Abstract
Cell division involves a series of ordered and controlled events that lead to cell proliferation. Cell cycle progression implies not only demanding amounts of cell mass, protein, lipid, and nucleic acid content but also a favorable energy state. The mammalian target of rapamycin (mTOR), in response to the energy state, nutrient status, and growth factor stimulation of cells, plays a pivotal role in the coordination of cell growth and the cell cycle. Here, we review how the nutrient-sensing mTOR-signaling cascade molecularly integrates nutritional and mitogenic/anti-apoptotic cues to accurately coordinate cell growth and cell cycle. First, we briefly outline the structure, functions, and regulation of the mTOR complexes (mTORC1 and mTORC2). Second, we concisely evaluate the best known ability of mTOR to control G1-phase progression. Third, we discuss in detail the recent evidence that indicates a new genome stability caretaker function of mTOR based on the specific ability of phosphorylated forms of several mTOR-signaling components (AMPK, raptor, TSC, mTOR, and S6K1), which spatially and temporally associate with essential mitotic regulators at the mitotic spindle and at the cytokinetic cleavage furrow.
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References
Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166
Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81(3):323–330
Cobrinik D (2005) Pocket proteins and cell cycle control. Oncogene 24 (17):2796–2809
Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512
Barbash O, Diehl JA (2008) Regulation of the cell cycle. In: Mendelsohn J, Howley PM, Israel MA, Gray JW, Thompson CB (eds) The molecular basis of cancer, 3rd edn. WB Saunders, Philadelphia, PA, pp 177–188
Massagué J (2004) G1 cell-cycle control and cancer. Nature 432(7015):298–306
Santoni-Rugiu E, Falck J, Mailand N, Bartek J, Lukas J (2000) Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the pRb/E2F pathway. Mol Cell Biol 20(10):3497–3509
Stark GR, Taylor WR (2006) Control of the G2/M transition. Mol Biotechnol 32(3):227–248
Pyronnet S, Sonenberg N (2001) Cell-cycle-dependent translational control. Curr Opin Genet Dev 11(1):13–18
Pyronnet S, Dostie J, Sonenberg N (2001) Suppression of cap-dependent translation in mitosis. Genes Dev 15(16):2083–2093
Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7(9):644–656
Horn HF, Vousden KH (2007) Coping with stress: multiple ways to activate p53. Oncogene 26(9):1306–1316
Baus F, Gire V, Fisher D, Piette J, Dulić V (2003) Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. EMBO J 22(15):3992–4002
Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253(5022):905–909
Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596
Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369(6483):756–758
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78(1):35–43
Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270(2):815–822
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(2):159–168
Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137(5):873–886
Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11(4):895–904
Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N (2010) Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 285(26):20109–20116
Kim SG, Hoffman GR, Poulogiannis G, Buel GR, Jang YJ, Lee KW, Kim BY, Erikson RL, Cantley LC, Choo AY, Blenis J (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 49(1):172–185
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175
Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189
Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P, Arrieumerlou C, Hall MN (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2(11):e1217
Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25(6):903–915
Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128
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(14):1296–1302
Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20(20):2820–2832
Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127(1):125–137
Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16(18):1865–1870
Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405(3):513–522
Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282(35):25604–25612
Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9(3):316–323
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(5882):1496–1501
Dunlop EA, Dodd KM, Seymour LA, Tee AR (2009) Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cell Signal 21(7):1073–1084
Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13(15):1259–1268
Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47(4):535–546
Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17(15):1829–1834
Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4(9):648–657
Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) 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(1):151–162
Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37(Pt 1):217–222
Dibble CC, Asara JM, Manning BD (2009) Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 29(21):5657–5670
Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332(6035):1317–1322
Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121(2):179–193
Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282(19):14056–14064
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262
Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101(10):3329–3335
Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590
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(2):214–226
Hardie DG (2008) AMPK and Raptor: matching cell growth to energy supply. Mol Cell 30(3):263–265
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955–968
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534
Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280(19):18717–18727
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(8):935–945
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(2):290–303
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(6056):678–683
Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S (2012) Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149(2):410–424
Jewell JL, Guan KL (2013) Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 38(5):233–242
Kim SG, Buel GR, Blenis J (2013) Nutrient regulation of the mTOR Complex 1 signaling pathway. Mol Cells 35(6):463–473
Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18(23):2893–2904
Sofer A, Lei K, Johannessen CM, Ellisen LW (2005) Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 25(14):5834–5845
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(2):239–251
Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134(3):451–460
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(23):8204–8209
Lee DF, Hung MC (2007) All roads lead to mTOR: integrating inflammation and tumor angiogenesis. Cell Cycle 6(24):3011–3014
Foster DA (2009) Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim Biophys Acta 1791(9):949–955
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293
Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318
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(4):423–434
Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ (2010) mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci U S A 107(26):11823–11828
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(3):224–236
Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39(2):171–183
Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146(3):408–420
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(11):2748–2756
Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19(22):R1046–R1052
Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS, Finkel T (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281(37):27643–27652
Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1[agr] transcriptional complex. Nature 450(7170):736–740
Ramanathan A, Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A 106(52):22229–22232
Ganley IG, Lam DH, 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(18):12297–12305
Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584(7):1287–1295
Koren I, Reem E, Kimchi A (2010) DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol 20(12):1093–1098
Koren I, Reem E, Kimchi A (2010) Autophagy gets a brake: DAP1, a novel mTOR substrate, is activated to suppress the autophagic process. Autophagy 6(8):1179–1180
Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10(14):2305–2316
García-Martínez 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(3):375–385
Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144(5):757–768
Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28(12):4104–4115
Copp J, Manning G, Hunter T (2009) TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69(5):1821–1827
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101
Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Rüegg MA, Hall MN (2012) Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 15(5):725–738
Yuan M, Pino E, Wu L, Kacergis M, Soukas AA (2012) Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J Biol Chem 287(35):29579–29588
Lamming DW, Sabatini DM (2013) A Central role for mTOR in lipid homeostasis. Cell Metab 18(4):465–469
Blagosklonny MV (2011) Cell cycle arrest is not senescence. Aging (Albany NY) 3(2):94–101
Foster DA, Yellen P, Xu L, Saqcena M (2010) Regulation of G1 cell cycle progression: distinguishing the restriction point from a nutrient-sensing cell growth checkpoint(s). Genes Cancer 1(11):1123–1131
Saqcena M, Menon D, Patel D, Mukhopadhyay S, Chow V, Foster DA (2013) Amino acids and mTOR mediate distinct metabolic checkpoints in mammalian G1 cell cycle. PLoS One 8(8):e74157
Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24(1):200–216
Averous J, Fonseca BD, Proud CG (2008) Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27(8):1106–1113
Balcazar N, Sathyamurthy A, Elghazi L, Gould A, Weiss A, Shiojima I, Walsh K, Bernal-Mizrachi E (2009) mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J Biol Chem 284(12):7832–7842
Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, Kozma SC, Thomas G, Sonenberg N (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328(5982):1172–1176
Hong F, Larrea MD, Doughty C, Kwiatkowski DJ, Squillace R, Slingerland JM (2008) mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell 30(6):701–711
Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404(6779):782–787
Vadlakonda L, Pasupuleti M, Pallu R (2013) Role of PI3K-AKT-mTOR and Wnt Signaling Pathways in Transition of G1-S Phase of Cell Cycle in Cancer Cells. Front Oncol 3:85
Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, Levine AJ (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67(7):3043–3053
Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20(3):267–275
Lee CH, Inoki K, Karbowniczek M, Petroulakis E, Sonenberg N, Henske EP, Guan KL (2007) Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 26(23):4812–4823
Brenman JE (2007) AMPK/LKB1 signaling in epithelial cell polarity and cell division. Cell Cycle 6(22):2755–2759
Koh H, Chung J (2007) AMPK links energy status to cell structure and mitosis. Biochem Biophys Res Commun 362(4):789–792
Williams T, Brenman JE (2008) LKB1 and AMPK in cell polarity and division. Trends Cell Biol 18(4):193–198
Bettencourt-Dias M, Giet R, Sinka R, Mazumdar A, Lock WG, Balloux F, Zafiropoulos PJ, Yamaguchi S, Winter S, Carthew RW, Cooper M, Jones D, Frenz L, Glover DM (2004) Genome-wide survey of protein kinases required for cell cycle progression. Nature 432(7020):980–987
Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J (2007) Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447(7147):1017–1020
Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA (2009) Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells. Cell Cycle 8(10):1633–1636
Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Menendez JA (2009) AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor. Cell Cycle 8(22):3679–3683
Vazquez-Martin A, López-Bonet E, Oliveras-Ferraros C, Pérez-Martínez MC, Bernadó L, Menendez JA (2009) Mitotic kinase dynamics of the active form of AMPK (phospho-AMPKalphaThr172) in human cancer cells. Cell Cycle 8(5):788–791
Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) The active form of the metabolic sensor: AMP-activated protein kinase (AMPK) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis. Cell Cycle 8(15):2385–2398
Pinter K, Jefferson A, Czibik G, Watkins H, Redwood C (2012) Subunit composition of AMPK trimers present in the cytokinetic apparatus: implications for drug target identification. Cell Cycle 11(5):917–921
Menendez JA, Vazquez-Martin A (2012) AMPK: a bona fide resident of the mitotic spindle midzone. Cell Cycle 11(5):841–842
Banko MR, Allen JJ, Schaffer BE, Wilker EW, Tsou P, White JL, Villén J, Wang B, Kim SR, Sakamoto K, Gygi SP, Cantley LC, Yaffe MB, Shokat KM, Brunet A (2011) Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis. Mol Cell 44(6):878–892
Robitaille AM, Hall MN (2012) Ramping up mitosis: an AMPKα2-regulated signaling network promotes mitotic progression. Mol Cell 45(1):8–9
Thaiparambil JT, Eggers CM, Marcus AI (2012) AMPK regulates mitotic spindle orientation through phosphorylation of myosin regulatory light chain. Mol Cell Biol 32(16):3203–3217
Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Menendez JA (2012) Polo-like kinase 1 directs the AMPK-mediated activation of myosin regulatory light chain at the cytokinetic cleavage furrow independently of energy balance. Cell Cycle 11(13):2422–2426
Rafalski VA, Mancini E, Brunet A (2012) Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J Cell Sci 125(Pt23):5597–5608
Mao L, Li N, Guo Y, Xu X, Gao L, Xu Y, Zhou L, Liu W (2013) AMPK phosphorylates GBF1 for mitotic Golgi disassembly. J Cell Sci 126(Pt 6):1498–1505
Vazquez-Martin A, Corominas-Faja B, Oliveras-Ferraros C, Cufí S, Dalla Venezia N, Menendez JA (2013) Serine79-phosphorylated acetyl-CoA carboxylase, a downstream target of AMPK, localizes to the mitotic spindle poles and the cytokinesis furrow. Cell Cycle 12(10):1639–1641
Ito N, Rubin GM (1999) gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96(4):529–539
Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105(3):345–355
Catania MG, Mischel PS, Vinters HV (2001) Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. J Neuropathol Exp Neurol 60(7):711–723
