The tor pathway: a target for cancer therapy (original) (raw)

• Sehgal, S. N., Baker, H. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. 28, 727–732 (1975).
  Article CAS Google Scholar
• Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726 (1975).
  CAS Google Scholar
• Sehgal, S. N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin. Biochem. 31, 335–340 (1998).
  CAS PubMed Google Scholar
• Calne, R. Y. et al. Rapamycin for immunosuppression in organ allografting. Lancet 2, 227 (1989).
  CAS PubMed Google Scholar
• Schreiber, S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 251, 283–287 (1991).
  CAS PubMed Google Scholar
• Pohanka, E. New immunosuppressive drugs: an update. Curr. Opin. Urol. 11, 143–151 (2001).
  CAS PubMed Google Scholar
• Saunders, R. N., Metcalfe, M. S. & Nicholson, M. L. Rapamycin in transplantation: a review of the evidence. Kidney Int. 59, 3–16 (2001).
  CAS PubMed Google Scholar
• Harris, T. E. & Lawrence, J. C. Jr. TOR signaling. Sci. STKE 9 Dec 2003 (doi: 10.1126/stke.2122003re15).
• Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).
  CAS PubMed Google Scholar
• Gingras, A. C., Raught, B. & Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 15, 807–826 (2001).
  CAS PubMed Google Scholar
• Jacinto, E. & Hall, M. N. Tor signalling in bugs, brain and brawn. Nature Rev. Mol. Cell Biol. 4, 117–126 (2003).
  CAS Google Scholar
• Abraham, R. T. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 111, 9–12 (2002).
  CAS PubMed Google Scholar
• Hentges, K. E. et al. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc. Natl Acad. Sci. USA 98, 13796–13801 (2001).
  CAS PubMed PubMed Central Google Scholar
• Hentges, K., Thompson, K. & Peterson, A. The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. Development 126, 1601–1609 (1999).
  CAS PubMed Google Scholar
• Cardenas, M. E., Cutler, N. S., Lorenz, M. C., Di Como, C. J. & Heitman, J. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13, 3271–3279 (1999).
  CAS PubMed PubMed Central Google Scholar
• Hardwick, J. S., Kuruvilla, F. G., Tong, J. K., Shamji, A. F. & Schreiber, S. L. Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. Proc. Natl Acad. Sci. USA 96, 14866–14870 (1999).
  CAS PubMed PubMed Central Google Scholar
• Powers, T. & Walter, P. Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol. Biol. Cell 10, 987–1000 (1999).
  CAS PubMed PubMed Central Google Scholar
• Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).
  CAS PubMed Google Scholar
• Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002). References 18 and 19 report the identification of raptor as a 150-kDa TOR-binding protein that also binds 4E-BP1 and S6K1. The binding of raptor to TOR is necessary for the TOR-catalysed phosphorylation of 4E-BP1 in vitro and strongly enhances the TOR kinase activity towards p70α. So, raptor is an essential scaffold for the TOR-catalysed phosphorylation of 4E-BP1 and mediates TOR action in vivo.
  CAS PubMed Google Scholar
• Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).
  CAS PubMed Google Scholar
• Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003). References 20 and 21 identified GβL (the homologue of yeast Lst8) as a modulator of TOR kinase activity, stabilizing the interaction of raptor with TOR. The binding of GβL to TOR strongly stimulates the kinase activity of TOR towards S6K1 and 4E-BP1, an effect that is reversed by the stable interaction of raptor with TOR.
  CAS PubMed Google Scholar
• Schalm, S. S. & Blenis, J. Identification of a conserved motif required for mTOR signaling. Curr. Biol. 12, 632–639 (2002).
  CAS PubMed Google Scholar
• Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS Motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797–806 (2003).
  CAS PubMed Google Scholar
• Rajan, P., Panchision, D. M., Newell, L. F. & McKay, R. D. BMPs signal alternately through a SMAD or FRAP–STAT pathway to regulate fate choice in CNS stem cells. J. Cell Biol. 161, 911–921 (2003).
  CAS PubMed PubMed Central Google Scholar
• Coolican, S. A., Samuel, D. S., Ewton, D. Z., McWade, F. J. & Florini, J. R. The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J. Biol. Chem. 272, 6653–6662 (1997).
  CAS PubMed Google Scholar
• Shu, L., Zhang, X. & Houghton, P. J. Myogenic differentiation is dependent on both the kinase function and the N-terminal sequence of mammalian target of rapamycin. J. Biol. Chem. 277, 16726–16732 (2002).
  CAS PubMed Google Scholar
• Erbay, E. & Chen, J. The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism. J. Biol. Chem. 276, 36079–36082 (2001).
  CAS PubMed Google Scholar
• Martin, K. A. et al. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am. J. Physiol. Cell Physiol. 286, C507–C17 (2004).
  CAS PubMed Google Scholar
• Drenan, R. M., Liu, X., Bertram, P. G. & Zheng, X. F. FRAP/mTOR localization in the ER and the golgi apparatus. J. Biol. Chem. 24, 24 (2003).
  Google Scholar
• Kim, J. E. & Chen, J. Cytoplasmic–nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc. Natl Acad. Sci. USA 97, 14340–14345 (2000). This study reveals a novel regulatory mechanism, which involves cytoplasmic–nuclear shuttling of TOR. Results indicate that TOR is a cytoplasmic–nuclear shuttling protein and uncover a function for the nucleus in the direct regulation of the protein-synthesis machinery.
  CAS PubMed PubMed Central Google Scholar
• Zhang, X., Shu, L., Hosoi, H., Murti, K. G. & Houghton, P. J. Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. J. Biol. Chem. 277, 28127–28134 (2002).
  CAS PubMed Google Scholar
• Tirado, O. M., Mateo-Lozano, S., Sanders, S., Dettin, L. E. & Notario, V. The PCPH oncoprotein antagonizes the proapoptotic role of the mammalian target of rapamycin in the response of normal fibroblasts to ionizing radiation. Cancer Res. 63, 6290–6298 (2003).
  CAS PubMed Google Scholar
• Sabatini, D. M. et al. Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. Science 284, 1161–1164 (1999).
  CAS PubMed Google Scholar
• Tang, S. J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl Acad. Sci. USA 99, 467–472 (2002).
  CAS PubMed Google Scholar
• Lawrence, J. C., Lin, T. A., McMahon, L. P. & Choi, K. M. Modulation of the protein kinase activity of mTOR. Curr. Top. Microbiol. Immunol. 279, 199–213 (2004).
  CAS PubMed Google Scholar
• Dan, H. C. et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277, 35364–35370 (2002).
  CAS PubMed Google Scholar
• Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).
  CAS PubMed Google Scholar
• Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002).
  CAS PubMed Google Scholar
• Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).
  CAS PubMed Google Scholar
• Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biol. 4, 699–704 (2002).
  CAS PubMed Google Scholar
• Tee, A. R. et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl Acad. Sci. USA 99, 13571–13576 (2002). References 37–41 show that TSC1–TSC2 inhibits S6K1 and activates 4E-BP1. These functions of TSC1–TSC2 are mediated by inhibiting TOR. Furthermore, TSC2 is directly phosphorylated and inactivated by AKT. Phosphorylation destabilizes TSC2 and disrupts its interaction with TSC1.
  CAS PubMed PubMed Central Google Scholar
• Zhang, H. et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112, 1223–1233 (2003).
  CAS PubMed PubMed Central Google Scholar
• Tee, A. R., Anjum, R. & Blenis, J. Inactivation of the tuberous sclerosis complex-1 and-2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and-independent phosphorylation of tuberin. J. Biol. Chem. 278, 37288–37296 (2003).
  CAS PubMed Google Scholar
• Potter, C. J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).
  CAS PubMed Google Scholar
• Nellist, M. et al. Identification and characterization of the interaction between tuberin and 14-3-3ζ. J. Biol. Chem. 277, 39417–39424 (2002).
  CAS PubMed Google Scholar
• Li, Y., Inoki, K., Yeung, R. & Guan, K. L. Regulation of TSC2 by 14-3-3 binding. J. Biol. Chem. 277, 44593–44596 (2002).
  CAS PubMed Google Scholar
• Liu, M. Y., Cai, S., Espejo, A., Bedford, M. T. & Walker, C. L. 14-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s). Cancer Res. 62, 6475–6480 (2002).
  CAS PubMed Google Scholar
• Shumway, S. D., Li, Y. & Xiong, Y. 14-3-3β binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J. Biol. Chem. 278, 2089–2092 (2003).
  CAS PubMed Google Scholar
• Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 16, 2627–2632 (2002).
  CAS PubMed PubMed Central Google Scholar
• Jaeschke, A. et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J. Cell Biol. 159, 217–224 (2002).
  CAS PubMed PubMed Central Google Scholar
• Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
  CAS PubMed Google Scholar
• Wienecke, R., Konig, A. & DeClue, J. E. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J. Biol. Chem. 270, 16409–16414 (1995).
  CAS PubMed Google Scholar
• Xiao, G. H., Shoarinejad, F., Jin, F., Golemis, E. A. & Yeung, R. S. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272, 6097–6100 (1997).
  CAS PubMed Google Scholar
• Astrinidis, A. et al. Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene 21, 8470–8476 (2002).
  CAS PubMed Google Scholar
• Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).
  CAS PubMed Google Scholar
• Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003). References 55 and 56 show that the small GTPase RHEB is a direct target of TSC2 GAP activity both in vivo and in vitro . These studies identify RHEB as a molecular target of the TSC tumour suppressors.
  CAS PubMed Google Scholar
• Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature Cell Biol. 5, 559–565 (2003).
  CAS PubMed Google Scholar
• Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566–571 (2003).
  CAS PubMed Google Scholar
• Volarevic, S. & Thomas, G. Role of S6 phosphorylation and S6 kinase in cell growth. Prog. Nucleic Acid Res. Mol. Biol. 65, 101–127 (2001).
  CAS PubMed Google Scholar
• Shah, O. J., Anthony, J. C., Kimball, S. R. & Jefferson, L. S. 4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle. Am. J. Physiol. Endocrinol. Metab. 279, E715–E729 (2000).
  CAS PubMed Google Scholar
• Pullen, N. et al. Phosphorylation and activation of p70s6k by PDK1. Science 279, 707–710 (1998).
  CAS PubMed Google Scholar
• Dennis, P. B., Pullen, N., Kozma, S. C. & Thomas, G. The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol. Cell Biol. 16, 6242–6251 (1996).
  CAS PubMed PubMed Central Google Scholar
• Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H. & Sabatini, D. M. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA 95, 1432–1437 (1998).
  CAS PubMed PubMed Central Google Scholar
• von Manteuffel, S. R. et al. The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k. Mol. Cell Biol. 17, 5426–5436 (1997).
  CAS PubMed PubMed Central Google Scholar
• Phin, S., Kupferwasser, D., Lam, J. & Lee-Fruman, K. K. Mutational analysis of ribosomal S6 kinase 2 shows differential regulation of its kinase activity from that of ribosomal S6 kinase 1. Biochem. J. 373, 583–591 (2003).
  CAS PubMed PubMed Central Google Scholar
• Peterson, R. T., Desai, B. N., Hardwick, J. S. & Schreiber, S. L. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc. Natl Acad. Sci. USA 96, 4438–4442 (1999).
  CAS PubMed PubMed Central Google Scholar
• Duvel, K., Santhanam, A., Garrett, S., Schneper, L. & Broach, J. R. Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast. Mol. Cell 11, 1467–1478 (2003).
  PubMed Google Scholar
• Schmelzle, T., Beck, T., Martin, D. E. & Hall, M. N. Activation of the RAS/cyclic AMP pathway suppresses a TOR deficiency in yeast. Mol. Cell Biol. 24, 338–351 (2004).
  CAS PubMed PubMed Central Google Scholar
• Dennis, P. B., Fumagalli, S. & Thomas, G. Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curr. Opin. Genet. Dev. 9, 49–54 (1999).
  CAS PubMed Google Scholar
• Murata, K., Wu, J. & Brautigan, D. L. B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc. Natl Acad. Sci. USA 94, 10624–10629 (1997).
