MTOR and regulation of translation

Translation and Its Regulation in Cancer Biology and Medicine

Volumn , Issue , 2014, Pages 307-343

  Tsukumo, Yoshinori ^a   Laplante, Mathieu ^b   Parsyan, Armen ^c   Ruggero, Davide ^d   Fonseca, Bruno ^a  

^a MCGILL UNIVERSITY   (Canada)

^b LAVAL UNIVERSITY   (Canada)

^c MCGILL UNIVERSITY   (Canada)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cancer; Cell signaling; eIF4E; eIF4E binding protein (4E BP); mTOR; mTOR complex; mTOR inhibitor; Protein synthesis; Rapalog; Translation

Indexed keywords

EID: 84930914923     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-94-017-9078-9_15     Document Type: Chapter

References (234)

1. Alain T, Morita M, Fonseca BD, Yanagiya A, Siddiqui N, Bhat M, Zammit D, Marcus V, Metrakos P, Voyer LA et al (2012) eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res 72:6468-6476
2. Altman JK, Sassano A, Kaur S, Glaser H, Kroczynska B, Redig AJ, Russo S, Barr S, Platanias LC (2011) Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res 17:4378-4388
3. Andersen CL, Monni O, Wagner U, Kononen J, Barlund M, Bucher C, Haas P, Nocito A, Bissig H, Sauter G et al (2002) High-throughput copy number analysis of 17q23 in 3520 tissue specimens by fluorescence in situ hybridization to tissue microarrays. Am J Pathol 161:73-79
4. Andre F, Campone M, O'Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay P, Soria JC, Naughton M, Hurvitz SA (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110-5115
5. Arora S, Yang JM, Kinzy TG, Utsumi R, Okamoto T, Kitayama T, Ortiz PA, Hait WN (2003) Identification and characterization of an inhibitor of eukaryotic elongation factor 2 kinase against human cancer cell lines. Cancer Res 63:6894-6899
6. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP et al (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918
7. Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM, Manivel JC, Sonenberg N, Yee D, Bitterman PB et al (2004) Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5:553-563
8. Aziz SA, Jilaveanu LB, Zito C, Camp RL, Rimm DL, Conrad P, Kluger HM (2010) Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res 16:6029-6039
9. Banko JL, Poulin F, Hou L, DeMaria CT, Sonenberg N, Klann E (2005) The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci 25:9581-9590
10. Barlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G, Kallioniemi O-P, Kallioniemi A (2000) Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res 60:5340-5344
11. Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, Rao PH, Ruggero D (2008) Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456:971-975
12. Baselga J, Campone M, Piccart M, Burris HA III, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529
13. Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R. (2009) The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res 315:485-497
14. Ben-Sahra I, Howell JJ, Asara JM, Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339:1323-1328
15. Benjamin D, Colombi M, Moroni C, Hall MN (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10:868-880
16. Berkel HJ, Turbat-Herrera EA, Shi R, de Benedetti A (2001) Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol Biomarkers Prev 10:663-666
17. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M. et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395-402
18. Bertoni F, Zucca E, Cotter FE (2004) Molecular basis of mantle cell lymphoma. Br J Haematol 124:130-140
19. Bertram J, Peacock JW, Fazli L, Mui AL, Chung SW, Cox ME, Monia B, Gleave ME, Ong CJ (2006) Loss of PTEN is associated with progression to androgen independence. Prostate 66:895-902
20. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr (2003) TSC2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell 4:147-158
21. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893-2904
22. Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr, Abraham RT (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99-101
23. Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451-460
24. Burris HA III (2013) Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 71:829-842
25. Carayol N, Vakana E, Sassano A, Kaur S, Goussetis DJ, Glaser H, Druker BJ, Donato NJ, Altman JK, Barr S et al (2010) Critical roles for mTORC2-and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A 107:12469-12474
26. Cavazzoni A, Bonelli MA, Fumarola C, La Monica S, Airoud K, Bertoni R, Alfieri RR, Galetti M, Tramonti S, Galvani E et al (2012) Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett 323:77-87
27. Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22:1926-1933
28. Chawla SP, Staddon AP, Baker LH, Schuetze SM, Tolcher AW, D'Amato GZ, Blay JY, Mita MM, Sankhala KK, Berk L et al (2012) Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 30:78-84
29. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. ProcNatl Acad Sci U S A 93:3636-3641
30. Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J (2008) Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A 105:17414-17419
31. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P et al (2010) AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 70:288-298
32. Cinar B, De Benedetti A, Freeman MR (2005) Post-transcriptional regulation of the androgen receptor by mammalian target of rapamycin. Cancer Res 65:2547-2553
33. Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S, Colburn NH (1999) Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci U S A 96:14037-14042
34. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450:736-740
35. Dancey J (2010) mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 7:209-219
36. deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA, Hidalgo M (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10:8059-8067
37. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66:5549-5554
38. Deng H, Hershenson MB, Lei J, Bitar KN, Fingar DC, Solway J, Bentley JK (2010) p70 Ribosomal S6 kinase is required for airway smooth muscle cell size enlargement but not increased contractile protein expression. Am J Respiratory Cell Mol Biol 42:744-752
39. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (2008) Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 22:239-251
40. Dobashi Y, Suzuki S, Sato E, Hamada Y, Yanagawa T, Ooi A (2009) EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors. Mod Pathol 22:1328-1340
41. Doi T, Muro K, Boku N, Yamada Y, Nishina T, Takiuchi H, Komatsu Y, Hamamoto Y, Ohno N, Fujita Y et al (2010) Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 28:1904-1910
42. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M (2006) S6K1-and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314:467-471
43. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804-10812
44. Dowling, RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y et al (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328:1172-1176
45. Duncan R, Hershey JW (1985) Regulation of initiation factors during translational repression caused by serum depletion. Covalent modification. J Biol Chem 260:5493-5497
46. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S et al (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171-183
47. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221-9230
48. Ellard SL, Clemons M, Gelmon KA, Norris B, Kennecke H, Chia S, Pritchard K, Eisen A, Vandenberg T, Taylor M et al (2009) Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 27:4536-4541
49. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-1356
50. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. Br Med J 330:1304-1305
51. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Activesite inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38
52. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204-8209
53. Floc'h N, Kinkade CW, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A, Cardiff RD, Califano A, Shen MM, Abate-Shen C (2012) Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res 72:4483-4493
54. Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, Petroulakis E, Robichaud N, Pollak M, Gaboury LA et al (2010) eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci U S A 107:14134-14139
55. Gabardi S, Baroletti SA (2010) Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy 30:1044-1056
56. Gallardo A, Lerma E, Escuin D, Tibau A, Munoz J, Ojeda B, Barnadas A, Adrover E, Sanchez-Tejada L, Giner D et al (2012) Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer 106:1367-1373
57. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297-12305
58. Garcia-Garcia C, Ibrahim YH, Serra V, Calvo MT, Guzman M, Grueso J, Aura C, Perez J, Jessen K, Liu Y et al (2012) Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 18:2603-2612
59. Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1) Biochem J 416:375-385
60. Garlich JR, De P, Dey N, Su JD, Peng X, Miller A, Murali R, Lu Y, Mills GB, Kundra V et al (2008) A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 68:206-215
61. Gayle SS, Arnold SL, O'Regan RM, Nahta R (2012) Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anticancer Agents Med Chem 12:151-162
62. Ghayad SE, Bieche I, Vendrell JA, Keime C, Lidereau R, Dumontet C, Cohen PA (2008) mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci 99:1992-2003
63. Ghayad SE, Vendrell JA, Ben Larbi S, Dumontet C, Bieche I, Cohen PA (2010) Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int J Cancer 126:545-562
64. Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (1999a) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 13:1422-1437
65. Gingras AC, Raught B, Sonenberg N (1999b) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913-963
66. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852-2864
67. Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P et al (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371-377
68. Gomez-Pinillos A, Ferrari AC (2012) mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematol Oncol Clin North Am 26:483-505, vii
69. Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, Schwier P, Capen A, Goode RL, Dowless MS et al (2007) Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest 117:2638-2648
70. Graff JR, Konicek BW, Lynch RL, Dumstorf CA, Dowless MS, McNulty AM, Parsons SH, Brail LH, Colligan BM, Koop JW et al (2009) eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. Cancer Res 69:3866-3873
71. Grove JR, Banerjee P, Balasubramanyam A, Coffer PJ, Price DJ, Avruch J, Woodgett JR (1991) Cloning and expression of two human p70 S6 kinase polypeptides differing only at their amino termini. Mol Cell Biol 11:5541-5550
72. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128-135
73. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353-361
74. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214-226
