Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1

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 combin...

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Main Authors: Düvel, Katrin (Author), Yecies, Jessica L. (Author), Menon, Suchithra (Author), Raman, Pichai (Author), Triantafellow, Ellen (Author), Ma, Qicheng (Author), Gorski, Regina (Author), Cleaver, Stephen (Author), MacKeigan, Jeffrey P. (Author), Finan, Peter M. (Author), Murphy, Leon O. (Author), Manning, Brendan D. (Author), Lipovsky, Alex (Contributor), Souza, Amanda (Contributor), Vander Heiden, Matthew G. (Contributor), Clish, Clary (Contributor)
Other Authors: Broad Institute of MIT and Harvard (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
Format: Article
Language:English
Published: Elsevier BV, 2018-07-12T17:04:03Z.
Subjects:
Online Access:Get fulltext
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100 1 0 |a Düvel, Katrin  |e author 
100 1 0 |a Broad Institute of MIT and Harvard  |e contributor 
100 1 0 |a Massachusetts Institute of Technology. Department of Biology  |e contributor 
100 1 0 |a Koch Institute for Integrative Cancer Research at MIT  |e contributor 
100 1 0 |a Lipovsky, Alex  |e contributor 
100 1 0 |a Souza, Amanda  |e contributor 
100 1 0 |a Vander Heiden, Matthew G.  |e contributor 
100 1 0 |a Clish, Clary  |e contributor 
700 1 0 |a Yecies, Jessica L.  |e author 
700 1 0 |a Menon, Suchithra  |e author 
700 1 0 |a Raman, Pichai  |e author 
700 1 0 |a Triantafellow, Ellen  |e author 
700 1 0 |a Ma, Qicheng  |e author 
700 1 0 |a Gorski, Regina  |e author 
700 1 0 |a Cleaver, Stephen  |e author 
700 1 0 |a MacKeigan, Jeffrey P.  |e author 
700 1 0 |a Finan, Peter M.  |e author 
700 1 0 |a Murphy, Leon O.  |e author 
700 1 0 |a Manning, Brendan D.  |e author 
700 1 0 |a Lipovsky, Alex  |e author 
700 1 0 |a Souza, Amanda  |e author 
700 1 0 |a Vander Heiden, Matthew G.  |e author 
700 1 0 |a Clish, Clary  |e author 
245 0 0 |a Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1 
260 |b Elsevier BV,   |c 2018-07-12T17:04:03Z. 
856 |z Get fulltext  |u http://hdl.handle.net/1721.1/116937 
520 |a 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. 
655 7 |a Article 
773 |t Molecular Cell