TSC1-2 tumour suppressor and regulation of mTOR signalling: Linking cell growth and proliferation?

Current Opinion in Genetics and Development

Volumn 15, Issue 1, 2005, Pages 69-76

  Findlay, Greg M ^a   Harrington, Laura S ^a   Lamb, Richard F ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; ADENYLATE KINASE; GUANOSINE TRIPHOSPHATASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RAPAMYCIN; RAS PROTEIN; TARGET OF RAPAMYCIN KINASE; TUBERIN; TUMOR SUPPRESSOR PROTEIN;

BRAIN; CARCINOGENESIS; CELL GROWTH; CELL PROLIFERATION; PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN FUNCTION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE; UPREGULATION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ADENOSINE TRIPHOSPHATE; ANIMALS; BRAIN; CELL DIVISION; CELL ENLARGEMENT; HUMANS; MONOMERIC GTP-BINDING PROTEINS; NEUROPEPTIDES; PROTEIN KINASES; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; REPRESSOR PROTEINS; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEINS;

EID: 12344279947     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2004.11.002     Document Type: Review

References (66)

1. M. van Slegtenhorst, M. Nellist, B. Nagelkerken, J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson, D. Halley, and P. van der Sluijs Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products Hum Mol Genet 7 1998 1053 1057
2. A.K. Hodges, S. Li, J. Maynard, L. Parry, R. Braverman, J.P. Cheadle, J.E. DeClue, and J.R. Sampson Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin Hum Mol Genet 10 2001 2899 2905
3. C.J. Potter, H. Huang, and T. Xu Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size Cell 105 2001 357 368
4. N. Ito, and G.M. Rubin gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle Cell 96 1999 529 539
5. X. Gao, T.P. Neufeld, and D. Pan Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways Dev Biol 221 2000 404 418
6. N. Tapon, N. Ito, B.J. Dickson, J.E. Treisman, and I.K. Hariharan The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation Cell 105 2001 345 355
7. X. Gao, and D. Pan TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth Genes Dev 15 2001 1383 1392
8. D.J. Kwiatkowski, H. Zhang, J.L. Bandura, K.M. Heiberger, M. Glogauer, N. el-Hashemite, and H. Onda A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells Hum Mol Genet 11 2002 525 534
9. A. Jaeschke, J. Hartkamp, M. Saitoh, W. Roworth, T. Nobukuni, A. Hodges, J. Sampson, G. Thomas, and R. Lamb Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent J Cell Biol 159 2002 217 224
10. K. Inoki, Y. Li, T. Zhu, J. Wu, and K.L. Guan TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling Nat Cell Biol 4 2002 648 657
11. O.J. Shah, and T. Hunter Critical role of T-loop and H-motif phosphorylation in the regulation of S6 kinase 1 by the tuberous sclerosis complex J Biol Chem 279 2004 20816 20823
12. H. Stocker, T. Radimerski, B. Schindelholz, F. Wittwer, P. Belawat, P. Daram, S. Breuer, G. Thomas, and E. Hafen Rheb is an essential regulator of S6K in controlling cell growth in Drosophila Nat Cell Biol 5 2003 559 565 This report, together with [13] and [14], indicates that Rheb is the critical mediator of TSC1-2-mediated effects on growth. This report also indicates that Rheb overexpression does not give increased proliferation in the Drosophila wing imaginal disc.
13. L.J. Saucedo, X. Gao, D.A. Chiarelli, L. Li, D. Pan, and B.A. Edgar Rheb promotes cell growth as a component of the insulin/TOR signalling network Nat Cell Biol 5 2003 566 571
14. P.H. Patel, N. Thapar, L. Guo, M. Martinez, J. Maris, C.L. Gau, J.A. Lengyel, and F. Tamanoi Drosophila Rheb GTPase is required for cell cycle progression and cell growth J Cell Sci 116 2003 3601 3610
15. K. Inoki, Y. Li, T. Xu, and K.L. Guan Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling Genes Dev 17 2003 1829 1834
16. A. Garami, F.J. Zwartkruis, T. Nobukuni, M. Joaquin, M. Roccio, H. Stocker, S.C. Kozma, E. Hafen, J.L. Bos, and G. Thomas Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 Mol Cell 11 2003 1457 1466
17. A.R. Tee, B.D. Manning, P.P. Roux, L.C. Cantley, and J. Blenis Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb Curr Biol 13 2003 1259 1268
18. Y. Zhang, X. Gao, L.J. Saucedo, B. Ru, B.A. Edgar, and D. Pan Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins Nat Cell Biol 5 2003 578 581
19. D.H. Kim, D.D. Sarbassov, S.M. Ali, J.E. King, R.R. Latek, H. Erdjument-Bromage, P. Tempst, and D.M. Sabatini mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery Cell 110 2002 163 175
