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 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 (HIF1alpha) 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.
Düvel
Katrin
K
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Yecies
Jessica L
JL
Menon
Suchithra
S
Raman
Pichai
P
Lipovsky
Alex I
AI
Souza
Amanda L
AL
Triantafellow
Ellen
E
Ma
Qicheng
Q
Gorski
Regina
R
Cleaver
Stephen
S
Vander Heiden
Matthew G
MG
MacKeigan
Jeffrey P
JP
Finan
Peter M
PM
Clish
Clary B
CB
Murphy
Leon O
LO
Manning
Brendan D
BD
D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology*; D023281:Genomics / Q000379:methods; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D055432:Metabolomics / Q000379:methods; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008055:Lipids; D046912:Multiprotein Complexes; D011506:Proteins; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases