Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1

Ben-Sahra, Issam; Howell, Jessica J.; Asara, John M.; Manning, Brendan D.

doi:10.1126/science.1228792

Cited by 623 publications

(574 citation statements)

References 25 publications

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“…27,28 An increase in 13 C-labeled glycolytic intermediates in 0.1 Gy irradiated cells was detected (Figure 2e), accompanied by a decrease in labeling of TCA cycle intermediates (Figure 2f), suggesting a metabolic switch from oxidative phosphorylation to glycolysis. In addition, increased labeling of 6-phospho-D-gluconate, a metabolite specific to the oxidative PPP, was detected following 0.1 Gy irradiation (Figure 2g).…”

Section: Resultsmentioning

confidence: 99%

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1a, which is induced specifically by lowdose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to lowdose radiation has important implications in understanding and assessing the health risks of radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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“…In the first case, S6K1 phosphorylates the enzyme CAD to increase the production of N ‐carbamoyl‐ l ‐aspartate, a pyrimidine precursor (Ben‐Sahra, Howell, Asara, & Manning, 2013). In the second case, mTORC1 promotes the translation of the transcription factor Atf4, which in turn induces the transcription of Mthfd2, an enzyme in the purine pathway (Ben‐Sahra, Hoxhaj, Ricoult, Asara, & Manning, 2016).…”

Section: Mtor and Metabolismmentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

133

120

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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“…mTORC1 increases the ATF4-dependent expression of MTHFD2, a key component of the mitochondrial tetrahydrofolate cycle that provides one-carbon units for purine synthesis (Ben-Sahra et al, 2016). Additionally, S6K1 phosphorylates and activates carbamoylphosphate synthetase (CAD), a critical component of the de novo pyrimidine synthesis pathway (Ben-Sahra et al, 2013;Robataille et al, 2013). mTORC1 also facilitates growth by promoting a shift in glucose metabolism from oxidative phosphorylation to glycolysis, which likely facilitates the incorporation of nutrients into new biomass.…”

Section: Downstream Of Mtorc1mentioning

confidence: 99%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,224

2,558

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The mechanistic Target of Rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR-signaling network contributes to human disease, and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1

Cited by 623 publications

References 25 publications

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Myelination and mTOR

mTOR Signaling in Growth, Metabolism, and Disease

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