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.
|Year of Publication||
2010 Jul 30
|PubMed Central ID||
R01 CA122617-04 / CA / NCI NIH HHS / United States
T90-DK070078 / DK / NIDDK NIH HHS / United States
T90 DK070078 / DK / NIDDK NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P01 CA120964-03 / CA / NCI NIH HHS / United States
R01 CA122617 / CA / NCI NIH HHS / United States
P01-CA120964 / CA / NCI NIH HHS / United States
R01-CA122617 / CA / NCI NIH HHS / United States