  CAS PubMed PubMed Central Google Scholar
• Inui, S. et al. Ig receptor binding protein 1 (α4) is associated with a rapamycin-sensitive signal transduction in lymphocytes through direct binding to the catalytic subunit of protein phosphatase 2A. Blood 92, 539–546 (1998).
  CAS PubMed Google Scholar
• Chen, J., Peterson, R. T. & Schreiber, S. L. α4 associates with protein phosphatases 2A, 4 and 6. Biochim. Biophys. Res. Commun. 247, 827–832 (1998).
  CAS Google Scholar
• Kloeker, S. et al. Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with α4 protein. Protein Expr. Purif. 31, 19–33 (2003).
  CAS PubMed Google Scholar
• Jefferies, H. B. et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 16, 3693–3704 (1997).
  CAS PubMed PubMed Central Google Scholar
• Terada, N. et al. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc. Natl Acad. Sci. USA 91, 11477–11481 (1994).
  CAS PubMed PubMed Central Google Scholar
• Jefferies, H. B., Reinhard, C., Kozma, S. C. & Thomas, G. Rapamycin selectively represses translation of the 'polypyrimidine tract' mRNA family. Proc. Natl Acad. Sci. USA 91, 4441–4445 (1994).
  CAS PubMed PubMed Central Google Scholar
• Tang, H. et al. Amino acid-induced translation of TOP mRNAs is fully dependent on phosphatidylinositol 3-kinase-mediated signaling, is partially inhibited by rapamycin, and is independent of S6K1 and rpS6 phosphorylation. Mol. Cell Biol. 21, 8671–8683 (2001).
  CAS PubMed PubMed Central Google Scholar
• Stolovich, M. et al. Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol. Cell Biol. 22, 8101–8113 (2002).
  CAS PubMed PubMed Central Google Scholar
• Pende, M. et al. Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408, 994–997 (2000).
  CAS PubMed Google Scholar
• Wang, X. et al. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).
  CAS PubMed PubMed Central Google Scholar
• Brunn, G. J. et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99–101 (1997).
  CAS PubMed Google Scholar
• Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).
  CAS PubMed Google Scholar
• Gingras, A. C. et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13, 1422–1437 (1999).
  CAS PubMed PubMed Central Google Scholar
• Yang, D. Q. & Kastan, M. B. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nature Cell Biol. 2, 893–898 (2000).
  CAS PubMed Google Scholar
• Lin, T. A. et al. PHAS-I as a link between mitogen-activated protein kinase and translation initiation. Science 266, 653–656 (1994).
  CAS PubMed Google Scholar
• Mothe-Satney, I. et al. Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J. Biol. Chem. 275, 33836–33843 (2000).
  CAS PubMed Google Scholar
• Mothe-Satney, I., Yang, D., Fadden, P., Haystead, T. A. & Lawrence, J. C. Jr. Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol. Cell. Biol. 20, 3558–3567 (2000).
  CAS PubMed PubMed Central Google Scholar
• Gingras, A. C. et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 15, 2852–2864 (2001).
  CAS PubMed PubMed Central Google Scholar
• Rosenwald, I. B. et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J. Biol. Chem. 270, 21176–21180 (1995).
  CAS PubMed Google Scholar
• Hashemolhosseini, S. et al. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 273, 14424–14429 (1998).
  CAS PubMed Google Scholar
• Shantz, L. M. & Pegg, A. E. Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res. 54, 2313–2316 (1994).
  CAS PubMed Google Scholar
• Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472–1487 (2002).
  CAS PubMed PubMed Central Google Scholar
• Montagne, J. et al. Drosophila S6 kinase: a regulator of cell size. Science 285, 2126–2129 (1999).
  CAS PubMed Google Scholar
• Kozma, S. C. & Thomas, G. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 24, 65–71 (2002).
  CAS PubMed Google Scholar
• Shima, H. et al. Disruption of the p70 s6k /p85 s6k gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 17, 6649–6659 (1998).
  CAS PubMed PubMed Central Google Scholar
• Volarevic, S. et al. Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science 288, 2045–2047 (2000).
  CAS PubMed Google Scholar
• Dilling, M. B. et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J. Biol. Chem. 277, 13907–13917 (2002).
