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mTOR Complex 1, Metabolism and Cell Growth Control
Author(s) -
Blenis John,
Csibi Alfredo,
Kim Sang Gyun,
Gu Xiaoxiao,
Li Jeannie,
Buel Gwen,
Lee Gina,
Jang Young Jin
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.455.1
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , autophagy , ampk , tsc2 , tsc1 , microbiology and biotechnology , glutamine , glutaminolysis , mechanistic target of rapamycin , cell growth , glutaminase , biology , kinase , protein kinase a , chemistry , cancer research , signal transduction , biochemistry , apoptosis , amino acid
Mutations in the TSC1 or TSC2 genes are responsible for causing Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM). These mutations lead to the uncontrolled activation of the mTOR complex 1 (mTORC1), a cellular protein kinase complex that regulates metabolism, autophagy and cell growth. Cells with TSC1/2 mutations require increased energy and carbon sources to meet their high metabolic needs for cell growth. To meet this demand, we have found that activated mTORC1 uses distinct mechanisms to increase glutamine consumption (glutaminolysis) by elevating the expression of glutaminase and the activity of glutamate dehydrogenase. Furthermore, TSC mutant cells sense the increased energy production and in a positive feedback loop, promote more mTORC1 assembly via an AMP kinase (AMPK)‐dependent, and a novel AMPK‐independent mechanism. This acquired addiction to glutamine provides a novel therapeutic strategy for treating patients with activated mTORC1. Indeed, by acutely blocking the ability of TSC ‐mutant cells to use glutamine, we are able to selectively kill cells with mutations in TSC1 or TSC2 without damaging normal cells. We anticipate that these studies will lead to the development of “synthetic‐lethal” drugs useful in the treatment of cancers with inappropriate regulation of mTORC1.