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Science 14 August 1992:
Vol. 257. no. 5072, pp. 973 - 977
DOI: 10.1126/science.1380182
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Articles

Science, Vol 257, Issue 5072, 973-977
Copyright © 1992 by American Association for the Advancement of Science

articles

Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase

DJ Price, Grove JR, V Calvo, J Avruch, and BE Bierer

Diabetes Unit, Massachusetts General Hospital, Boston.

The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line. Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. Rapamycin treatment of COS cells transfected with recombinant p70 S6 kinase completely inhibited the appearance of the hyperphosphorylated form of p70 S6 kinase concomitant with the inhibition of enzyme activity toward 40S subunits. Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase.


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Y. Iijima, M. Laser, H. Shiraishi, C. D. Willey, B. Sundaravadivel, L. Xu, P. J. McDermott, and D. Kuppuswamy (2002)
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J. Biol. Chem. 277, 9889-9895
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H. Tang, E. Hornstein, M. Stolovich, G. Levy, M. Livingstone, D. Templeton, J. Avruch, and O. Meyuhas (2001)
Mol. Cell. Biol. 21, 8671-8683
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M. Kimura, S. Osumi, and M. Ogihara (2001)
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Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells.
W. Lieberthal, R. Fuhro, C. C. Andry, H. Rennke, V. E. Abernathy, J. S. Koh, R. Valeri, and J. S. Levine (2001)
Am J Physiol Renal Physiol 281, F693-F706
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Bystander Activation Involving T Lymphocytes in Herpetic Stromal Keratitis.
S. Deshpande, M. Zheng, S. Lee, K. Banerjee, S. Gangappa, U. Kumaraguru, and B. T. Rouse (2001)
J. Immunol. 167, 2902-2910
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Bench to Bedside: The Development of Rapamycin and Its Application to Stent Restenosis.
S. O. Marx and A. R. Marks (2001)
Circulation 104, 852-855
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Transcriptional Regulation of Plasminogen Activator Inhibitor Type 1 Gene by Insulin: Insights Into the Signaling Pathway.
C. Banfi, P. Eriksson, G. Giandomenico, L. Mussoni, L. Sironi, A. Hamsten, and E. Tremoli (2001)
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Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages.
A. M. Woltman, J. W. de Fijter, S. W. A. Kamerling, S. W. van der Kooij, L. C. Paul, M. R. Daha, and C. van Kooten (2001)
Blood 98, 174-180
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Biochemical Correlates of mTOR Inhibition by the Rapamycin Ester CCI-779 and Tumor Growth Inhibition.
L. Dudkin, M. B. Dilling, P. J. Cheshire, F. C. Harwood, M. Hollingshead, S. G. Arbuck, R. Travis, E. A. Sausville, and P. J. Houghton (2001)
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L.-H. Zhang and J. O. Liu (2001)
J. Immunol. 166, 5611-5618
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E. N. Kaytor, J. L. Zhu, C.-I Pao, and L. S. Phillips (2001)
Endocrinology 142, 1041-1049
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J. M. Slavik, D.-G. Lim, S. J. Burakoff, and D. A. Hafler (2001)
J. Immunol. 166, 3201-3209
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Cold Spring Harb Symp Quant Biol 66, 477-484
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S. R. Kimball, L. S. Jefferson, H. V. Nguyen, A. Suryawan, J. A. Bush, and T. A. Davis (2000)
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M. Araki, K. Hasegawa, E. Iwai-Kanai, M. Fujita, T. Sawamura, T. Kakita, H. Wada, T. Morimoto, and S. Sasayama (2000)
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L. A. Sellers, F. Alderton, A. M. Carruthers, M. Schindler, and P. P. A. Humphrey (2000)
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A. Sekulic, C. C. Hudson, J. L. Homme, P. Yin, D. M. Otterness, L. M. Karnitz, and R. T. Abraham (2000)
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S. Herzig and J. Neumann (2000)
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M. E. Cardenas, N. S. Cutler, M. C. Lorenz, C. J. Di Como, and J. Heitman (1999)
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Hydrogen Peroxide Activates p70S6k Signaling Pathway.
G.-U. Bae, D.-W. Seo, H.-K. Kwon, H. Y. Lee, S. Hong, Z.-W. Lee, K.-S. Ha, H.-W. Lee, and J.-W. Han (1999)
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V. Cottin, A. Van Linden, and D. W. H. Riches (1999)
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R. R. Baliga, D. R. Pimental, Y.-Y. Zhao, W. W. Simmons, M. A. Marchionni, D. B. Sawyer, and R. A. Kelly (1999)
Am J Physiol Heart Circ Physiol 277, H2026-H2037