  CAS PubMed Google Scholar
• Jiang, H., Coleman, J., Miskimins, R. & Miskimins, W. K. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int. 3, 2 (2003).
  PubMed PubMed Central Google Scholar
• Law, B. K. et al. Rapamycin potentiates transforming growth factor β-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol. Cell. Biol. 22, 8184–8198 (2002).
  CAS PubMed PubMed Central Google Scholar
• Nourse, J. et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372, 570–573 (1994).
  CAS PubMed Google Scholar
• Barata, J. T., Cardoso, A. A., Nadler, L. M. & Boussiotis, V. A. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1. Blood 98, 1524–1531 (2001).
  CAS PubMed Google Scholar
• Kato, J. Y., Matsuoka, M., Polyak, K., Massague, J. & Sherr, C. J. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell 79, 487–496 (1994).
  CAS PubMed Google Scholar
• Huang, S. et al. p53/p21CIP1 cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin. Cancer Res. 61, 3373–3381 (2001).
  CAS PubMed Google Scholar
• Lieberthal, W. et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am. J. Physiol. Renal Physiol. 281, F693–F706 (2001).
  CAS PubMed Google Scholar
• Thimmaiah, K. N. et al. Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras–Erk1–Erk2 and phosphatidylinositol 3′-kinase–Akt signaling pathways. Cancer Res. 63, 364–374 (2003).
  CAS PubMed Google Scholar
• Woltman, A. M. et al. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 101, 1439–1445 (2003).
  CAS PubMed Google Scholar
• Kenerson, H. L., Aicher, L. D., True, L. D. & Yeung, R. S. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 62, 5645–5650 (2002).
  CAS PubMed Google Scholar
• Huang, S. et al. Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1. Mol. Cell 11, 1491–1501 (2003). This work shows that, in the absence of IGF1, prolonged activation of the ASK1–JNK pathway induced apoptosis in response to rapamycin-mediated inhibition of TOR. In the presence of wild-type p53, in a pathway dependent on WAF1, ASK1–JNK activation was transient and apoptosis was suppressed.
  CAS PubMed Google Scholar
• Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).
  CAS Google Scholar
• Luo, J., Manning, B. D. & Cantley, L. C. Targeting the PI3K–Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257–262 (2003).
  CAS PubMed Google Scholar
• Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).
  CAS PubMed Google Scholar
• Nakamura, N. et al. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol. Cell Biol. 20, 8969–8982 (2000).
  CAS PubMed PubMed Central Google Scholar
• Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001). This work first identified hypersensitivity to rapamycins in cells lacking the dual phosphatase PTEN. These results provided the initial rationale for testing TOR inhibitors in PTEN -null human cancers.
  CAS PubMed PubMed Central Google Scholar
• Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).
  CAS PubMed PubMed Central Google Scholar
• Shi, Y. et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 62, 5027–5034 (2002).
  CAS PubMed Google Scholar
• Mutter, G. L. et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl Cancer Inst. 92, 924–930 (2000).
  CAS PubMed Google Scholar
• Yu, K. et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Relat. Cancer 8, 249–258 (2001).
  PubMed Google Scholar
• Zhou, C., Gehrig, P. A., Whang, Y. E. & Boggess, J. F. Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol. Cancer Ther. 2, 789–795 (2003).
  CAS PubMed Google Scholar
• Cheadle, J. P., Reeve, M. P., Sampson, J. R. & Kwiatkowski, D. J. Molecular genetic advances in tuberous sclerosis. Hum. Genet. 107, 97–114 (2000).
  CAS PubMed Google Scholar
• Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. Jr. TSC2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell 4, 147–158 (2003). This study found that TSC2 regulates VEGF through TOR-dependent and -independent pathways. Rapamycin normalized hypoxia-inducible factor levels in TSC 2 −/− cells, but only partially downregulated VEGF in this setting. The results imply a TOR-independent link between TSC2 loss and VEGF.
  CAS PubMed Google Scholar
• Treins, C., Giorgetti-Peraldi, S., Murdaca, J., Semenza, G. L. & Van Obberghen, E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem. 277, 27975–27981 (2002).
  CAS PubMed Google Scholar
• Zhong, H. et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).
