The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4 Academic Article uri icon

Overview

MeSH Major

  • Glutamine
  • Mitochondrial Proteins
  • Neoplasms
  • Sirtuins

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 date

  • May 9, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3684628

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2013.04.023

PubMed ID

  • 23663782

Additional Document Info

start page

  • 840

end page

  • 54

volume

  • 153

number

  • 4