell Cycle. 2012; 12(1):20-5. PMC: 3570511. DOI: 10.4161/cc.22912. View

17.

Vandenburgh H, Karlisch P, Shansky J, Feldstein R . Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture. Am J Physiol. 1991; 260(3 Pt 1):C475-84. DOI: 10.1152/ajpcell.1991.260.3.C475. View

18.

Baar E, Carbajal K, Ong I, Lamming D . Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell. 2015; 15(1):155-66. PMC: 4717274. DOI: 10.1111/acel.12425. View

19.

Zhao Y, Wu L, Yue X, Zhang C, Wang J, Li J . A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models. Elife. 2018; 7. PMC: 5906094. DOI: 10.7554/eLife.34701. View

20.

Feng Z, Hu W, de Stanchina E, Teresky A, Jin S, Lowe S . The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 2007; 67(7):3043-53. DOI: 10.1158/0008-5472.CAN-06-4149. View