Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser
| العنوان: | Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser |
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| المؤلفون: | Madeline Good, Maureen E. Murphy, Thibaut Barnoud, Donna L. George, Subhasree Basu, William J. Quinn, Che-Pei Kung, Julia I-Ju Leu, Joseph A. Baur, Zachary T. Schug, Rexford S. Ahima, Joyce V. Lee, Qin Liu, Kathryn E. Wellen, Keerthana Gnanapradeepan |
| المصدر: | eLife eLife, Vol 9 (2020) |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, p53, Mouse, Regulator, SLC7A11, chemistry.chemical_compound, 0302 clinical medicine, Biology (General), Glyceraldehyde 3-phosphate dehydrogenase, Cancer Biology, biology, GAPDH, General Neuroscience, TOR Serine-Threonine Kinases, General Medicine, Glutathione, Mitochondria, Cell biology, mTOR, Medicine, Glycolysis, Oxidation-Reduction, Research Article, Human, RHEB, QH301-705.5, Rheb, Science, Cystine, Black People, General Biochemistry, Genetics and Molecular Biology, Pro47Ser, Cell Line, 03 medical and health sciences, Animals, Humans, Psychological repression, PI3K/AKT/mTOR pathway, General Immunology and Microbiology, Wild type, Metabolism, 030104 developmental biology, Amino Acid Substitution, chemistry, biology.protein, Tumor Suppressor Protein p53, metabolism, 030217 neurology & neurosurgery, Cysteine |
| الوصف: | The 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. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5b18a4957505cae05a51584f1f861ac0 https://doi.org/10.1101/2020.02.14.946269 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....5b18a4957505cae05a51584f1f861ac0 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |