Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence

Cell Cycle

Volumn 11, Issue 12, 2012, Pages 2391-2401

  Kolesnichenko, Marina ^a   Hong, Lixin ^a   Liao, Rong ^a   Vogt, Peter K ^a   Sun, Peiqing ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

Rapamycin; Senescence; TOR; TORC1

Indexed keywords

DNA; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; RAPAMYCIN; RAS PROTEIN; REGULATED IN DNA DAMAGE RESPONSE AND DEVELOPMENT1; UNCLASSIFIED DRUG;

ARTICLE; CARCINOGENESIS; CELL DIVISION; CELL TRANSFORMATION; CONTROLLED STUDY; DNA DAMAGE; ENZYME INHIBITION; GENE EXPRESSION; GENE REPLICATION; HUMAN; HUMAN CELL; ONCOGENE; SENESCENCE; SIGNAL TRANSDUCTION; TELOMERE;

EID: 84862881961     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.20683     Document Type: Article

References (98)

1. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of premalignant hepatocytes limits liver cancer development. Nature 2011; 479:547-51; PMID:22080947; http:// dx.doi.org/10.1038/nature10599.
2. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol 2011; 192:547-56; PMID:21321098; http:// dx.doi.org/10.1083/jcb.201009094.
3. Blagosklonny MV. Cell cycle arrest is not senescence. Aging 2011; 3:94-101; PMID:21297220.
4. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007; 130:223-33; PMID:17662938; http://dx.doi.org/10.1016/j.cell.2007.07. 003.
5. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010; 24:2463-79; PMID:21078816; http://dx.doi.org/10.1101/ gad.1971610.
6. INK4a. Cell 1997; 88:593-602; PMID:9054499; http://dx.doi.org/10. 1016/S0092-8674(00)81902-9.
7. DeNicola GM, Tuveson DA. RAS in cellular transformation and senescence. Eur J Cancer 2009; 45:211-6; PMID:19775620; http://dx.doi.org/10.1016/S0959- 8049(09)70036-X.
8. Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, et al. Amplification of PPM1D in human tumors abrogates p53 tumorsuppressor activity. Nat Genet 2002; 31:210-5; PMID:12021785; http://dx.doi.org/10.1038/ ng894.
9. Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 2002; 22:3389-403; PMID:11971971; http://dx.doi.org/10.1128/MCB.22.10.3389-403.2002.
10. Bulavin DV, Kovalsky O, Hollander MC, Fornace AJ Jr. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Mol Cell Biol 2003; 23:3859-71; PMID:12748288; http://dx.doi.org/10.1128/MCB.23.11.3859-71.2003.
11. Han J, Sun P. The pathways to tumor suppression via route p38. Trends Biochem Sci 2007; 32:364-71; PMID:17624785; http://dx.doi.org/10.1016/j.tibs. 2007.06.007.
12. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 2007; 128:295-308; PMID:17254968; http://dx.doi.org/10.1016/j.cell.2006.11.050.
13. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 2006; 444:638-42; PMID:17136094; http://dx.doi.org/10. 1038/nature05327.
14. Mallette FA, Gaumont-Leclerc MF, Ferbeyre G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 2007; 21:43-8; PMID:17210786; http://dx.doi.org/10.1101/gad.1487307.
15. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25:585-621; http://dx.doi.org/10.1016/0014-4827(61) 90192-6.
16. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985; 43:405-13; PMID:3907856; http://dx.doi.org/10.1016/0092-8674(85)90170-9.
17. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426:194-8; PMID:14608368; http://dx.doi.org/10.1038/ nature02118.
18. Gire V, Roux P, Wynford-Thomas D, Brondello JM, Dulic V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 2004; 23:2554-63; PMID:15192702; http://dx.doi.org/10.1038/sj.emboj.7600259.
19. Shay JW, Pereira-Smith OM, Wright WE. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 1991; 196:33-9; PMID:1652450; http://dx.doi.org/10.1016/0014-4827(91)90453-2.
20. Deng Q, Liao R, Wu BL, Sun P. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J Biol Chem 2004; 279:1050-9; PMID:14593117; http://dx.doi.org/10.1074/jbc. M308644200.
21. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92:9363-7; PMID:7568133; http://dx.doi.org/ 10.1073/pnas.92.20.9363.
22. MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 2011; 30:1536-48; PMID:21399611; http://dx.doi.org/10.1038/emboj.2011. 69.
23. Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescencesignalling pathway. Genes Cells 2003; 8:131-44; PMID:12581156; http://dx.doi.org/10.1046/j.1365-2443.2003.00620.x.
24. Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 1994; 211:90-8; PMID:8125163; http://dx.doi.org/10.1006/excr.1994. 1063.
25. Beauséjour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003; 22:4212-22; PMID:12912919; http://dx.doi.org/10.1093/emboj/cdg417.
26. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279:349-52; PMID:9454332; http://dx.doi.org/10.1126/science.279. 5349.349.
27. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle 2009; 8:1888-95; PMID:19471117; http://dx.doi.org/10.4161/cc.8.12.8606.
28. Leontieva OV, Blagosklonny MV. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging 2010; 2:924-35; PMID:21212465.
29. Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging 2012; 4:159-65; PMID:22394614.
30. Jiang H, Vogt PK. Constitutively active Rheb induces oncogenic transformation. Oncogene 2008; 27:5729-40; PMID:18521078; http://dx.doi.org/10. 1038/onc.2008.180.
31. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 1997; 276:1848-50; PMID:9188528; http://dx.doi.org/10.1126/ science.276.5320.1848.
32. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 1987; 84:5034-7; PMID:3037531; http://dx.doi.org/10.1073/ pnas.84.14.5034.
33. Vogt PK, Hart JR, Gymnopoulos M, Jiang H, Kang S, Bader AG, et al. Phosphatidylinositol-3-kinase: the oncoprotein. Curr Top Microbiol Immunol 2010; 347:79-104; PMID:20582532; http://dx.doi.org/10.1007/82-2010-80.
34. Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK. The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci USA 1998; 95:14950-5; PMID:9843996; http://dx.doi.org/10.1073/pnas.95.25.14950.
35. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008; 27:5486-96; PMID:18794883; http://dx.doi.org/10.1038/onc.2008. 244.
36. Ciraolo E, Morello F, Hirsch E. Present and future of PI3K pathway inhibition in cancer: perspectives and limitations. Curr Med Chem 2011; 18:2674-85; PMID:21649577; http://dx.doi.org/10.2174/092986711796011193.
37. Dancey J. mTOR signaling and drug development in cancer. Nature reviews. Clin Oncol 2010; 7:209-19.
38. Vanhaesebroeck B, Vogt PK, Rommel C. PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 2010; 347:1-19; PMID:20549473; http://dx.doi.org/10.1007/82-2010-65.
39. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66:1500-8; PMID:16452206; http://dx.doi.org/10.1158/0008- 5472.CAN-05-2925.
40. Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C, et al. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 2008; 27:1932-43; PMID:18566586; http://dx.doi.org/10.1038/emboj.2008.120.
41. Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 2009; 29:5657-70; PMID:19720745; http://dx.doi.org/10.1128/MCB.00735- 09.
42. Efeyan A, Sabatini DM. mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 2010; 22:169-76; PMID:19945836; http://dx.doi.org/10.1016/j.ceb. 2009.10.007.
43. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118:3065-74; PMID:18725988.
44. Lempiäinen H, Halazonetis TD. Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J 2009; 28:3067-73; PMID:19779456; http://dx.doi.org/ 10.1038/emboj.2009.281.
45. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002; 10:457-68; PMID:12408816; http://dx.doi.org/10.1016/S1097-2765(02)00636-6.
46. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14:1296-302; PMID:15268862; http://dx.doi.org/10.1016/j.cub.2004.06.054.
47. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6:1122-8; PMID:15467718; http://dx.doi.org/10. 1038/ncb1183.
48. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18:1926-45; PMID:15314020; http://dx.doi.org/10.1101/gad.1212704.
49. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12:21-35; PMID:21157483;http://dx.doi.org/10.1038/nrm3025.
50. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307:1098-101;PMID:15718470; http://dx.doi.org/10.1126/science.1106148.
51. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127:125-37; PMID:16962653; http://dx.doi.org/10.1016/j.cell.2006.08.033.
52. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 1998; 95:1432-7; PMID:9465032; http://dx.doi.org/10.1073/pnas. 95.4.1432.
53. Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 1998; 12:502-13; PMID:9472019; http://dx.doi.org/10.1101/gad.12.4.502.
54. Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T, et al. Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 2005; 19:2199-211; PMID:16166381; http://dx.doi.org/10. 1101/gad.351605.
55. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001; 15:2852-64; PMID:11691836.
56. Haghighat A, Mader S, Pause A, Sonenberg N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J 1995; 14:5701-9; PMID:8521827.
57. Petroulakis E, Parsyan A, Dowling RJ, LeBacquer O, Martineau Y, Bidinosti M, et al. p53-dependent translational control of senescence and transformation via 4E-BPs. Cancer Cell 2009; 16:439-46; PMID:19878875; http://dx.doi.org/10. 1016/j.ccr.2009.09.025.
58. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008; 133:1019-31; PMID:18555778; http://dx.doi.org/10.1016/j.cell.2008.03.039.
59. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/ IL-8 cytokine network. Proc Natl Acad Sci USA 2009; 106:17031-6; PMID:19805069; http://dx.doi.org/10.1073/pnas.0905299106.
60. Atadja P, Wong H, Garkavtsev I, Veillette C, Riabowol K. Increased activity of p53 in senescing fibroblasts. Proc Natl Acad Sci USA 1995; 92:8348-52; PMID:7667293; http://dx.doi.org/10.1073/pnas.92.18.8348.
61. Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T, et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 2000; 20:2803-8; PMID:10733583; http://dx.doi.org/10.1128/MCB.20.8.2803-8.2000.
62. Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc Natl Acad Sci USA 1996; 93:1065-70; PMID:8577715; http://dx.doi.org/10. 1073/pnas.93.3.1065.
63. Liu Q, Kirubakaran S, Hur W, Niepel M, Westover K, Thoreen CC, et al. Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. J Biol Chem 2012; 287:9742-52; PMID:22223645; http://dx.doi.org/10.1074/jbc.M111. 304485.
64. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177-89; PMID:12150926; http://dx.doi.org/10.1016/S0092-8674(02)00833-4.
65. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163-75; PMID:12150925; http://dx.doi.org/10.1016/S0092-8674(02)00808-5.
66. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-84; PMID:16469695; http://dx.doi.org/10.1016/j. cell.2006.01.016.
67. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22:159-68; PMID:16603397; http://dx.doi.org/10.1016/j.molcel.2006.03.029.
68. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:2893-904; PMID:15545625; http://dx.doi.org/10.1101/gad.1256804.
69. Wang H, Kubica N, Ellisen LW, Jefferson LS, Kimball SR. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1. J Biol Chem 2006; 281:39128-34; PMID:17074751; http://dx.doi.org/10.1074/jbc.M610023200.
70. Molitoris JK, McColl KS, Swerdlow S, Matsuyama M, Lam M, Finkel TH, et al. Glucocorticoid elevation of dexamethasone-induced gene 2 (Dig2/RTP801/ REDD1) protein mediates autophagy in lymphocytes. J Biol Chem 2011; 286:30181-9; PMID:21733849; http://dx.doi.org/10.1074/jbc.M111.245423.
71. Corradetti MN, Inoki K, Guan KL. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 2005; 280:9769-72; PMID:15632201; http://dx.doi.org/10.1074/jbc. C400557200.
72. Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C, et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004; 10:484-6; PMID:15098029; http://dx.doi.org/10. 1038/nm1042.
73. Dulić V, Drullinger LF, Lees E, Reed SI, Stein GH. Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci USA 1993; 90:11034-8; PMID:8248208; http://dx.doi.org/10.1073/pnas.90.23.11034.
74. Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. Oncogene 1999; 18:2789-97; PMID:10362249; http://dx.doi.org/10.1038/sj.onc.1202615.
75. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci USA 2010; 107:9660-4; PMID:20457898; http://dx.doi.org/10.1073/pnas.1002298107.
76. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle 2009; 8:1896-900; PMID:19478560; http://dx.doi.org/10. 4161/cc.8.12.8809.
77. Harrington LS, Findlay GM, Lamb RF. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci 2005; 30:35-42; PMID:15653324; http://dx.doi.org/10.1016/j.tibs.2004.11.003.
78. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270:1326-31; PMID:7481820; http://dx.doi.org/10.1126/science.270.5240.1326.
79. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282:1318-21; PMID:9812896; http://dx.doi.org/10.1126/science.282.5392. 1318.
80. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231-41; PMID:9346240; http://dx.doi.org/10.1016/S0092- 8674(00)80405-5.
81. del Peso L, González-García M, Page C, Herrera R, Nuñez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278:687-9; PMID:9381178; http://dx.doi.org/10.1126/ science.278.5338.687.
82. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002; 8:1153-60; PMID:12244302; http://dx.doi.org/10.1038/nm761.
83. Mayo LD, Donner DB. A phosphatidylinositol-3-kinase/ Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001; 98:11598-603; PMID:11504915; http:// dx.doi.org/10.1073/pnas.181181198.
84. Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, et al. PKB/Akt mediates cell cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002; 8:1145-52; PMID:12244301; http://dx.doi.org/10.1038/nm759.
85. Tran H, Brunet A, Griffith EC, Greenberg ME. The many forks in FOXO's road. Sci STKE 2003; 2003:5; PMID:12621150; http://dx.doi.org/10.1126/stke.2003. 172.re5.
86. Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002; 8:1136-44; PMID:12244303; http://dx.doi.org/10.1038/nm762.
87. Feng J, Park J, Cron P, Hess D, Hemmings BA. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 2004; 279:41189-96; PMID:15262962; http:// dx.doi.org/10.1074/jbc.M406731200.
88. Viniegra JG, Martínez N, Modirassari P, Hernández Losa J, Parada Cobo C, Sánchez-Areválo Lobo VJ, et al. Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM. J Biol Chem 2005; 280:4029-36; PMID:15546863; http:// dx.doi.org/10.1074/jbc. M410344200.
89. Hresko RC, Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 2005; 280:40406-16; PMID:16221682; http://dx.doi.org/10.1074/jbc.M508361200.
90. Yellen P, Saqcena M, Salloum D, Feng J, Preda A, Xu L, et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 2011; 10:3948-56; PMID:22071574; http://dx.doi.org/10.4161/cc.10.22.18124.
91. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, et al. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci USA 2011; 108:6474-9; PMID:21464307; http://dx.doi.org/10.1073/ pnas.1016132108.
92. Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T, et al. TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 2011; 41:458-70; PMID:21329883; http://dx.doi.org/10.1016/j.molcel. 2011.01.019.
93. Kennedy AL, Morton JP, Manoharan I, Nelson DM, Jamieson NB, Pawlikowski JS, et al. Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol Cell 2011; 42:36-49; PMID:21474066; http://dx.doi.org/10.1016/j.molcel.2011.02.020.
94. Astle MV, Hannan KM, Ng PY, Lee RS, George AJ, Hsu AK, et al. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene 2011; PMID:21909130.
95. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 2005; 433:477-80; PMID:15690031; http://dx.doi.org/10.1038/nature03205.
96. Kang HT, Lee KB, Kim SY, Choi HR, Park SC. Autophagy impairment induces premature senescence in primary human fibroblasts. PLoS ONE 2011; 6:23367; PMID:21858089; http://dx.doi.org/10.1371/journal.pone.0023367.
97. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 2011; 10:868-80; PMID:22037041; http://dx.doi.org/10.1038/nrd3531.
98. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007; 129:1261-74; PMID:17604717; http://dx.doi.org/10.1016/j.cell.2007.06.009.