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Science 2 November 2001:
Vol. 294. no. 5544, pp. 1102 - 1105
DOI: 10.1126/science.1063518
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Reports

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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Plant Physiology 134, 1527-1535
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Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398.
G. J. Browne, S. G. Finn, and C. G. Proud (2004)
J. Biol. Chem. 279, 12220-12231
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Inhibition of Epidermal Growth Factor Receptor Signaling Protects Human Malignant Glioma Cells from Hypoxia-Induced Cell Death.
J. P. Steinbach, A. Klumpp, H. Wolburg, and M. Weller (2004)
Cancer Res. 64, 1575-1578
   Abstract »    Full Text »    PDF »
mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability.
C. Mayer, J. Zhao, X. Yuan, and I. Grummt (2004)
Genes & Dev. 18, 423-434
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AKT Activity Determines Sensitivity to Mammalian Target of Rapamycin (mTOR) Inhibitors by Regulating Cyclin D1 and c-myc Expression.
J. F. Gera, I. K. Mellinghoff, Y. Shi, M. B. Rettig, C. Tran, J.-h. Hsu, C. L. Sawyers, and A. K. Lichtenstein (2004)
J. Biol. Chem. 279, 2737-2746
   Abstract »    Full Text »    PDF »
Carbohydrates Induce Mono-ubiquitination of H2B in Yeast.
L. Dong and C. W. Xu (2004)
J. Biol. Chem. 279, 1577-1580
   Abstract »    Full Text »    PDF »
FKBP12-Rapamycin-associated Protein or Mammalian Target of Rapamycin (FRAP/mTOR) Localization in the Endoplasmic Reticulum and the Golgi Apparatus.
R. M. Drenan, X. Liu, P. G. Bertram, and X. F. S. Zheng (2004)
J. Biol. Chem. 279, 772-778
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Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells.
A. Boulay, S. Zumstein-Mecker, C. Stephan, I. Beuvink, F. Zilbermann, R. Haller, S. Tobler, C. Heusser, T. O'Reilly, B. Stolz, et al. (2004)
Cancer Res. 64, 252-261
   Abstract »    Full Text »    PDF »
TOR Signaling.
T. E. Harris and J. C. Lawrence Jr. (2003)
Sci. STKE 2003, re15
   Abstract »    Full Text »    PDF »
Differential Effects of Rapamycin on Mammalian Target of Rapamycin Signaling Functions in Mammalian Cells.
A. L. Edinger, C. M. Linardic, G. G. Chiang, C. B. Thompson, and R. T. Abraham (2003)
Cancer Res. 63, 8451-8460
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The PCPH Oncoprotein Antagonizes the Proapoptotic Role of the Mammalian Target of Rapamycin in the Response of Normal Fibroblasts to Ionizing Radiation.
O. M. Tirado, S. Mateo-Lozano, S. Sanders, L. E. Dettin, and V. Notario (2003)
Cancer Res. 63, 6290-6298
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Tissue-specific regulation of protein synthesis by insulin and free fatty acids.
S. J. Crozier, J. C. Anthony, C. M. Schworer, A. K. Reiter, T. G. Anthony, S. R. Kimball, and L. S. Jefferson (2003)
Am J Physiol Endocrinol Metab 285, E754-E762
   Abstract »    Full Text »    PDF »
Interpreting the Plastid Carbon, Nitrogen, and Energy Status. A Role for PII?.
G. B.G. Moorhead and C. S. Smith (2003)
Plant Physiology 133, 492-498
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Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells.
L. Wang, C. D. Fraley, J. Faridi, A. Kornberg, and R. A. Roth (2003)
PNAS 100, 11249-11254
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Stimulation of Signal Transducer and Activator of Transcription-1 (STAT1)-dependent Gene Transcription by Lipopolysaccharide and Interferon-{gamma} Is Regulated by Mammalian Target of Rapamycin.
A. S. Kristof, J. Marks-Konczalik, E. Billings, and J. Moss (2003)
J. Biol. Chem. 278, 33637-33644
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Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner.
A. F. Castro, J. F. Rebhun, G. J. Clark, and L. A. Quilliam (2003)
J. Biol. Chem. 278, 32493-32496
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A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets.
A. M. Arsham, J. J. Howell, and M. C. Simon (2003)
J. Biol. Chem. 278, 29655-29660
   Abstract »    Full Text »    PDF »


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