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Platelet-derived Growth Factor Stimulation of Monocyte Chemoattractant Protein-1 Gene Expression Is Mediated by Transient Activation of the Phosphoinositide 3-Kinase Signal Transduction Pathway.
J. A. Alberta, K. R. Auger, D. Batt, P. Iannarelli, G. Hwang, H. L. Elliott, R. Duke, T. M. Roberts, and C. D. Stiles (1999)
J. Biol. Chem. 274, 31062-31067
   Abstract »    Full Text »    PDF »
Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin.
J. Lotem, R. Kama, and L. Sachs (1999)
PNAS 96, 12016-12020
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Antifungal Activities of Antineoplastic Agents: Saccharomyces cerevisiae as a Model System To Study Drug Action.
M. E. Cardenas, M. C. Cruz, M. Del Poeta, N. Chung, J. R. Perfect, and J. Heitman (1999)
Clin. Microbiol. Rev. 12, 583-611
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Stimulation by Transforming Growth Factor-alpha of DNA Synthesis and Proliferation of Adult Rat Hepatocytes in Primary Cultures: Modulation by alpha - and beta -Adrenoceptor Agonists.
M. Kimura and M. Ogihara (1999)
J. Pharmacol. Exp. Ther. 291, 171-180
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Regulation of Glycogen Synthase in Rat Hepatocytes. EVIDENCE FOR MULTIPLE SIGNALING PATHWAYS.
L. Lavoie, C. J. Band, M. Kong, J. J. M. Bergeron, and B. I. Posner (1999)
J. Biol. Chem. 274, 28279-28285
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Regulation of p21cip1 Expression by Growth Factors and the Extracellular Matrix Reveals a Role for Transient ERK Activity in G1 Phase.
M. E. Bottazzi, X. Zhu, R. M. Bohmer, and R. K. Assoian (1999)
J. Cell Biol. 146, 1255-1264
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Commitment of Neutrophilic Differentiation and Proliferation of HL-60 Cells Coincides with Expression of Transferrin Receptor. EFFECT OF GRANULOCYTE COLONY STIMULATING FACTOR ON DIFFERENTIATION AND PROLIFERATION.
T. Kanayasu-Toyoda, T. Yamaguchi, E. Uchida, and T. Hayakawa (1999)
J. Biol. Chem. 274, 25471-25480
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Coordinate Regulation of the alpha 2-Macroglobulin Signaling Receptor and the Low Density Lipoprotein Receptor-related Protein/alpha 2-Macroglobulin Receptor by Insulin.
U. K. Misra, G. Gawdi, M. Gonzalez-Gronow, and S. V. Pizzo (1999)
J. Biol. Chem. 274, 25785-25791
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Regulation of Cell Growth and Cyclin D1 Expression by the Constitutively Active FRAP-p70s6K Pathway in Human Pancreatic Cancer Cells.
M. Grewe, F. Gansauge, R. M. Schmid, G. Adler, and T. Seufferlein (1999)
Cancer Res. 59, 3581-3587
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Protein Kinase B Localization and Activation Differentially Affect S6 Kinase 1 Activity and Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 Phosphorylation.
A. Dufner, M. Andjelkovic, B. M. T. Burgering, B. A. Hemmings, and G. Thomas (1999)
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Cyclin D1 Expression Mediated by Phosphatidylinositol 3-Kinase through mTOR-p70S6K-Independent Signaling in Growth Factor-Stimulated NIH 3T3 Fibroblasts.
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Rapamycin Causes Poorly Reversible Inhibition of mTOR and Induces p53-independent Apoptosis in Human Rhabdomyosarcoma Cells.
H. Hosoi, M. B. Dilling, T. Shikata, L. N. Liu, L. Shu, R. A. Ashmun, G. S. Germain, R. T. Abraham, and P. J. Houghton (1999)
Cancer Res. 59, 886-894
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Cloning and Characterization of RLPK, a Novel RSK-related Protein Kinase.
L. New, M. Zhao, Y. Li, W. W. Bassett, Y. Feng, S. Ludwig, F. D. Padova, H. Gram, and J. Han (1999)
J. Biol. Chem. 274, 1026-1032
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Attenuation of Mammalian Target of Rapamycin Activity by Increased cAMP in 3T3-L1 Adipocytes.
P. H. Scott and J. C. Lawrence Jr. (1998)
J. Biol. Chem. 273, 34496-34501
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Metabotropic glutamate receptor-initiated translocation of protein kinase p90rsk to polyribosomes: A possible factor regulating synaptic protein synthesis.
F. Angenstein, W. T. Greenough, and I. J. Weiler (1998)
PNAS 95, 15078-15083
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p70 S6 Kinase Activation Is Not Required for Insulin-Like Growth Factor-Induced Differentiation of Rat, Mouse, or Human Skeletal Muscle Cells.
J. Canicio, E. Gallardo, I. Illa, X. Testar, M. Palacin, A. Zorzano, and P. Kaliman (1998)
Endocrinology 139, 5042-5049
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Molecular Cloning and Characterization of a Novel p70 S6 Kinase, p70 S6 Kinase beta  Containing a Proline-rich Region.
I. Gout, T. Minami, K. Hara, Y. Tsujishita, V. Filonenko, M. D. Waterfield, and K. Yonezawa (1998)
J. Biol. Chem. 273, 30061-30064
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