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When translation meets transformation: the mTOR story

Abstract

There is currently a high level of interest in signalling through the mammalian target of rapamycin (mTOR). This reflects both its key role in many cell functions and its involvement in disease states such as cancers. The best understood targets for mTOR signalling are proteins involved in controlling the translational machinery, including the ribosomal protein S6 kinases and proteins that regulate the initiation and elongation phases of translation. Indeed, there is compelling evidence that at least one of these targets of mTOR (eukaryotic initiation factor eIF4E) plays a key role in tumorigenesis. It is regulated through the mTOR-dependent phosphorylation of inhibitory proteins such as eIF4E-binding protein 1. Thus, targeting mTOR signalling may be an effective anticancer strategy, in at least a significant subset of tumours. Not all effects of mTOR are sensitive to the classical anti-mTOR drug rapamycin, and this compound also interferes with other processes besides eIF4E function. Developing new approaches to targeting mTOR for cancer therapy requires more detailed knowledge of signalling downstream of mTOR. Such advances are likely to come from further work to understand the regulation of mTOR targets such as components of the translational apparatus.

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References

  • Alessi DR, Kozlowski MT, Weng Q-P, Morrice N, Avruch J . (1998). Curr Biol 8: 69–81.

  • Ali SM, Sabatini DM . (2005). J Biol Chem 280: 19445–19448.

  • Arora S, Yang JM, Kinzy TG, Utsumi R, Okamoto T, Kitayama T et al. (2003). Cancer Res 63: 6894–6899.

  • Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM et al. (2004). Cancer Cell 5: 553–563.

  • Avruch J, Belham C, Weng Q, Hara K, Yonezawa K . (2001). Prog Mol Subcell Biol 26: 115–154.

  • Bagaglio DM, Cheng EH, Gorelick FS, Mitsui K, Nairn AC, Hait WN . (1993). Cancer Res 53: 2260–2264.

  • Bagaglio DM, Hait WN . (1994). Cell Growth Differ 5: 1403–1408.

  • Barlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G et al. (2000). Cancer Res 60: 5340–5344.

  • Beugnet A, Wang X, Proud CG . (2003). J Biol Chem 278: 40722.

  • Bjornsti MA, Houghton PJ . (2004). Cancer Cell 5: 519–523.

  • Bradley CA, Padovan JC, Thompson TL, Benoit CA, Chait BT, Rhoads RE . (2002). J Biol Chem 277: 12559–12571.

  • Browne GJ, Proud CG . (2002). Eur J Biochem 269: 5360–5368.

  • Browne GJ, Proud CG . (2004). Mol Cell Biol 24: 2986–2997.

  • Byfield MP, Murray JT, Backer JM . (2005). J Biol Chem 280: 33076–33082.

  • Byrd MP, Zamora M, Lloyd RE . (2005). J Biol Chem 280: 18610–18622.

  • Calastretti A, Bevilacqua A, Ceriani C, Vigano S, Zancai P, Capaccioli S et al. (2001a). Oncogene 20: 6172–6180.

  • Calastretti A, Rancati F, Ceriani MC, Asnaghi L, Canti G, Nicolin A . (2001b). Eur J Cancer 37: 2121–2128.

  • Carlberg U, Nilsson A, Nygard O . (1990). Eur J Biochem 191: 639–645.

  • Cheng EH, Gorelick FS, Czernik AJ, Bagaglio DM, Hait WN . (1995). Cell Growth Differ 6: 615–621.

  • Choo AY, Blenis J . (2006). Cancer Cell 9: 77–79.

  • Clemens MJ . (2004). Oncogene 23: 3180–3188.

  • Cohen N, Sharma M, Kentsis A, Perez JM, Strudwick S, Borden KLB . (2001). EMBO J 20: 4547–4559.

  • Coldwell MJ, Mitchell SA, Stoneley M, MacFarlane M, Willis AE . (2000). Oncogene 19: 899–905.

  • Constantinou C, Clemens MJ . (2005). Oncogene 24: 4839–4850.

  • Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL . (2005). J Cell Biol 169: 245–256.

  • Davies SP, Reddy H, Caivano M, Cohen P . (2000). Biochem J 351: 95–105.

  • De Benedetti A, Graff JR . (2004). Oncogene 23: 3189–3199.

