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

Katrin Düvel1, Jessica L Yecies, Suchithra Menon

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Molecular Cell
|July 31, 2010
PubMed

Insights

Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) stimulates key metabolic pathways like glycolysis and lipid synthesis. This mTORC1 activation drives cell proliferation and contributes to various diseases.

Area of Science:

  • Cellular metabolism
  • Molecular biology
  • Cancer research

Background:

  • Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is prevalent in pathological conditions such as cancer and obesity.
  • The precise intracellular effects of mTORC1 activation are not fully understood.

Purpose of the Study:

  • To elucidate the cell-intrinsic consequences of mTORC1 activation.
  • To identify the metabolic pathways and transcriptional programs regulated by mTORC1.

Main Methods:

  • Unbiased genomic, metabolomic, and bioinformatic analyses were employed.
  • Investigated the role of hypoxia-inducible factor (HIF1alpha) and sterol regulatory element-binding proteins (SREBP1 and SREBP2) in mediating mTORC1 effects.
  • Assessed the contribution of S6 kinase 1 (S6K1) in SREBP activation.

Main Results:

  • mTORC1 activation was found to be sufficient for stimulating glycolysis, the pentose phosphate pathway, and de novo lipid biosynthesis.
  • A transcriptional program involving HIF1alpha and SREBP1/2 targets was activated by mTORC1.
  • SREBP1 and SREBP2 were identified as promoters of cell proliferation downstream of mTORC1, with S6K1 mediating their activation.

Conclusions:

  • mTORC1 activation orchestrates specific metabolic and anabolic processes beyond protein synthesis.
  • These mTORC1-driven pathways, including those regulated by SREBP transcription factors, play a significant role in cell proliferation and are implicated in human diseases.

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