Advertisement

The Mammalian Target of Rapamycin and Multiple Myeloma

  • Patrick Frost
  • Alan Lichtenstein
Part of the Contemporary Hematology book series (CH)

The Biochemistry and Molecular Biology of TOR

Eukaryotic cells have evolved a highly integrated regulatory process linking progrowth environmental stimuli (e.g., growth factors, nutrient, and energy levels) with the activation and regulation of the protein synthesis machinery, thereby ensuring that the proteins critical for cell growth and cell cycle progression are expressed only when conditions are appropriate. While multiple intracellular proteins and signaling pathways are involved in this process, the mammalian target of rapamycin (mTOR) is an especially important component and acts as a convergence point for these diverse regulatory and sensory pathways. The TOR protein (also known as FRAP, RAFT, RAPT, or SEP) is a −290 kD serine/threonine kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family and was initially identified by mutations that conferred resistance to the growth inhibitory effects of rapamycin in the budding yeast Saccharomyces cereviseae.

Keywords

Multiple Myeloma Myeloma Cell Mantle Cell Lymphoma mTOR Inhibitor P70S6 Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosup-pressant rapamycin in yeast. Science 1991; 253:905–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT 1: A mammalian protein that binds to FKBP 12 in a rapamycin-dependent fashion and ishomologous to yeast TORs. Cell 1994; 78:35–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by Gl-arrest-ing rapamycin-receptor complex. Nature 1994; 369:756–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Chiu MI, Katz H, Berlin V. RAPTl, a mammalian homolog of yeast Tor, interacts with the FKBPl2/rapamycin complex. Proc Natl Acad Sci USA 1994; 91:12574–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D. The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 1999; 96:99–110.PubMedCrossRefGoogle Scholar
  6. 6.
    Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBPl2-rapamycin complex interacting with the binding domain of human FRAP. Science 1996; 273:239–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177–89.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6:1122–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15:807–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Abraham RT. Identification of TOR signaling complexes: More TORC for the cell growth engine. Cell 2002; 111:9–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471–84.PubMedCrossRefGoogle Scholar
  13. 13.
    Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17:1829–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Inoki K, Li Y, Zhu T, W u J Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648–57.PubMedCrossRefGoogle Scholar
  15. 15.
    Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:151–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase activating protein complex toward. Rheb Curr Biol 2003; 13:1259–68.CrossRefGoogle Scholar
  17. 17.
    Hyun T, Yam A, Pece S, et al. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 2000; 96:3560–8.PubMedGoogle Scholar
  18. 18.
    Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB 1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 2004; 18:1533–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Nobukuni T, Joaquin M, Roccio M, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 30H-kinase. Proc Natl Acad Sci USA 2005; 102:14238–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Hsu J, Shi Y, Krajewski S, et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001; 98:2853–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Qiang YW, Kopantzev E, Rudikoff S. Insulinlike growth factor-I signaling in multiple myeloma: Downstream elements, functional correlates, and pathway cross-talk. Blood 2002; 99:4138–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Hsu JH, Shi Y, Frost P, et al. Interleukin-6 activates phosphoinositol-3 kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene 2004; 23:3368–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Shi Y, Hsu JH, Hu L, Gera J, Lichtenstein A. Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. J Biol Chem 2002; 277:15712–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Liu P, Leong T, Quam L, et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: Analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 1996; 88:2699–706.PubMedGoogle Scholar
  25. 25.
    Neri A, Murphy JP, Cro L, et al. Ras oncogene mutation in multiple myeloma. J Exp Med 1989; 170:1715–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Yoganathan N, Yee A, Zhang Z, et al. Integrin-linked kinase, a promIsmg cancer therapeutic target: Biochemical and biological properties. Pharmacol Ther 2002; 93:23342.CrossRefGoogle Scholar
  27. 27.
    Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002; 62:5027–34.PubMedGoogle Scholar
  28. 28.
    Chang H, Qi XY, Claudio J, Zhuang L, Patterson B, Stewart AK. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res 2006; 30:262–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Bahlis NJ, Miao Y, Koc ON, Lee K, Boise LH, Gerson SL. N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells. Leuk Lymphoma 2005; 46:899–908.PubMedCrossRefGoogle Scholar