  CAS PubMed Google Scholar
• Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).
  CAS PubMed PubMed Central Google Scholar
• Jiang, B. H. et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 12, 363–369 (2001).
  CAS PubMed Google Scholar
• Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995–4004 (2001).
  CAS PubMed PubMed Central Google Scholar
• Mayerhofer, M., Valent, P., Sperr, W. R., Griffin, J. D. & Sillaber, C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100, 3767–3775 (2002).
  CAS PubMed Google Scholar
• El-Hashemite, N., Walker, V., Zhang, H. & Kwiatkowski, D. J. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 63, 5173–5177 (2003).
  CAS PubMed Google Scholar
• Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med. 8, 128–135 (2002). It was found that rapamycin inhibited metastatic tumour growth and angiogenesis in in vivo mouse models. Rapamycin showed anti-angiogenic activities linked to a decrease in production of Vegf and to a markedly inhibited response of vascular endothelial cells to stimulation by Vegf.
  CAS PubMed Google Scholar
• Humar, R., Kiefer, F. N., Berns, H., Resink, T. J. & Battegay, E. J. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J. 16, 771–780 (2002).
  CAS PubMed Google Scholar
• Gromov, P. S., Madsen, P., Tomerup, N. & Celis, J. E. A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb. FEBS Lett. 377, 221–226 (1995).
  CAS PubMed Google Scholar
• Kwon, H. K. et al. Constitutive activation of p70S6k in cancer cells. Arch. Pharm. Res. 25, 685–690 (2002).
  CAS PubMed Google Scholar
• Salh, B., Marotta, A., Wagey, R., Sayed, M. & Pelech, S. Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. Int. J. Cancer 98, 148–154 (2002).
  CAS PubMed Google Scholar
• Wong, A. S. et al. Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis? Oncogene 20, 1318–1328 (2001).
  CAS PubMed Google Scholar
• Lazaris-Karatzas, A. & Sonenberg, N. The mRNA 5′ cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts. Mol. Cell. Biol. 12, 1234–1238 (1992).
  CAS PubMed PubMed Central Google Scholar
• Lazaris-Karatzas, A. et al. Ras mediates translation initiation factor 4E-induced malignant transformation. Genes Dev. 6, 1631–1642 (1992). Previous work had shown that overexpression of eIF4E transformed rodent cells. In this paper, it is shown that such overexpression upregulates Ras and that transformation is Ras-dependent. Together, these studies indicate that eIF4E is an oncogene.
  CAS PubMed Google Scholar
• Abid, M. R., Li, Y., Anthony, C. & De Benedetti, A. Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication. J. Biol. Chem. 274, 35991–35998 (1999).
  CAS PubMed Google Scholar
• Chabes, A. et al. Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell 112, 391–401 (2003).
  CAS PubMed Google Scholar
• Topisirovic, I. et al. The proline-rich homeodomain protein, PRH, is a tissue-specific inhibitor of eIF4E-dependent cyclin D1 mRNA transport and growth. EMBO J. 22, 689–703 (2003).
  CAS PubMed PubMed Central Google Scholar
• Rosenwald, I. B. Upregulated expression of the genes encoding translation initiation factors eIF-4E and eIF-2α in transformed cells. Cancer Lett. 102, 113–123 (1996).
  CAS PubMed Google Scholar
• Miyagi, Y. et al. Elevated levels of eukaryotic translation initiation factor eIF-4E, mRNA in a broad spectrum of transformed cell lines. Cancer Lett. 91, 247–252 (1995).
  CAS PubMed Google Scholar
• Graff, J. R. et al. Reduction of translation initiation factor 4E decreases the malignancy of ras-transformed cloned rat embryo fibroblasts. Int. J. Cancer 60, 255–263 (1995).
  CAS PubMed Google Scholar
• Rinker-Schaeffer, C. W., Graff, J. R., De Benedetti, A., Zimmer, S. G. & Rhoads, R. E. Decreasing the level of translation initiation factor 4E with antisense RNA causes reversal of ras-mediated transformation and tumorigenesis of cloned rat embryo fibroblasts. Int. J. Cancer 55, 841–847 (1993).