75. Haghighat A, Mader S, Pause A, Sonenberg N (1995) Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J 14:5701-5709
76. Hannan KM, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L, Moss T, Poortinga G, McArthur GA, Pearson RB et al (2003) mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 23:8862-8877
77. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR et al (2004) The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213-223
78. Heesom KJ, Denton RM (1999) Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase. FEBS Lett 457:489-493
79. Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J, Socci ND, Behrendt N, Ma L, Maki RG et al (2007) The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13:748-753
80. Hernandez-Aya LF, Gonzalez-Angulo AM (2011) Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 16:404-414
81. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A et al (2009) Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822-3829
82. Holt SV, Logie A, Davies BR, Alferez D, Runswick S, Fenton S, Chresta CM, Gu Y, Zhang J, Wu YL et al (2012) Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055) Cancer Res 72:1804-1813
83. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981-1991
84. Hsieh AC, Costa M, Zollo O, Davis C, Feldman ME, Testa JR, Meyuhas O, Shokat KM, Ruggero D (2010) Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17:249-261
85. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ et al (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485:55-61
86. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB et al (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317-1322
87. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I et al (2007) Temsirolimus, interferon alfa, or both for advanced renalcell carcinoma. N Engl J Med 356:2271-2281
88. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004-7014
89. Inoki K, Li Y, Xu T, Guan KL (2003a) RHEB GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829-1834
90. Inoki K, Zhu T, Guan KL (2003b) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577-590
91. Ip CK, Wong AS (2012) Exploiting p70 S6 kinase as a target for ovarian cancer. Expert Opin Ther Targets 16:619-630
92. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122-1128
93. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, Vu C, Lilly MB, Mallya S, Ong ST et al (2010) Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16:205-213
94. Janes MR, Vu C, Mallya S, Shieh MP, Limon JJ, Li LS, Jessen KA, Martin MB, Ren P, Lilly MB et al (2013) Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia 27:586-594
95. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199-1203
96. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20:1992-2003
97. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429-440
98. Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H (2010) Association between gainof-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 21:255-262
99. Keedy VL (2012) Treating metastatic soft-tissue or bone sarcomas-potential role of ridaforolimus. Oncol Targets Ther 5:153-160
100. Kim JE, Chen J (2004) Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53:2748-2756
101. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10:935-945
102. Koren I, Reem E, Kimchi A (2010) DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 20:1093-1098
103. Krueger DA, Franz DN (2008) Current management of tuberous sclerosis complex. Paediatr Drugs 10:299-313
104. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801-1811
105. Kurokawa H, Arteaga CL (2003) ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 9:511S-515S
106. Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, Arteaga CL (2000) Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 60:5887-5894
107. Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19:R1046-R1052
108. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274-293
109. Larsson O, Morita M, Topisirovic I, Alain T, Blouin MJ, Pollak M, Sonenberg N (2012) Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci U S A 109:8977-8982
110. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995-4004
111. Lazaris-Karatzas A, Montine KS, Sonenberg N (1990) Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5? cap. Nature 345:544-547
112. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, Agnihotri S, El-Naggar A, Yu B, Somasekharan SP et al (2013) The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153:064-1079
113. Li S, Brown MS, Goldstein JL (2010) Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A 107:3441-3446
114. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620-1625
115. Lin HK, Hu YC, Lee DK, Chang C (2004) Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Mol Endocrinol 18:2409-2423
116. Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS (2011) Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem 54:1473-1480
117. Liu Q, Xu C, Kirubakaran S, Zhang X, Hur W, Liu Y, Kwiatkowski NP, Wang J, Westover KD, Gao P et al (2013) Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR. Cancer Res 73:2574-2586
118. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307-318
119. Mader S, Lee H, Pause A, Sonenberg N (1995) The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mol Cell Biol 15:4990-4997
120. Magnuson B, Ekim B, Fingar DC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441:1-21
