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Activation of a metabolic gene regulatory network downstream of mTOR complex 1

Düvel, Katrin and Yecies, Jessica L. and Raman, Pichai and Menon, Suchithra and Lipovsky, Alex I. and Souza, Amanda L. and Triantafellow, Ellen and Ma, Qicheng and Gorski, Regina and Cleaver, Stephen and Mackeigan, Jeff and Finan, Peter and Clish, Clary B. and Murphy, Leon and Manning, Brendan D. (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular Cell, 39 (2). pp. 171-183. ISSN 1097-2765

Abstract

Aberrant activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a common molecular event in a large 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 (HIF1) 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.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2314

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