Title: The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4
Authors: Csibi, Alfred
Fendt, Sarah-Maria
Li, Chenggang
Poulogiannis, George
Choo, Andrew Y
Chapski, Douglas J
Jeong, Seung Min
Dempsey, Jamie M
Parkhitko, Andrey
Morrison, Tasha
Henske, Elizabeth P
Haigis, Marcia C
Cantley, Lewis C
Stephanopoulos, Gregory
Yu, Jane
Blenis, John # ×
Issue Date: May-2013
Publisher: MIT Press
Series Title: Cell vol:153 issue:4 pages:840-54
Article number: 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.
ISSN: 0092-8674
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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