-
[show abstract]
[hide abstract]
ABSTRACT: Mechanistic target of rapamycin complex 1 (mTORC1) regulates growth and metabolism by integrating signals from the cellular environment. Ben-Sahra et al. (2013) and Robitaille et al. (2013) demonstrate a role for mTORC1 in nucleotide production via S6K1 phosphorylation of CAD, which catalyzes the initial steps of de novo pyrimidine biosynthesis.
Cell metabolism 05/2013; 17(5):633-5. · 17.35 Impact Factor
-
Sang Gyun Kim,
Gregory R Hoffman,
George Poulogiannis,
Gwen R Buel,
Young Jin Jang,
Ki Won Lee,
Bo-Yeon Kim,
Raymond L Erikson,
Lewis C Cantley,
Andrew Y Choo,
John Blenis
[show abstract]
[hide abstract]
ABSTRACT: The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.
Molecular cell 11/2012; · 14.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cells must sense environmental conditions and adjust to maintain metabolic homeostasis and survive stress conditions; in this issue, Cam et al. (2010) show that the tumor suppressor kinase ATM is activated by hypoxia, phosphorylates and stabilizes HIF-1α, and inhibits mTORC1.
Molecular cell 11/2010; 40(4):501-2. · 14.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mTORC1-signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation, and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.
Molecular cell 05/2010; 38(4):487-99. · 14.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mammalian translational initiation machinery is a tightly controlled system that is composed of eukaryotic initiation factors, and which controls the recruitment of ribosomes to mediate cap-dependent translation. Accordingly, the mTORC1 complex functionally controls this cap-dependent translation machinery through the phosphorylation of its downstream substrates 4E-BPs and S6Ks. It is generally accepted that rapamycin, a specific inhibitor of mTORC1, is a potent translational repressor. Here we report the unexpected discovery that rapamycin's ability to regulate cap-dependent translation varies significantly among cell types. We show that this effect is mechanistically caused by rapamycin's differential effect on 4E-BP1 versus S6Ks. While rapamycin potently inhibits S6K activity throughout the duration of treatment, 4E-BP1 recovers in phosphorylation within 6 h despite initial inhibition (1-3 h). This reemerged 4E-BP1 phosphorylation is rapamycin-resistant but still requires mTOR, Raptor, and mTORC1's activity. Therefore, these results explain how cap-dependent translation can be maintained in the presence of rapamycin. In addition, we have also defined the condition by which rapamycin can control cap-dependent translation in various cell types. Finally, we show that mTOR catalytic inhibitors are effective inhibitors of the rapamycin-resistant phenotype.
Proceedings of the National Academy of Sciences 12/2008; 105(45):17414-9. · 9.68 Impact Factor
