mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle
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Controlling supplies for DNA and RNA synthesis: The mTORC1 protein kinase complex regulates anabolic metabolism and coordinates cellular signals that promote growth with availability of required precursor metabolites. Signaling through mTORC1 controls pyrimidine synthesis. Ben-Sahra et al. found that mTORC1 also functions by a different mechanism to regulate purine biosynthesis, thus generating precursors for the synthesis of RNA and DNA (see the Perspective by Ma and Jones). Signaling by mTORC1 caused accumulation of the transcription factor ATF4, which enhances production of the enzyme methylenetetrahydrofolate dehydrogenase 2, thus leading to increased production of the purine nucleotides needed for cell growth. Science , this issue p. 728 ; see also p. 670
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Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway and enhance flux through pyrimidine and purine synthesis pathways.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ben-Sahra et al., 2016
Targeting nucleotide metabolism may be more effective in tumor contexts with mTOR hyperactivation.
“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ben-Sahra et al., 2016
Mutant KRAS induces folate cycle enzymes and aberrant mTOR activation, a regulator of serine synthesis and the folate cycle.
“Mutant KRAS has also been implicated in the induction of enzymes involved in the folate cycle42 and the aberrant activation of mTOR, a key regulator for both serine synthesis and the folate cycle43,44.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [44]
MTHFD2 expression is regulated by mTORC1 and is critical for growth and proliferation.
“MTHFD2 expression is regulated by mTORC1, and is critical for growth and proliferation.70”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [70]
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Self-citation
- Authors
- Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M., & Manning, B. D.
- Affiliations
- Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Hoxhaj, Gerta
- Manning, Brendan D.
- Venue
- Science
- Published
- 2016-02-12
- Volume
- 351
- Issue
- 6274
- Pages
- 728-733
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4786372
- OpenAlex
- W2258318060
- Cited by
- 795
- References
- 25
- Citations by year
- 2026: 39 · 2025: 65 · 2024: 106 · 2023: 87 · 2022: 91 · 2021: 102 · 2020: 77 · 2019: 81 · 2018: 67 · 2017: 57 · 2016: 23
- FWCI
- 39.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bettencourt Foundation
- LAM Foundation
- TS Alliance
- NSF (DGE-1144152)
- NIH (K99-CA194192, P01-CA120964, P30-CA006516, R01-CA181390, R35-CA197459)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- mTORC1, purine biosynthesis, de novo purine synthesis, MTHFD2, ATF4, one-carbon metabolism, nucleotide pools, cell growth signaling, eIF2α phosphorylation, cancer cells, transcriptional regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Phosphorylation, Purines, Tetrahydrofolates, Transcription, Genetic, Protein Biosynthesis, Eukaryotic Initiation Factor-2, Methenyltetrahydrofolate Cyclohydrolase, Multiprotein Complexes, Mice, Activating Transcription Factor 4, HEK293 Cells, TOR Serine-Threonine Kinases
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