  CAS PubMed Google Scholar
• DeFatta, R. J., Nathan, C. A. & De Benedetti, A. Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line. Laryngoscope 110, 928–933 (2000).
  CAS PubMed Google Scholar
• Wang, S. et al. Expression of eukaryotic translation initiation factors 4E and 2α correlates with the progression of thyroid carcinoma. Thyroid 11, 1101–1107 (2001).
  CAS PubMed Google Scholar
• Rosenwald, I. B., Hutzler, M. J., Wang, S., Savas, L. & Fraire, A. E. Expression of eukaryotic translation initiation factors 4E and 2α is increased frequently in bronchioloalveolar but not in squamous cell carcinomas of the lung. Cancer 92, 2164–2171 (2001).
  CAS PubMed Google Scholar
• Wang, S. et al. Expression of the eukaryotic translation initiation factors 4E and 2α in non-Hodgkin's lymphomas. Am. J. Pathol. 155, 247–255 (1999).
  CAS PubMed PubMed Central Google Scholar
• Bauer, C. et al. Overexpression of the eukaryotic translation initiation factor 4G (eIF4G-1) in squamous cell lung carcinoma. Int. J. Cancer 98, 181–185 (2002).
  CAS PubMed Google Scholar
• Fukuchi-Shimogori, T. et al. Malignant transformation by overproduction of translation initiation factor eIF4G. Cancer Res. 57, 5041–5044 (1997).
  CAS PubMed Google Scholar
• Martin, M. E. et al. 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int. J. Biochem. Cell Biol. 32, 633–642 (2000).
  CAS PubMed Google Scholar
• Nomura, M. et al. Involvement of the Akt/mTOR pathway on EGF-induced cell transformation. Mol. Carcinog. 38, 25–32 (2003).
  CAS PubMed Google Scholar
• Skorski, T. et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 16, 6151–6161 (1997).
  CAS PubMed PubMed Central Google Scholar
• Ly, C., Arechiga, A. F., Melo, J. V., Walsh, C. M. & Ong, S. T. Bcr–Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res. 63, 5716–5722 (2003).
  CAS PubMed Google Scholar
• Gera, J. F. et al. AKT activity determines sensitivity to mTOR inhibitors by regulating cyclin D1 and c-myc expression. J. Biol. Chem. 279, 2737–2746 (2003).
  PubMed Google Scholar
• Louro, I. D. et al. The zinc finger protein GLI induces cellular sensitivity to the mTOR inhibitor rapamycin. Cell Growth Differ. 10, 503–516 (1999).
  CAS PubMed Google Scholar
• Pietenpol, J. A. et al. TGF-β 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 61, 777–785 (1990).
  CAS PubMed Google Scholar
• Song, K., Cornelius, S. C., Reiss, M. & Danielpour, D. Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-β by phosphatidylinositol 3-kinase/Akt-dependent suppression of the activation of Smad3 but not Smad2. J. Biol. Chem. 278, 38342–38351 (2003).
  CAS PubMed Google Scholar
• Douros, J. & Suffness, M. New antitumor substances of natural origin. Cancer Treat. Rev. 8, 63–87 (1981).
  CAS PubMed Google Scholar
• Houchens, D. P., Ovejera, A. A., Riblet, S. M. & Slagel, D. E. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur. J. Cancer Clin. Oncol. 19, 799–805 (1983).
  CAS PubMed Google Scholar
• Eng, C. P., Sehgal, S. N. & Vezina, C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. 37, 1231–1237 (1984).
  CAS Google Scholar
• Dancey, J. E. Clinical development of mammalian target of rapamycin inhibitors. Hematol. Oncol. Clin. North Am. 16, 1101–1114 (2002).
  PubMed Google Scholar
• Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI–779, a novel mTOR kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–918 (2004).
  CAS PubMed Google Scholar
• Boulay, A. et al. 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. Cancer Res. 64, 252–261 (2004).
  CAS PubMed Google Scholar
• Peralba, J. M. et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin. Cancer Res. 9, 2887–2892 (2003).
  CAS PubMed Google Scholar
• Huang, S., Bjornsti, M. A. & Houghton, P. J. Rapamycins: mechanism of action and cellular resistance. Cancer Biol. Ther. 2, 222–232 (2003).