  • Dostie J, Ferraiuolo M, Pause A, Adam SA, Sonenberg N . (2000). EMBO J 19: 3142–3156.

  • Eberle J, Krasagakis K, Orfanos CE . (1997). Int J Cancer 71: 396–401.

  • Fang P, Hwa V, Rosenfeld RG . (2006). Exp Cell Res 312: 1229–1239.

  • Feng Z, Zhang H, Levine AJ, Jin S . (2005). Proc Natl Acad Sci USA 102: 8204–8209.

  • Ferguson G, Mothe-Satney I, Lawrence Jr JC . (2003). J Biol Chem 278: 47459–47465.

  • Ferraiuolo MA, Basak S, Dostie J, Murray EL, Schoenberg DR, Sonenberg N . (2005). J Cell Biol 170: 913–924.

  • Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J . (2004). Mol Cell Biol 24: 200–216.

  • Fingar DC, Salama S, Tsou C, Harlow E, Blenis J . (2002). Genes Dev 16: 1472–1487.

  • Flynn A, Proud CG . (1995). J Biol Chem 270: 21684–21688.

  • Fukuchi-Shimogori T, Ishii I, Kashiwagi K, Mashiba H, Ekimoto J, Igarashi K . (1997). Cancer Res 57: 5041–5044.

  • Fukunaga R, Hunter T . (1997). EMBO J 16: 1921–1933.

  • Gingras A-C, Raught B, Gygi SP, Niedzwieka A, Miron M, Burley SK et al. (2001). Genes Dev 15: 2852–2864.

  • Gingras A-C, Raught B, Sonenberg N . (1999). Annu Rev Biochem 68: 913–963.

  • Graff JR, Zimmer SG . (2003). Clin Exp Metastasis 20: 265–273.

  • Gressner AM, Wool IG . (1974). Biochem Biophys Res Commun 60: 1482–1490.

  • Guertin DA, Sabatini DM . (2005). Trends Mol Med 11: 353–361.

  • Hait WN, Jin S, Yang JM . (2006). Clin Cancer Res 12: 1961–1965.

  • Hannan KM, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L et al. (2003). Mol Cell Biol 23: 8862–8877.

  • Harris TE, Chi A, Shabanowitz J, Hunt DF, Rhoads RE, Lawrence Jr JC . (2006). EMBO J 25: 1659–1668.

  • Herbert TP, Fahraeus R, Prescott A, Lane DP, Proud CG . (2000). Curr Biol 10: 793–796.

  • Herbert TP, Tee AR, Proud CG . (2002). J Biol Chem 277: 11591–11596.

  • Holz MK, Ballif BA, Gygi SP, Blenis J . (2005). Cell 123: 569–580.

  • Horton LE, Bushell M, Barth-Baus D, Tilleray VJ, Clemens MJ, Hensold JO . (2002). Oncogene 21: 5325–5334.

  • Houghton PJ, Huang S . (2004). Curr Top Microbiol Immunol 279: 339–359.

  • Hui AS, Bauer AL, Striet JB, Schnell PO, Czyzyk-Krzeska MF . (2006). FASEB J 20: 466–475.

  • Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Nat Cell Biol 6: 1122–1128.

  • Joshi B, Cai AL, Keiper BD, Minich WB, Mendez R, Beach CM et al. (1995). J Biol Chem 270: 14597–14603.

  • Kentsis A, Campbell Dwyer E, Perez JM, Sharma M, Chen A, Pan ZQ et al. (2001). J Mol Biol 312: 609–623.

  • Kimball SR, Jefferson LS . (2006). J Nutr 136: 227S–231S.

  • Klampfer L . (2006). Curr Cancer Drug Targets 6: 107–121.

  • Kleijn M, Scheper GC, Wilson ML, Tee AR, Proud CG . (2002). FEBS Lett 532: 319–323.

  • Klionsky DJ, Emr SD . (2000). Science 290: 1717–1721.

  • Knebel A, Morrice N, Cohen P . (2001). EMBO J 20: 4360–4369.

  • Koh H, Jee K, Lee B, Kim J, Kim D, Yun YH et al. (1999). Oncogene 18: 5115–5119.

  • Koromilas AE, Lazaris-Karatzas A, Sonenberg N . (1992). EMBO J 11: 4153–4158.

  • Lazaris-Karatzas A, Montine KS, Sonenberg N . (1990). Nature 345: 544–547.

  • Li S, Perlman DM, Peterson MS, Burrichter D, Avdulov S, Polunovsky VA et al. (2004). J Biol Chem 279: 21312–21317.

  • Li S, Takasu T, Perlman DM, Peterson MS, Burrichter D, Avdulov S et al. (2003). J Biol Chem 278: 3015–3022.

  • Lynch M, Fitzgerald C, Johnston KA, Wang S, Schmidt EV . (2004). J Biol Chem 279: 3327–3339.

  • Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . (2005). Cell 121: 179–193.

  • Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW, Sonenberg N . (2004). Oncogene 23: 3172–3179.

  • Manning BD . (2004). J Cell Biol 167: 399–403.

  • Mayer C, Zhao J, Yuan X, Grummt I . (2004). Genes Dev 18: 423–434.

  • Meijer AJ, Codogno P . (2004). Int J Biochem Cell Biol 36: 2445–2462.

  • Meyuhas O, Hornstein E . (2000). In: Sonenberg N, Hershey JWB, Mathews MB (eds). Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, pp. 671–693.

  • Mothe-Satney I, Brunn GJ, McMahon LP, Capaldo CT, Abraham RT, Lawrence JC . (2000a). J Biol Chem 275: 33836–33843.

  • Mothe-Satney I, Yang D, Fadden P, Haystead TAJ, Lawrence JC . (2000b). Mol Cell Biol 20: 3558–3567.

  • Ng G, Huang J . (2005). Mol Carcinog 43: 183–187.

  • Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P et al. (2005). Proc Natl Acad Sci USA 102: 14238–14243.

  • O'Loghlen A, Gonzalez VM, Pineiro D, Perez-Morgado MI, Salinas M, Martin ME . (2004). Exp Cell Res 299: 343–355.

  • Parmer TG, Ward MD, Hait WN . (1997). Cell Growth Differ 8: 327–334.

  • Parmer TG, Ward MD, Yurkow EJ, Vyas VH, Kearney TJ, Hait WN . (1999). Br J Cancer 79: 59–64.

  • Parra JL, Buxade M, Proud CG . (2005). J Biol Chem 280: 37623–37633.

  • Parra-Palau JL, Scheper GC, Wilson ML, Proud CG . (2003). J Biol Chem 278: 44197–44204.

  • Pattingre S, Levine B . (2006). Cancer Res 66: 2885–2888.

  • Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y et al. (2000). Nature 408: 994–997.

  • Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J et al. (2004). Mol Cell Biol 24: 3112–3124.

  • Polunovsky VA, Gingras AC, Sonenberg N, Peterson M, Tan A, Rubins JB et al. (2000). J Biol Chem 275: 24776–24780.

  • Polunovsky VA, Rosenwald IB, Tan AT, White J, Chiang L, Sonenburg N et al. (1996). Mol and Cell Biol 16: 6573–6581.

  • Proud CG . (2005). Cell Death Differ 12: 541–546.

  • Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA et al. (1998). Science 279: 707–710.

  • Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T, Sonenberg N . (1999). EMBO J 18: 270–279.

  • Raught B, Gingras AC, Gygi SP, Imataka H, Morino S, Gradi A et al. (2000). EMBO J 19: 434–444.

  • Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL et al. (2004). EMBO J 23: 1761–1769.

  • Redpath NT, Foulstone EJ, Proud CG . (1996). EMBO J 15: 2291–2297.

  • Rousseau D, Gingras A-C, Pause A, Sonenberg N . (1996a). Oncogene 13: 2415–2420.

  • Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N . (1996b). Proc Natl Acad Sci USA 93: 1065–1070.

  • Roux PP, Blenis J . (2004). Microbiol Mol Biol Rev 68: 320–344.

  • Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C et al. (2004). Nat Med 10: 484–486.

  • Ruvinsky I, Meyuhas O . (2006). Trends Biochem Sci 31: 342–348.

  • Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T et al. (2005). Genes Dev 19: 2199–2211.

  • Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M et al. (1997). Proc Natl Acad Sci USA 94: 4884–4889.

