Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1
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Author(s)
Düvel, Katrin
Yecies, Jessica L.
Menon, Suchithra
Raman, Pichai
Triantafellow, Ellen
Ma, Qicheng
Gorski, Regina
Cleaver, Stephen
MacKeigan, Jeffrey P.
Finan, Peter M.
Date Issued
July 2010
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Düvel, Katrin, Jessica L. Yecies, Suchithra Menon, Pichai Raman, Alex I. Lipovsky, Amanda L. Souza, Ellen Triantafellow, et al. “Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1.” Molecular Cell 39, no. 2 (July 2010): 171–183.
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Author's final manuscript
Abstract
Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1α) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease.
MIT Department
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2010.06.022
