title: The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.
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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Csibi
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Choo
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Chapski
authors.forename: Seung Min
authors.initials: SM
authors.lastname: Jeong
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Dempsey
authors.forename: Andrey
authors.initials: A
authors.lastname: Parkhitko
authors.forename: Tasha
authors.initials: T
authors.lastname: Morrison
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Henske
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.forename: Jane
authors.initials: J
authors.lastname: Yu
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology; D004734:Energy Metabolism; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D037761:Sirtuins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D051696:Activating Transcription Factors; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D005973:Glutamine; D005969:Glutamate Dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C525357:SIRT4 protein, human; D037761:Sirtuins