  • Sarbassov dD, Ali SM, Sabatini DM . (2005). Curr Opin Cell Biol 17: 596–603.

  • Sarbassov dD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF et al. (2006). Mol Cell 22: 159–168.

  • Schalm SS, Blenis J . (2002). Curr Biol 12: 632–639.

  • Schalm SS, Tee AR, Blenis J . (2005). J Biol Chem 280: 11101–11106.

  • Scheper GC, Morrice NA, Kleijn M, Proud CG . (2001). Mol Cell Biol 21: 743–754.

  • Scheper GC, Parra J-L, Wilson ML, van Kollenburg B, Vertegaal ACO, Han Z-G et al. (2003). Mol Cell Biol 23: 5692–5705.

  • Scheper GC, Proud CG . (2002). Eur J Biochem 269: 5350–5359.

  • Scheper GC, van Kollenburg B, Hu J, Luo Y, Goss DJ, Proud CG . (2002). J Biol Chem 277: 3303–3309.

  • Schmidt EV . (2004). Oncogene 23: 3217–3221.

  • Shuda M, Kondoh N, Tanaka K, Ryo A, Wakatsuki T, Hada A et al. (2000). Anticancer Res 20: 2489–2494.

  • Slepenkov SV, Darzynkiewicz E, Rhoads RE . (2006). J Biol Chem 281: 14927–14938.

  • Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG . (2005). J Biol Chem 280: 18717–18727.

  • Strudwick S, Borden KL . (2002). Differentiation 70: 10–22.

  • Surace EI, Lusis E, Haipek CA, Gutmann DH . (2004). Ann Neurol 56: 295–298.

  • Tee AR, Proud CG . (2000). Oncogene 19: 3021–3031.

  • Tee AR, Proud CG . (2001). Cell Death Differ 8: 841–849.

  • Tee AR, Proud CG . (2002). Mol Cell Biol 22: 1674–1683.

  • Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B et al. (2006). Nat Med 12: 122–127.

  • Tomoo K, Matsushita Y, Fujisaki H, Abiko F, Shen X, Taniguchi T et al. (2005). Biochim Biophys Acta 1753: 191–208.

  • Topisirovic I, Capili AD, Borden KL . (2002). Mol Cell Biol 22: 6183–6198.

  • Topisirovic I, Culjkovic B, Cohen N, Perez JM, Skrabanek L, Borden KL . (2003). EMBO J 22: 689–703.

  • Topisirovic I, Ruiz-Gutierrez M, Borden KL . (2004). Cancer Res 64: 8639–8642.

  • Tuhackova Z, Sovova V, Sloncova E, Proud CG . (1999). Int J Cancer 81: 963–969.

  • Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R . (2004). Mol Cell Biol 24: 6539–6549.

  • Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG . (2005). Mol Cell Biol 25: 2558–2572.

  • Wang X, Li W, Parra J-L, Beugnet A, Proud CG . (2003). Mol Cell Biol 23: 1546–1557.

  • Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG . (2001). EMBO J 20: 4370–4379.

  • Waskiewicz AJ, Flynn A, Proud CG, Cooper JA . (1997). EMBO J 16: 1909–1920.

  • Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA . (1999). Mol Cell Biol 19: 1871–1880.

  • Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. (2004). Nature 428: 332–337.

  • Wu H, Yang JM, Jin S, Zhang H, Hait WN . (2006). Cancer Res 66: 3015–3023.

  • Wullschleger S, Loewith R, Hall MN . (2006). Cell 124: 471–484.

  • Yokogami K, Wakisaka S, Avruch J, Reeves SA . (2000). Curr Biol 10: 47–50.

  • Zhou HY, Wong AS . (2006). Endocrinology 147: 2557–2566.

  • Zuberek J, Jemielity J, Jablonowska A, Stepinski J, Dadlez M, Stolarski R et al. (2004). Biochemistry 43: 5370–5379.

  • Zuberek J, Wyslouch-Cieszynska A, Niedzwiecka A, Dadlez M, Stepinski J, Augustyniak W et al. (2003). RNA 9: 52–61.

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Averous, J., Proud, C. When translation meets transformation: the mTOR story. Oncogene 25, 6423–6435 (2006). https://doi.org/10.1038/sj.onc.1209887

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