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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Additional file 4 of Pre-implantation exogenous progesterone and pregnancy in sheep. II. Effects on fetal-placental development and nutrient transporters in late pregnancy
Halloran, K. M., Hoskins, E. C., Stenhouse, C., Moses, R. M., Dunlap, K. A., Satterfield, M. C., Seo, H., Johnson, G. A., Wu, G., & Bazer, F. W. (2021) · Figshare · doi:10.6084/m9.figshare.14385258
Additional file 19 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758375
Additional file 17 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758369
Additional file 2 of Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2
Montori-Grau, M., Aguilar-Recarte, D., Zarei, M., Pizarro‐Delgado, J., Palomer, X., & Vázquez-Carrera, M. (2022) · Figshare · doi:10.6084/m9.figshare.19606690
Additional file 14 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758360
Additional file 3 of Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells
Haitzmann, T., Schindlmaier, K., Frech, T., Mondal, A., Bubalo, V., Konrad, B., Bluemel, G., Stiegler, P., Lackner, S., Hrzenjak, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26696289
Additional file 13 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22616008
Additional file 9 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758345
Additional file 12 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758354
Additional file 6 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758336
Additional file 3 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758327
Additional file 8 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758342
Additional file 11 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22616002
Additional file 5 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758333
Additional file 4 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758330
Additional file 7 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22615990
Additional file 10 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758348
Additional file 4 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22615981
Additional file 12 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22616005
Additional file 5 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22615984
Additional file 15 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22616014
Additional file 1 of Glioma cells require one-carbon metabolism to survive glutamine starvation
Tanaka, K., Sasayama, T., Nagashima, H., Irino, Y., Takahashi, M., Izumi, Y., Uno, T., Satoh, N., Kitta, A., Kyotani, K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13612770
Additional file 13 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758357
Additional file 16 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758366
Additional file 18 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758372
Additional file 3 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22615978
Additional file 2 of Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells
Haitzmann, T., Schindlmaier, K., Frech, T., Mondal, A., Bubalo, V., Konrad, B., Bluemel, G., Stiegler, P., Lackner, S., Hrzenjak, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25459513
Additional file 2 of Glioma cells require one-carbon metabolism to survive glutamine starvation
Tanaka, K., Sasayama, T., Nagashima, H., Irino, Y., Takahashi, M., Izumi, Y., Uno, T., Satoh, N., Kitta, A., Kyotani, K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13612773
Additional file 2 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26507305
Additional file 15 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758363
Additional file 7 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758339
Additional file 14 of MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway
Tange, S., Hirano, T., Idogawa, M., Hirata, E., Imoto, I., & Tokino, T. (2023) · Figshare · doi:10.6084/m9.figshare.22616011
Additional file 4 of Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells
Haitzmann, T., Schindlmaier, K., Frech, T., Mondal, A., Bubalo, V., Konrad, B., Bluemel, G., Stiegler, P., Lackner, S., Hrzenjak, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26696292
Additional file 6 of Pre-implantation exogenous progesterone and pregnancy in sheep. II. Effects on fetal-placental development and nutrient transporters in late pregnancy
Halloran, K. M., Hoskins, E. C., Stenhouse, C., Moses, R. M., Dunlap, K. A., Satterfield, M. C., Seo, H., Johnson, G. A., Wu, G., & Bazer, F. W. (2021) · Figshare · doi:10.6084/m9.figshare.14385264
Additional file 11 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26758351
Additional file 1 of Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila
Raynes, Y., Santiago, J. C., Lemieux, F. A., Darwin, L., & Rand, D. M. (2024) · Figshare · doi:10.6084/m9.figshare.26507211
Additional file 5 of Pre-implantation exogenous progesterone and pregnancy in sheep. II. Effects on fetal-placental development and nutrient transporters in late pregnancy
Halloran, K. M., Hoskins, E. C., Stenhouse, C., Moses, R. M., Dunlap, K. A., Satterfield, M. C., Seo, H., Johnson, G. A., Wu, G., & Bazer, F. W. (2021) · Figshare · doi:10.6084/m9.figshare.14385261
Additional file 1 of Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells
Haitzmann, T., Schindlmaier, K., Frech, T., Mondal, A., Bubalo, V., Konrad, B., Bluemel, G., Stiegler, P., Lackner, S., Hrzenjak, A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25459328
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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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