The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4

Cell. 2013 May 9;153(4):840-54. doi: 10.1016/j.cell.2013.04.023.

Abstract

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factors / metabolism
  • Animals
  • Cell Proliferation
  • Embryo, Mammalian / cytology
  • Energy Metabolism
  • Glutamate Dehydrogenase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mitochondrial Proteins / metabolism*
  • Multiprotein Complexes
  • Neoplasm Transplantation
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Sirtuins / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription, Genetic
  • Transplantation, Heterologous
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitination

Substances

  • Activating Transcription Factors
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Glutamine
  • Glutamate Dehydrogenase
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • SIRT4 protein, human
  • Sirtuins