Cited by 807Biochemical and Molecular ResearchPI3K/AKT/mTOR signaling in cancerFolate and B Vitamins Research

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mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle

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Ben-Sahra, Issam, Hoxhaj, Gerta, Ricoult, Stéphane J. H., Asara, John M., Manning, Brendan D.·2016·Science

DOI 10.1126/science.aad0489PMC PMC4786372

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Abstract

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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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.
ORCID: Hoxhaj, Gerta
Asara, John M.
Manning, Brendan D.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2016-02-12
Volume: 351
Issue: 6274
Pages: 728-733
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aad0489
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 › Nursing › Nutrition and Dietetics › 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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mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle

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