121. Mahadevan D, Chiorean EG, Harris WB, Von Hoff DD, Stejskal-Barnett A, Qi W, Anthony SP, Younger AE, Rensvold DM, Cordova F et al (2012) Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer 48:3319-3327
122. Mamane Y, Petroulakis E, Martineau Y, Sato TA, Larsson O, Rajasekhar VK, Sonenberg N (2007) Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PloS ONE 2:e242
123. Manara MC, Nicoletti G, Zambelli D, Ventura S, Guerzoni C, Landuzzi L, Lollini PL, Maira SM, Garcia-Echeverria C, Mercuri M et al (2010) NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res 16:530-540
124. Manning BD (2013) Adaptation to starvation: translating a matter of life or death. Cancer Cell 23:713-715
125. Marcotrigiano J, Gingras AC, Sonenberg N, Burley SK (1999) Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 3:707-716
126. Marshall G, Howard Z, Dry J, Fenton S, Heathcote D, Gray N, Keen H, Logie A, Holt S, Smith P et al (2011) Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem Soc Trans 39:456-459
127. Martin DE, Soulard A, Hall MN (2004) TOR regulates ribosomal protein gene expression via PKA and the forkhead transcription factor FHL1. Cell 119:969-979
128. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J (2007) mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 67:11712-11720
129. Mavrakis KJ, Zhu H, Silva RL, Mills JR, Teruya-Feldstein J, Lowe SW, Tam W, Pelletier J, Wendel HG (2008) Tumorigenic activity and therapeutic inhibition of RHEB GTPase. Genes Dev 22:2178-2188
130. Mayer C, Zhao J, Yuan X, Grummt I (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18:423-434
131. McMahon LP, Yue W, Santen RJ, Lawrence JC Jr (2005) Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex. Mol Endocrinol 19:175-183
132. Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M, Ribero D, Muratore A, Massucco P, Pisacane A et al (2012) Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res 18:2515-2525
133. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, Garcia-Echeverria C, Shyr Y, Arteaga CL (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 120:2406-2413
134. Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, Trojahn U, Wendel HG, Charest A, Bronson RT et al (2008) mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci U S A 105:10853-10858
135. Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F (2008) Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Invest Drugs 17:1947-1954
136. Molckovsky A, Siu LL (2008) First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting. J Hematol Oncol 1:20
137. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP et al (2011) Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 29:3126-3132
138. Mothe-Satney I, Yang D, Fadden P, Haystead TA, Lawrence JC Jr (2000) Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol Cell Biol 20:3558-3567
139. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449-456
140. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256-4265
141. Mulholland DJ, Dedhar S, Wu H, Nelson CC (2006) PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene 25:329-337
142. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117-127
143. Nasr Z, Robert F, Porco JA Jr, Muller WJ, Pelletier J (2013) eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32:861-871
144. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ (2010) Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 9:1489-1502
145. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500-1508
146. Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, Sonenberg N, Kelly PA, Sotiropoulos A, Pende M (2005) Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol 7:286-294
147. Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS et al (2011) Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC clinical trials group. J Clin Oncol 29:3278-3285
148. Pal SK, Quinn DI (2013) Differentiating mTOR inhibitors in renal cell carcinoma. Cancer Treat Rev 39:709-719
149. Pan CC, Chung MY, Ng KF, Liu CY, Wang JS, Chai CY, Huang SH, Chen PC, Ho DM (2008) Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol 214:387-393
150. Pandya KJ, Dahlberg S, Hidalgo M, Cohen RB, Lee MW, Schiller JH, Johnson DH (2007) A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensivestage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500) J Thorac Oncol 2:1036-1041
151. Parsyan A, Svitkin Y, Shahbazian D, Gkogkas C, Lasko P, Merrick WC, Sonenberg N (2011) mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol 12:235-245
152. Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N (1994) Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5?-cap function. Nature 371:762-767
153. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G (2004) S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5?-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinasedependent S6 kinase pathway. Mol Cell Biol 24:3112-3124
154. Perez-Tenorio G, Karlsson E, Waltersson MA, Olsson B, Holmlund B, Nordenskjold B, Fornander T, Skoog L, Stal O (2011) Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res Treat 128:713-723
155. Pienta KJ, Bradley D (2006) Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 12:1665-1671
156. Pollak MN (2012) Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2:778-790
157. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224-236
158. Poulin F, Gingras AC, Olsen H, Chevalier S, Sonenberg N (1998) 4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family. J Biol Chem 273:14002-14007
