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Science 4 July 1997:
Vol. 277. no. 5322, pp. 99 - 101
DOI: 10.1126/science.277.5322.99
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Reports

Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin

Gregory J. Brunn, Christine C. Hudson, Aleksandar Sekulic, Josie M. Williams, Hajime Hosoi, Peter J. Houghton, John C. Lawrence Jr., Robert T. Abraham *

The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.

G. J. Brunn and J. C. Lawrence Jr., Departments of Pharmacology and Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
C. C. Hudson, A. Sekulic, J. M. Williams, R. T. Abraham, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
H. Hosoi and P. J. Houghton, Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
*   To whom correspondence should be addressed.

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   Abstract »    Full Text »    PDF »
Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus.
M. E. Hartman, J. C. O'Connor, J. P. Godbout, K. D. Minor, V. R. Mazzocco, and G. G. Freund (2004)
J. Biol. Chem. 279, 28045-28050
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Impact of Src Homology 2-Containing Inositol 5'-Phosphatase 2 on the Regulation of Insulin Signaling Leading to Protein Synthesis in 3T3-L1 Adipocytes Cultured with Excess Amino Acids.
S. Murakami, T. Sasaoka, T. Wada, K. Fukui, K. Nagira, H. Ishihara, I. Usui, and M. Kobayashi (2004)
Endocrinology 145, 3215-3223
   Abstract »    Full Text »    PDF »
Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone.
T. Stromberg, A. Dimberg, A. Hammarberg, K. Carlson, A. Osterborg, K. Nilsson, and H. Jernberg-Wiklund (2004)
Blood 103, 3138-3147
   Abstract »    Full Text »    PDF »
Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.
N. Oshiro, K.-i. Yoshino, S. Hidayat, C. Tokunaga, K. Hara, S. Eguchi, J. Avruch, and K. Yonezawa (2004)
Genes Cells 9, 359-366
   Abstract »    Full Text »    PDF »
Unlike insulin, amino acids stimulate p70S6K but not GSK-3 or glycogen synthase in human skeletal muscle.
Z. Liu, Y. Wu, E. W. Nicklas, L. A. Jahn, W. J. Price, and E. J. Barrett (2004)
Am J Physiol Endocrinol Metab 286, E523-E528
   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
   Abstract »    Full Text »    PDF »
Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid.
Y. KAM and J. H. EXTON (2004)
FASEB J 18, 311-319
   Abstract »    Full Text »    PDF »
mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E.
D. C. Fingar, C. J. Richardson, A. R. Tee, L. Cheatham, C. Tsou, and J. Blenis (2004)
Mol. Cell. Biol. 24, 200-216
   Abstract »    Full Text »    PDF »
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 »
Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene.
V. Bliskovsky, E. S. Ramsay, J. Scott, W. DuBois, W. Shi, S. Zhang, X. Qian, D. R. Lowy, and B. A. Mock (2003)
PNAS 100, 14982-14987
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Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling.
V. I. Brown, J. Fang, K. Alcorn, R. Barr, J. M. Kim, R. Wasserman, and S. A. Grupp (2003)
PNAS 100, 15113-15118
   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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Rapamycin Has a Deleterious Effect on MIN-6 Cells and Rat and Human Islets.
E. Bell, X. Cao, J. A. Moibi, S. R. Greene, R. Young, M. Trucco, Z. Gao, F. M. Matschinsky, S. Deng, J. F. Markman, et al. (2003)
Diabetes 52, 2731-2739
   Abstract »    Full Text »    PDF »
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 »
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
   Abstract »    Full Text »    PDF »
Cdc42 Promotes G1 Progression through p70 S6 Kinase-mediated Induction of Cyclin E Expression.
M. M. Chou, J. M. Masuda-Robens, and M. L. Gupta (2003)
J. Biol. Chem. 278, 35241-35247
   Abstract »    Full Text »    PDF »
Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients.
J. M. Peralba, L. deGraffenried, W. Friedrichs, L. Fulcher, V. Grunwald, G. Weiss, and M. Hidalgo (2003)
Clin. Cancer Res. 9, 2887-2892
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Activation of the p70 S6 Kinase and Phosphorylation of the 4E-BP1 Repressor of mRNA Translation by Type I Interferons.
F. Lekmine, S. Uddin, A. Sassano, S. Parmar, S. M. Brachmann, B. Majchrzak, N. Sonenberg, N. Hay, E. N. Fish, and L. C. Platanias (2003)
J. Biol. Chem. 278, 27772-27780
   Abstract »    Full Text »    PDF »
Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion.
J. J. Gu, K. Gathy, L. Santiago, E. Chen, M. Huang, L. M. Graves, and B. S. Mitchell (2003)
Blood 101, 4958-4965
   Abstract »    Full Text »    PDF »
Regulation of the Phosphatidylinositol 3-Kinase, Akt/Protein Kinase B, FRAP/Mammalian Target of Rapamycin, and Ribosomal S6 Kinase 1 Signaling Pathways by Thyroid-stimulating Hormone (TSH) and Stimulating type TSH Receptor Antibodies in the Thyroid Gland.
J. M. Suh, J. H. Song, D. W. Kim, H. Kim, H. K. Chung, J. H. Hwang, J. M. Kim, E. S. Hwang, J. Chung, J.-H. Han, et al. (2003)
J. Biol. Chem. 278, 21960-21971
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Identification of TOR-interacting Proteins.
K. Yonezawa (2003)
Mol. Interv. 3, 189-193
   Abstract »    Full Text »    PDF »


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