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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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C. M. Cham and T. F. Gajewski (2005)
J. Immunol. 174, 4670-4677
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Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl.
J. J. Gu, L. Santiago, and B. S. Mitchell (2005)
Blood 105, 3270-3277
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mTOR-targeted therapy of cancer with rapamycin derivatives.
S. Vignot, S. Faivre, D. Aguirre, and E. Raymond (2005)
Ann. Onc. 16, 525-537
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Signaling by Target of Rapamycin Proteins in Cell Growth Control.
K. Inoki, H. Ouyang, Y. Li, and K.-L. Guan (2005)
Microbiol. Mol. Biol. Rev. 69, 79-100
   Abstract »    Full Text »    PDF »
Patterns of Resistance and Incomplete Response to Docetaxel by Gene Expression Profiling in Breast Cancer Patients.
J. C. Chang, E. C. Wooten, A. Tsimelzon, S. G. Hilsenbeck, M. C. Gutierrez, Y.-L. Tham, M. Kalidas, R. Elledge, S. Mohsin, C. K. Osborne, et al. (2005)
J. Clin. Oncol. 23, 1169-1177
   Abstract »    Full Text »    PDF »
Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation.
E. V. Gerasimovskaya, D. A. Tucker, and K. R. Stenmark (2005)
J Appl Physiol 98, 722-731
   Abstract »    Full Text »    PDF »
Extracellular ATP-induced Proliferation of Adventitial Fibroblasts Requires Phosphoinositide 3-Kinase, Akt, Mammalian Target of Rapamycin, and p70 S6 Kinase Signaling Pathways.
E. V. Gerasimovskaya, D. A. Tucker, M. Weiser-Evans, J. M. Wenzlau, D. J. Klemm, M. Banks, and K. R. Stenmark (2005)
J. Biol. Chem. 280, 1838-1848
   Abstract »    Full Text »    PDF »
Mg2+ as activator of uridine phosphorylation in coordination with other cellular responses to growth factors.
C. Vidair and H. Rubin (2005)
PNAS 102, 662-666
   Abstract »    Full Text »    PDF »
Effects of Rapamycin on Cardiac and Skeletal Muscle Contraction and Crossbridge Cycling.
B. Schoffstall, A. Kataoka, A. Clark, and P. B. Chase (2005)
J. Pharmacol. Exp. Ther. 312, 12-18
   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
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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
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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
   Abstract »    Full Text »    PDF »
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 »

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