Astrinidis A, Senapedis W, Coleman TR, Henske EP (2003) Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J Biol Chem 278(51):51372–51379
Astrinidis A, Senapedis W, Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet 15(2):287–297
Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Wetzel W, Schulze-Osthoff K, Nürnberg B, Piekorz RP (2007) The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. J Biol Chem 282(40):29273–29283
Gómez-Baldó L, Schmidt S, Maxwell CA, Bonifaci N, Gabaldón T, Vidalain PO, Senapedis W, Kletke A, Rosing M, Barnekow A, Rottapel R, Capellá G, Vidal M, Astrinidis A, Piekorz RP, Pujana MA (2010) TACC3-TSC2 maintains nuclear envelope structure and controls cell division. Cell Cycle 9(6):1143–1155
Ramírez-Valle F, Badura ML, Braunstein S, Narasimhan M, Schneider RJ (2010) Mitotic raptor promotes mTORC1 activity, G(2)/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation. Mol Cell Biol 30(13):3151–3164
Gwinn DM, Asara JM, Shaw RJ (2010) Raptor is phosphorylated by cdc2 during mitosis. PLoS One 5(2):e9197
Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Menendez JA (2011) Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs). Cell Cycle 10(18):3140–3152
Bachmann RA, Kim JH, Wu AL, Park IH, Chen J (2006) A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem 281(11):7357–7363
Vazquez-Martin A, Oliveras-Ferraros C, Bernadó L, López-Bonet E, Menendez JA (2009) The serine 2481-autophosphorylated form of mammalian Target Of Rapamycin (mTOR) is localized to midzone and midbody in dividing cancer cells. Biochem Biophys Res Commun 380(3):638–643
Lopez-Bonet E, Vazquez-Martin A, Pérez-Martínez MC, Oliveras-Ferraros C, Pérez-Bueno F, Bernadó L, Menendez JA (2010) Serine 2481-autophosphorylation of mammalian target of rapamycin (mTOR) couples with chromosome condensation and segregation during mitosis: confocal microscopy characterization and immunohistochemical validation of PP-mTOR(Ser2481) as a novel high-contrast mitosis marker in breast cancer core biopsies. Int J Oncol 36(1):107–115
Vazquez-Martin A, Sauri-Nadal T, Menendez OJ, Oliveras-Ferraros C, Cufí S, Corominas-Faja B, López-Bonet E, Menendez JA (2012) Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis. Cell Cycle 11(22):4211–4221
Yaba A, Bianchi V, Borini A, Johnson J (2008) A putative mitotic checkpoint dependent on mTOR function control cell proliferation and survival in ovarian granulosa cells. Reprod Sci 15(2):128–138
Yu J, Yaba A, Kasiman C, Thomson T, Johnson J (2011) mTOR controls ovarian follicle growth by regulating granulosa cell proliferation. PLoS One 6(7):e21415
Heesom KJ, Gampel A, Mellor H, Denton RM (2001) Cell cycle-dependent phosphorylation of the translational repressor eIF-4E binding protein-1 (4E-BP1). Curr Biol 11(17):1374–1379
Boyer D, Quintanilla R, Lee-Fruman KK (2008) Regulation of catalytic activity of S6 kinase 2 during cell cycle. Mol Cell Biochem 307(1–2):59–64
Shah OJ, Ghosh S, Hunter T (2003) Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr, Pro phosphorylation of consensus and non-consensus sites by Cdc2. J Biol Chem 278(18):16433–16442
Schmidt T, Wahl P, Wüthrich RP, Vogetseder A, Picard N, Kaissling B, Le Hir M (2007) Immunolocalization of phospho-S6 kinases: a new way to detect mitosis in tissue sections and in cell culture. Histochem Cell Biol 127(2):123–129
Park IH, Bachmann R, Shirazi H, Chen J (2002) Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem 277(35):31423–31429
Filonenko VV, Tytarenko R, Azatjan SK, Savinska LO, Gaydar YA, Gout IT, Usenko VS, Lyzogubov VV (2004) Immuno-histochemical analysis of S6K1 and S6K2 localization in human breast tumors. Exp Oncol 26(4):294–299
Rossi R, Pester JM, McDowell M, Soza S, Montecucco A, Lee-Fruman KK (2007) Identification of S6K2 as a centrosome-located kinase. FEBS Lett 581(21):4058–4064
Fingar DC, Salama S, Tsou C, Harlow E, Blenis J (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 16(12):1472–1487
Acknowledgements
This work was supported financially by grants CP05-00090, PI06-0778, and RD06-0020-0028 from the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain; the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Spain); and the Ministerio de Ciencia e Innovación (SAF2009-11579 and SAF2012-389134, Plan Nacional de I + D + I, MICINN, Spain).
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Cuyàs, E., Corominas-Faja, B., Joven, J., Menendez, J.A. (2014). Cell Cycle Regulation by the Nutrient-Sensing Mammalian Target of Rapamycin (mTOR) Pathway. In: Noguchi, E., Gadaleta, M. (eds) Cell Cycle Control. Methods in Molecular Biology, vol 1170. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0888-2_7
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DOI: https://doi.org/10.1007/978-1-4939-0888-2_7
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