  CAS PubMed Google Scholar
• Peng, T., Golub, T. R. & Sabatini, D. M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell. Biol. 22, 5575–5584 (2002).
  CAS PubMed PubMed Central Google Scholar
• Rosenwald, A. et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3, 185–197 (2003).
  CAS PubMed Google Scholar
• Liang, A., Lei, T., LuYing, Z. & YuPing, G. The expression of proto-oncogene eIF4E in laryngeal squamous cell carcinoma. Laryngoscope 113, 1238–1243 (2003).
  PubMed Google Scholar
• Nathan, C. A. et al. Molecular analysis of surgical margins in head and neck squamous cell carcinoma patients. Laryngoscope 112, 2129–2140 (2002).
  CAS PubMed Google Scholar
• Haydon, M. S., Googe, J. D., Sorrells, D. S., Ghali, G. E. & Li, B. D. Progression of eIF4e gene amplification and overexpression in benign and malignant tumors of the head and neck. Cancer 88, 2803–2810 (2000).
  CAS PubMed Google Scholar
• Sorrells, D. L., Meschonat, C., Black, D. & Li, B. D. Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor. J. Surg. Res. 85, 37–42 (1999).
  CAS PubMed Google Scholar
• Seki, N. et al. Expression of eukaryotic initiation factor 4E in atypical adenomatous hyperplasia and adenocarcinoma of the human peripheral lung. Clin. Cancer Res. 8, 3046–3053 (2002).
  CAS PubMed Google Scholar
• Kerekatte, V. et al. The proto-oncogene/translation factor eIF4E: a survey of its expression in breast carcinomas. Int. J. Cancer 64, 27–31 (1995).
  CAS PubMed Google Scholar
• Li, B. D. et al. Prospective study of eukaryotic initiation factor 4E protein elevation and breast cancer outcome. Ann. Surg. 235, 732–738 (2002).
  PubMed PubMed Central Google Scholar
• Scott, P. A. et al. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br. J. Cancer 77, 2120–2128 (1998).
  CAS PubMed PubMed Central Google Scholar
• Nathan, C. A. et al. Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas. Oncogene 15, 1087–1094 (1997).
  CAS PubMed Google Scholar
• Berkel, H. J., Turbat-Herrera, E. A., Shi, R. & de Benedetti, A. Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol. Biomarkers Prev. 10, 663–666 (2001).
  CAS PubMed Google Scholar
• Rosenwald, I. B. et al. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18, 2507–2517 (1999).
  CAS PubMed Google Scholar
• Crew, J. P. et al. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br. J. Cancer 82, 161–166 (2000).
  CAS PubMed Google Scholar
• Chen, Y., Zheng, Y. & Foster, D. A. Phospholipase D confers rapamycin resistance in human breast cancer cells. Oncogene 22, 3937–3942 (2003).
  CAS PubMed Google Scholar
• Wang, L., Rolfe, M. & Proud, C. G. Ca2+-independent protein kinase C activity is required for α1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes. Biochem. J. 373, 603–611 (2003).
  CAS PubMed PubMed Central Google Scholar
• Lim, H. K. et al. Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin–p70 S6 kinase 1 pathway. J. Biol. Chem. 5, 5 (2003).
  Google Scholar
• Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001).
  CAS PubMed Google Scholar
• Meijer, A. J. Amino acids as regulators and components of nonproteinogenic pathways. J. Nutr. 133, 2057S–2062S (2003).
  CAS PubMed Google Scholar
• Wang, L., Fraley, C. D., Faridi, J., Kornberg, A. & Roth, R. A. Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells. Proc. Natl Acad. Sci. USA 100, 11249–11254 (2003).
  CAS PubMed PubMed Central Google Scholar
• Arsham, A. M., Howell, J. J. & Simon, M. C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655–29660 (2003). It is shown that hypoxia rapidly and reversibly triggers hypophosphorylation of TOR and its downstream effectors. Hypoxic regulation of TOR is dominant to activation through several distinct signalling pathways and implicates the role of TOR in sensing O 2 status of cells.
  CAS PubMed Google Scholar