20. S.S. Schalm, and J. Blenis Identification of a conserved motif required for mTOR signaling Curr Biol 12 2002 632 639
21. S.S. Schalm, D.C. Fingar, D.M. Sabatini, and J. Blenis TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function Curr Biol 13 2003 797 806
22. S. Oldham, J. Montagne, T. Radimerski, G. Thomas, and E. Hafen Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin Genes Dev 14 2000 2689 2694
23. H. Zhang, J.P. Stallock, J.C. Ng, C. Reinhard, and T.P. Neufeld Regulation of cellular growth by the Drosophila target of rapamycin dTOR Genes Dev 14 2000 2712 2724
24. B.D. Manning, A.R. Tee, M.N. Logsdon, J. Blenis, and L.C. Cantley 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 2002 151 162
25. B.D. Manning, and L.C. Cantley Rheb fills a GAP between TSC and TOR Trends Biochem Sci 28 2003 573 576
26. +/- mice Proc Natl Acad Sci USA 98 2001 10320 10325
27. P.K. Majumder, P.G. Febbo, R. Bikoff, R. Berger, Q. Xue, L.M. McMahon, J. Manola, J. Brugarolas, T.J. McDonnell, and T.R. Golub mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways Nat Med 10 2004 594 601
28. C.J. Potter, L.G. Pedraza, and T. Xu Akt regulates growth by directly phosphorylating Tsc2 Nat Cell Biol 4 2002 658 665
29. K. Inoki, T. Zhu, and K.L. Guan TSC2 mediates cellular energy response to control cell growth and survival Cell 115 2003 577 590 In this report, TSC2 is phosphorylated during treatments that cause AMPK activation, and one of the identified sites (S1345) is phosphorylated in vitro by AMPK. In response to AMPK activation, both S6K1 and 4E-BP1 are rapidly dephosphorylated, an effect that is somewhat reduced in cells deficient in TSC1-2.
30. D. Carling The AMP-activated protein kinase cascade - a unifying system for energy control Trends Biochem Sci 29 2004 18 24
31. A. Woods, S.R. Johnstone, K. Dickerson, F.C. Leiper, L.G. Fryer, D. Neumann, U. Schlattner, T. Wallimann, M. Carlson, and D. Carling LKB1 is the upstream kinase in the AMP-activated protein kinase cascade Curr Biol 13 2003 2004 2008 This report, together with [32] and [33], indicates that the major T-loop kinase for AMPK involved in AMPK activation is LKB1.
32. R.J. Shaw, M. Kosmatka, N. Bardeesy, R.L. Hurley, L.A. Witters, R.A. DePinho, and L.C. Cantley The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress Proc Natl Acad Sci USA 101 2004 3329 3335
33. S.A. Hawley, J. Boudeau, J.L. Reid, K.J. Mustard, L. Udd, T.P. Makela, D.R. Alessi, and D.G. Hardie Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade J Biol 2 2003 28
34. M.N. Corradetti, K. Inoki, N. Bardeesy, R.A. DePinho, and K.L. Guan Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome Genes Dev 18 2004 1533 1538 In this study, like the situation in TSC1-2-deficient cells, glucose depletion was found to cause increased apoptosis in cells lacking LKB1, an effect blocked by rapamycin, arguing again that inappropriate mTOR pathway activation is incompatible with survival when cells are confronted with energy stress.
35. +/- polyps is puzzling because these sites of phosphorylation are not apparently regulated by TSC1-2 [11].
36. T. Reis, and B.A. Edgar Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing Cell 117 2004 253 264
37. N. Tapon, K.H. Moberg, and I.K. Hariharan The coupling of cell growth to the cell cycle Curr Opin Cell Biol 13 2001 731 737
38. S. Volarevic, M.J. Stewart, B. Ledermann, F. Zilberman, L. Terracciano, E. Montini, M. Grompe, S.C. Kozma, and G. Thomas Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6 Science 288 2000 2045 2047
39. M.M. Chou, J.M. Masuda-Robens, and M.L. Gupta Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression J Biol Chem 278 2003 35241 35247
40. N. Hay, and N. Sonenberg Upstream and downstream of mTOR Genes Dev 18 2004 926 945 A comprehensive review discussing, in critical depth, models of mTOR pathway activation and function.
41. -/- mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway Mol Cell Biol 24 2004 3112 3124 This study reveals that S6K does not regulate 5′-TOP mRNA recruitment to polysomes. However, this 5′-TOP mRNA recruitment is rapamycin sensitive and is therefore regulated by mTOR through an unknown effector.
42. A. Dufner, and G. Thomas Ribosomal S6 kinase signaling and the control of translation Exp Cell Res 253 1999 100 109
43. J. Montagne, M.J. Stewart, H. Stocker, E. Hafen, S.C. Kozma, and G. Thomas Drosophila S6 kinase: a regulator of cell size Science 285 1999 2126 2129
