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Science 294 (5544): 1102-1105

Copyright © 2001 by the American Association for the Advancement of Science

Mammalian TOR: A Homeostatic ATP Sensor

Patrick B. Dennis,1 Anja Jaeschke,1 Masao Saitoh,1 Brian Fowler,2 Sara C. Kozma,1 George Thomas1*

The bacterial macrolide rapamycin is an efficacious anticancer agent against solid tumors. In a hypoxic environment, the increase in mass of solid tumors is dependent on the recruitment of mitogens and nutrients. When nutrient concentrations change, particularly those of essential amino acids, the mammalian Target of Rapamycin (mTOR) functions in regulatory pathways that control ribosome biogenesis and cell growth. In bacteria, ribosome biogenesis is independently regulated by amino acids and adenosine triphosphate (ATP). Here we demonstrate that the mTOR pathway is influenced by the intracellular concentration of ATP, independent of the abundance of amino acids, and that mTOR itself is an ATP sensor.

1 The Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
2 University Childrens Hospital CH-4005, Basel, Switzerland.
*   To whom correspondence should be addressed. E-mail: gthomas{at}fmi.ch

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Spatial Reorganization of Glycogen Synthase upon Activation in 3T3-L1 Adipocytes.
H. Ou, L. Yan, S. Osmanovic, C. C. Greenberg, and M. J. Brady (2005)
Endocrinology 146, 494-502
   Abstract »    Full Text »    PDF »
CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway.
L. X. Wu, J. La Rose, L. Chen, C. Neale, T. Mak, K. Okkenhaug, R. Wange, and R. Rottapel (2005)
J. Immunol. 174, 180-194
   Abstract »    Full Text »    PDF »
Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
D. J. VanderWeele, R. Zhou, and C. M. Rudin (2004)
Mol. Cancer Ther. 3, 1605-1613
   Abstract »    Full Text »    PDF »
Signaling Elements Involved in the Metabolic Regulation of mTOR by Nutrients, Incretins, and Growth Factors in Islets.
G. Kwon, C. A. Marshall, K. L. Pappan, M. S. Remedi, and M. L. McDaniel (2004)
Diabetes 53, S225-S232
   Abstract »    Full Text »    PDF »
Disruption of the Mouse mTOR Gene Leads to Early Postimplantation Lethality and Prohibits Embryonic Stem Cell Development.
Y.-G. Gangloff, M. Mueller, S. G. Dann, P. Svoboda, M. Sticker, J.-F. Spetz, S. H. Um, E. J. Brown, S. Cereghini, G. Thomas, et al. (2004)
Mol. Cell. Biol. 24, 9508-9516
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Regulation of Peroxisome Proliferator-Activated Receptor-{gamma} Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis.
J. E. Kim and J. Chen (2004)
Diabetes 53, 2748-2756
   Abstract »    Full Text »    PDF »
Linkage between Mitochondrial Hypovirulence and Viral Hypovirulence in the Chestnut Blight Fungus Revealed by cDNA Microarray Analysis.
T. D. Allen and D. L. Nuss (2004)
Eukaryot. Cell 3, 1227-1232
   Abstract »    Full Text »    PDF »
Mammalian Target of Rapamycin Inhibition.
J. P. Dutcher (2004)
Clin. Cancer Res. 10, 6382S-6387S
   Abstract »    Full Text »    PDF »
Inhibition of Mammalian Target of Rapamycin Activates Apoptosis Signal-regulating Kinase 1 Signaling by Suppressing Protein Phosphatase 5 Activity.
S. Huang, L. Shu, J. Easton, F. C. Harwood, G. S. Germain, H. Ichijo, and P. J. Houghton (2004)
J. Biol. Chem. 279, 36490-36496
   Abstract »    Full Text »    PDF »
Upstream and downstream of mTOR.
N. Hay and N. Sonenberg (2004)
Genes & Dev. 18, 1926-1945
   Abstract »    Full Text »    PDF »
Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome.
M. N. Corradetti, K. Inoki, N. Bardeesy, R. A. DePinho, and K.-L. Guan (2004)
Genes & Dev. 18, 1533-1538
   Abstract »    Full Text »    PDF »
"Sleeping Beauty": Quiescence in Saccharomyces cerevisiae.
J. V. Gray, G. A. Petsko, G. C. Johnston, D. Ringe, R. A. Singer, and M. Werner-Washburne (2004)
Microbiol. Mol. Biol. Rev. 68, 187-206
   Abstract »    Full Text »    PDF »
Energy state and its control on seed development: starch accumulation is associated with high ATP and steep oxygen gradients within barley grains.
H. Rolletschek, W. Weschke, H. Weber, U. Wobus, and L. Borisjuk (2004)
J. Exp. Bot. 55, 1351-1359
   Abstract »    Full Text »    PDF »
Thr2446 Is a Novel Mammalian Target of Rapamycin (mTOR) Phosphorylation Site Regulated by Nutrient Status.
S. W. Y. Cheng, L. G. D. Fryer, D. Carling, and P. R. Shepherd (2004)
J. Biol. Chem. 279, 15719-15722
   Abstract »    Full Text »    PDF »

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