  30. 30.
    Dufner A, Andjelkovic M, Burgering BM, Hemmings BA, Thomas G. Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol Cell Biol 1999; 19:4525–34.PubMedGoogle Scholar
  31. 31.
    Brown EJ, Schreiber SL. A signaling pathway to translational control. Cell 1996; 86:51720.Google Scholar
  32. 32.
    Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G. Rapamycin suppresses 5TOP mRNA translation through inhibition of p70s6k. Embo J 1997; 16:3693–704.PubMedCrossRefGoogle Scholar
  33. 33.
    Sachs AB. Cell cycle-dependent translation initiation: IRES elements prevail. Cell 2000; 101:243–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Vagner S, Galy B, Pyronnet S. Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. EMBO Rep 2001; 2:893–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Pestova TV, Kolupaeva VG, Lomakin IB, et al. Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci USA 2001; 98:7029–36.PubMedCrossRefGoogle Scholar
  36. 36.
    Tu Y, Gardner A, Lichtenstein A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses. Cancer Res 2000; 60:6763–70.PubMedGoogle Scholar
  37. 37.
    Hsu L, Shi Y, Hsu JH, Gera J, Van Ness B, Lichtenstein A. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 2003; 101:3126–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Yang YP, Liang ZQ, Gu ZL, Qin ZH. Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin 2005; 26:1421–34.PubMedCrossRefGoogle Scholar
  39. 39.
    van Sluijters DA, Dubbelhuis PF, Blommaart EF, Meijer AJ. Amino-acid-dependent signal transduction. Biochem J 2000; 351(Pt 3):545–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Codogno P, Meijer AJ. Autophagy and signaling: Their role in cell survival and cell death. Cell Death Differ 2005; 12(Supp. 12):1509–18.PubMedCrossRefGoogle Scholar
  41. 41.
    Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor-mediated induction of autophagy via an Apgl protein kinase complex. J Cell Biol 2000; 150:150713.CrossRefGoogle Scholar
  42. 42.
    Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 2001; 98:9666–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Yokogami K, Wakisaka S, Avruch J, Reeves SA. Serine phosphorylation and maximal activation of ST A T3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 2000; 10:47–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Kuo ML, Chuang SE, Lin MT, Yang SY. The involvement of PI 3-KJAkt-dependent upregulation of Mc1-1 in the prevention of apoptosis of Hep3B cells by interleukin-6. Oncogene 2001; 20:677–85.PubMedCrossRefGoogle Scholar
  45. 45.
    Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-l/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005; 4:1533–40.PubMedCrossRefGoogle Scholar
  46. 46.
    Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 2004; 104:4188–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Zangari M, Cavallo F, Tricot G. Farnesyltransferase inhibitors and rapamycin in the treatment of multiple myeloma. Curr Pharm Biotechnol 2006; 7:449–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Frost P, Moatomed F, Hoang B, et al. In vivo anti-tumor effects of the mTOR inhibitor, CCI-779, against human multiple myeloma cells in a xenograft model. Blood 2004; 104:4181–4187.PubMedCrossRefGoogle Scholar
  49. 49.
    Stromberg T, Dimberg A, Hammarberg A, et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 2004; 103:3138–47.PubMedCrossRefGoogle Scholar
  50. 50.
    Yan H, Frost P, Shi Y, et al. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma Cells to dexamethasone-induced apoptosis. Cancer Res 2006; 66:2305–2313.PubMedCrossRefGoogle Scholar
  51. 51.
    Frost P, Shi Y, Hoang B, Lichtenstein A. AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 2007; 26:2255–2262.PubMedCrossRefGoogle Scholar
  52. 52.
    Ikezoe T, Nishioka C, Tasaka T, et al. The antitumor effects of sunitinib (formerly SU 11248) against a variety of human hematologic malignancies: Enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 2006; 5:2522–30.PubMedCrossRefGoogle Scholar
  53. 53.
    Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res 2006; 12:6826–35.PubMedCrossRefGoogle Scholar
  54. 54.
    O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66:1500–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI779) for relapsed mantle cell lymphoma. J Clin Onco1 2005; 23:5347–56.CrossRefGoogle Scholar
  56. 56.
    Bertoni F, Zucca E, Cotter FE. Molecular basis of mantle cell lymphoma. Br J Haematol 2004; 124:130–40.PubMedCrossRefGoogle Scholar
  57. 57.
    Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2007; 21:333–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Farag S, Zhang S, Miller M, et al. Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple Myeloma: Preliminary results. Proc Amer Soc Clin Oncol 2006; 24(18s):450.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Patrick Frost
    • 1
  • Alan Lichtenstein
    • 1
  1. 1.Department of Medicine, UCLAThe Jonsson Comprehensive Cancer Center and Department of Hematology-Oncology, VA Medical CenterLos AngelesUSA

Personalised recommendations