159. Proud CG (2009) mTORC1 signalling and mRNA translation. Biochem Soc Trans 37:227-231
160. Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ (2008) eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol 181:293-307
161. Raught B, Gingras AC, Gygi SP, Imataka H, Morino S, Gradi A, Aebersold R, Sonenberg N (2000) Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 19:434-444
162. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW (2004) Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J 23:1761-1769
163. Reiling JH, Hafen E (2004) The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18:2879-2892
164. Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, Blenis J (2004) SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol 14:1540-1549
165. Rini BI (2008) Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res 14:1286-1290
166. Rivera VM, Squillace RM, Miller D, Berk L, Wardwell SD, Ning Y, Pollock R, Narasimhan NI, Iuliucci JD, Wang F et al (2011) Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 10:1059-1071
167. Roberts PJ, Usary JE, Darr DB, Dillon PM, Pfefferle AD, Whittle MC, Duncan JS, Johnson SM, Combest AJ, Jin J et al (2012) Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models. Clin Cancer Res 18:5290-5303
168. Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S, Prescianotto-Baschong C, Sauer U, Jenoe P, Hall MN (2013) Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339:1320-1323
169. Rogers GW Jr, Komar AA, Merrick WC (2002) eIF4A: the godfather of the DEAD box helicases. Prog Nucleic Acid Res Mol Biol 72:307-331
170. Rosenwald IB, Hutzler MJ, Wang S, Savas L, Fraire AE (2001) Expression of eukaryotic translation initiation factors 4E and 2alpha is increased frequently in bronchioloalveolar but not in squamous cell carcinomas of the lung. Cancer 92:2164-2171
171. Ruggero D (2009) The role of Myc-induced protein synthesis in cancer. Cancer Res 69:8839-8843
172. Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C, Pandolfi PP (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10:484-486
173. Ruvinsky I, Meyuhas O (2006) Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 31:342-348
174. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, Dor Y, Zisman P, Meyuhas O (2005) Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 19:2199-2211
175. Salehi Z, Mashayekhi F (2006) Expression of the eukaryotic translation initiation factor 4E (eIF4E) and 4E-BP1 in esophageal cancer. Clin Biochem 39:404-409
176. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496-1501
177. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290-303
178. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296-1302
179. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101
180. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159-168
181. Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, Brown PD, Uhm JH, Rao RD, Doyle L et al (2010) Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. Clin Cancer Res 16:5573-5580
182. Sarkaria JN, Galanis E, Wu W, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, Buckner JC (2011) North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81:468-475
183. Schmid T, Jansen AP, Baker AR, Hegamyer G, Hagan JP, Colburn NH (2008) Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. Cancer Res 68:1254-1260
184. Sendur MA, Zengin N, Aksoy S, Altundag K (2013) Everolimus: a new hope for patients with breast cancer. Curr Med Res Opin 30:75-87
185. Settembre C, Fraldi A, Medina DL, Ballabio A (2013) Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14:283-296
186. Shahbazian D, Parsyan A, Petroulakis E, Hershey J, Sonenberg N (2010) eIF4B controls survival and proliferation and is regulated by proto-oncogenic signaling pathways. Cell Cycle 9:4106-4109
187. Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC (1998) Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 17:6649-6659
188. Silvera D, Formenti SC, Schneider RJ (2010) Translational control in cancer. Nat Rev Cancer 10:254-266
189. Simmons BH, Lee JH, Lalwani K, Giddabasappa A, Snider BA, Wong A, Lappin PB, Eswaraka J, Kan JL, Christensen JG et al (2012) Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras(G12D-LSL) mice. Cancer Chemother Pharmacol 70:213-220
190. Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A, Alvarez K, Chen G, Darnel AD, Aprikian AG et al (2009) PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 218:505-513
191. Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, Walker C, Ramondetta LM, Burke TW, Gershenson DM et al (2010) A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116:5415-5419
192. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731-745
193. Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, Cappuzzo F, Sharma S, Gross SH, Dimitrijevic S et al (2009) Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 20:1674-1681
194. Sorrells DL, Black DR, Meschonat C, Rhoads R, De Benedetti A, Gao M, Williams BJ, Li BD (1998) Detection of eIF4E gene amplification in breast cancer by competitive PCR. Ann Surg Oncol 5:232-237
195. Sorrells DL, Ghali GE, Meschonat C, DeFatta RJ, Black D, Liu L, De Benedetti A, Nathan CO, Li BD (1999) Competitive PCR to detect eIF4E gene amplification in head and neck cancer. Head Neck 21:60-65
196. Squillace RM, Miller D, Cookson M, Wardwell SD, Moran L, Clapham D, Wang F, Clackson T, Rivera VM (2011) Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 10:1959-1968
197. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW (2001) Regulation of PTEN transcription by p53. Mol Cell 8:317-325
198. Stolovich M, Tang H, Hornstein E, Levy G, Cohen R, Bae SS, Birnbaum MJ, Meyuhas O (2002) 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
199. Stupp R, Hegi ME, Gilbert MR, Chakravarti A (2007) Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 25:4127-4136
200. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L et al (2008) Dose-and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603-1610
201. Tang H, Hornstein E, Stolovich M, Levy G, Livingstone M, Templeton D, Avruch J, Meyuhas O (2001) 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
202. Tarhini A, Kotsakis A, Gooding W, Shuai Y, Petro D, Friedland D, Belani CP, Dacic S, Argiris A (2010) Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 16:5900-5907
203. Tee AR, Proud CG (2002) Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Mol Cell Biol 22:1674-1683
204. The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068
205. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycinresistant functions of mTORC1. J Biol Chem 284:8023-8032
206. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM (2012) A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485:109-113
207. Tsukiyama-Kohara K, Poulin F, Kohara M, DeMaria CT, Cheng A, Wu Z, Gingras AC, Katsume A, Elchebly M, Spiegelman BM et al (2001) Adipose tissue reduction in mice lacking the translational inhibitor 4E-BP1. Nat Med 7:1128-1132
208. Tuazon PT, Merrick WC, Traugh JA (1989) Comparative analysis of phosphorylation of translational initiation and elongation factors by seven protein kinases. J Biol Chem 264:2773-2777
209. Tzatsos A, Kandror KV (2006) Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26:63-76
210. Uddin S, Hussain AR, Siraj AK, Manogaran PS, Al-Jomah NA, Moorji A, Atizado V, Al-Dayel F, Belgaumi A, El-Solh H et al (2006) Role of phosphatidylinositol 3?-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood 108:4178-4186
211. Ueda T, Sasaki M, Elia AJ, Chio II, Hamada K, Fukunaga R, Mak TW (2010) Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc Natl Acad Sci U S A 107:13984-13990
212. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J et al (2004) Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200-205
213. Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28:721-726
214. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932-1940
215. Wang X, Beugnet A, Murakami M, Yamanaka S, Proud CG (2005) Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol 25:2558-2572
216. Wang X, Hawk N, Yue P, Kauh J, Ramalingam SS, Fu H, Khuri FR, Sun SY (2008a) Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy. Cancer Biol Ther 7:1952-1958
217. Wang Y, Mikhailova M, Bose S, Pan CX, deVere White RW, Ghosh PM (2008b) Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 27:7106-7117
218. Wang R, Geng J, Wang JH, Chu XY, Geng HC, Chen LB (2009) Overexpression of eukaryotic initiation factor 4E (eIF4E) and its clinical significance in lung adenocarcinoma. Lung Cancer 66:237-244
219. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM (2011a) The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycinresistant transcriptional profile. Proc Natl Acad Sci U S A 108:15201-15206
220. Wang L, Zhang Q, Zhang J, Sun S, Guo H, Jia Z, Wang B, Shao Z, Wang Z, Hu X (2011b) PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 11:248
221. Wanner K, Hipp S, Oelsner M, Ringshausen I, Bogner C, Peschel C, Decker T (2006) Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. Br J Haematol 134:475-484
222. Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED et al (2011) A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 25:341-347
223. Xu Y, Chen SY, Ross KN, Balk SP (2006) Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res 66:7783-7792
224. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A et al (2008) One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-3072
225. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523
226. Yoon DH, Ryu MH, Park YS, Lee HJ, Lee C, Ryoo BY, Lee JL, Chang HM, Kim TW, Kang YK (2012) Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer 106:1039-1044
227. Yoshizawa A, Fukuoka J, Shimizu S, Shilo K, Franks TJ, Hewitt SM, Fujii T, Cordon-Cardo C, Jen J, Travis WD (2010) Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res 16:240-248
228. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villen J, Kubica N, Hoffman GR, Cantley LC, Gygi SP et al (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322-1326
229. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinasedependent growth inhibitor for breast cancer cells. Cancer Res 66:10269-10273
230. Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Byrd JC, Czuczman MS, Fayad L, Forero A, Glenn MJ, Gockerman JP et al (2010) NCCN clinical practice guidelines in oncology: non-Hodgkin's lymphomas. J Natl Compr Cancer Netw 8:288-334
231. Zhang HH, Huang J, Duvel K, Boback B, Wu S, Squillace RM, Wu CL, Manning BD (2009) Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PloS ONE 4:e6189
232. Zhang YJ, Duan Y, Zheng XF (2011) Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 16:325-331
233. Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, Yang W, Smith TL, Shi D, Yu D (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10:6779-6788
234. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334:678-683