44. s6k gene reveals a small mouse phenotype and a new functional S6 kinase EMBO J 17 1998 6649 6659
45. J.R. McMullen, T. Shioi, L. Zhang, O. Tarnavski, M.C. Sherwood, A.L. Dorfman, S. Longnus, M. Pende, K.A. Martin, and J. Blenis Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy Mol Cell Biol 24 2004 6231 6240
46. B. Raught, F. Peiretti, A.C. Gingras, M. Livingstone, D. Shahbazian, G.L. Mayeur, R.D. Polakiewicz, N. Sonenberg, and J.W. Hershey Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases EMBO J 23 2004 1761 1769 A new substrate of S6K is identified that could affect growth.
47. A. De Benedetti, and J.R. Graff eIF-4E expression and its role in malignancies and metastases Oncogene 23 2004 3189 3199
48. L.A. Johnston, D.A. Prober, B.A. Edgar, R.N. Eisenman, and P. Gallant Drosophila myc regulates cellular growth during development Cell 98 1999 779 790
49. ••,65] identify additional targets of S6Ks, indicating that other targets apart from S6 exist and may mediate the effects of S6K on cell growth. In this report, IRS-1 is identified as a phosphorylation target of S6K. However, it is unlikely to be involved in mediating the effect of S6K on cell growth because the phosphorylation has a negative impact on insulin and insulin-like growth factor signal-transduction.
50. H.A. Lane, A. Fernandez, N.J. Lamb, and G. Thomas p70s6k function is essential for G1 progression Nature 363 1993 170 172
51. D.C. Fingar, C.J. Richardson, A.R. Tee, L. Cheatham, C. Tsou, and J. Blenis mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E Mol Cell Biol 24 2004 200 216
52. A. Lazaris-Karatzas, and N. Sonenberg The mRNA 5′ cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts Mol Cell Biol 12 1992 1234 1238
53. D. Ruggero, L. Montanaro, L. Ma, W. Xu, P. Londei, C. Cordon-Cardo, and P.P. Pandolfi The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis Nat Med 10 2004 484 486
54. A. De Benedetti, S. Joshi-Barve, C. Rinker-Schaeffer, and R.E. Rhoads Expression of antisense RNA against initiation factor eIF-4E mRNA in HeLa cells results in lengthened cell division times, diminished translation rates, and reduced levels of both eIF-4E and the p220 component of eIF-4F Mol Cell Biol 11 1991 5435 5445
55. M.A. Bjornsti, and P.J. Houghton The TOR pathway: a target for cancer therapy Nat Rev Cancer 4 2004 335 348
56. H.L. Kenerson, L.D. Aicher, L.D. True, and R.S. Yeung Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors Cancer Res 62 2002 5645 5650
57. H.G. Wendel, E. De Stanchina, J.S. Fridman, A. Malina, S. Ray, S. Kogan, C. Cordon-Cardo, J. Pelletier, and S.W. Lowe Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy Nature 428 2004 332 337 This study suggests that rapamycin might sensitize cells to pro-apoptotic stimuli if mTOR signalling is activated (in this case, by active PKB).
58. M. Guba, P. von Breitenbuch, M. Steinbauer, G. Koehl, S. Flegel, M. Hornung, C.J. Bruns, C. Zuelke, S. Farkas, and M. Anthuber Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor Nat Med 8 2002 128 135
59. J.B. Brugarolas, F. Vazquez, A. Reddy, W.R. Sellers, and W.G. Kaelin Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways Cancer Cell 4 2003 147 158
60. N. El-Hashemite, V. Walker, H. Zhang, and D.J. Kwiatkowski Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin Cancer Res 63 2003 5173 5177
61. I.B. Weinstein Cancer. Addiction to oncogenes - the Achilles heal of cancer Science 297 2002 63 64
62. O.J. Shah, Z. Wang, and T. Hunter Inappropriate activation of the TSC1-TSC2/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies Curr Biol 14 2004 1650 1656
63. G.J. Clark, M.S. Kinch, K. Rogers-Graham, S.M. Sebti, A.D. Hamilton, and C.J. Der The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation J Biol Chem 272 1997 10608 10615
64. M. Karbowniczek, T. Cash, M. Cheung, G.P. Robertson, A. Astrinidis, and E.P. Henske Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent J Biol Chem 279 2004 29930 29937 This study identifies a potential mTOR-independent pathway downstream of Rheb inhibiting MAPK signalling, potentially through B-Raf.
65. C.J. Richardson, M. Broenstrup, D.C. Fingar, K. Julich, B.A. Ballif, S. Gygi, and J. Blenis SKAR is a specific target of S6 kinase 1 in cell growth control Curr Biol 14 2004 1540 1549
66. J. Dong, and D. Pan Tsc2 is not a critical target of Akt during normal Drosophila development Genes Dev 18 2004 2479 2484