The Cell Cycle and Neuronal Cell Death

  • Robert S. Freeman


Birth and death, the extremes of life, conjure images of antithetic and counteracting events necessary for maintaining a balance among living organisms. Their cellular counterparts, cell division and cell death, work in similar opposition to ensure proper development of an organism and to maintain homeostasis and normal function. A breakdown of either process can be detrimental and, in humans, may lead to birth defects, cancer, autoimmune disease, and neurological disorders. Although researchers have been well aware of the importance of proper cell division for decades, only recently has the significance of cell death attracted widespread appreciation. Consequently, we now have a relatively sophisticated understanding of the machinery that controls cell division; in comparison, we have only a rudimentary knowledge of the mechanisms that underlie cell death. But surprisingly, given our inclination to categorize birth and death as opposing and distinct forces, much of what we currently know about cell death has been fueled by research into cell cycle control. In this chapter, the hypothesis that the control of cell death and the cell cycle overlap will be discussed.


Cell Cycle Nerve Growth Factor Purkinje Cell Cell Cycle Protein Mitotic Catastrophe 
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  1. 1.
    Ko LJ and Prives C. p53: puzzle and paradigm. Genes Dev 1996, 10: 1054–1072.PubMedCrossRefGoogle Scholar
  2. 2.
    Askew DS, Ashmun RA, Simmons BC, Cleveland JL. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 1991, 6: 1915–1922.PubMedGoogle Scholar
  3. 3.
    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992, 69: 119–128.PubMedCrossRefGoogle Scholar
  4. 4.
    Evan G, Harrington E, Fanidi A, Land H, Amati B, Bennett M. Integrated control of cell proliferation and cell death by the c-myc oncogene. Phil Trans R Soc Lond B 1994, 345: 269–275.CrossRefGoogle Scholar
  5. 5.
    Heald R, McLoughlin M, McKeon F. Human weel maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell 1993, 74: 463–474.PubMedCrossRefGoogle Scholar
  6. 6.
    Hartwell LH and Kastan MB. Cell cycle control and cancer. Science 1994, 266: 1821–1828.PubMedCrossRefGoogle Scholar
  7. 7.
    Enoch T and Norbury C. Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem Sci 1995, 20: 426–430.PubMedCrossRefGoogle Scholar
  8. 8.
    Zetterberg A, Larsson O, Wilman KG. What is the restriction point? Curr Opin Cell Biol 1995, 7: 835–842.PubMedCrossRefGoogle Scholar
  9. 9.
    Morgan DO. Principles of CDK regulation. Nature 1995, 374: 131–134.PubMedCrossRefGoogle Scholar
  10. 10.
    Hunter T and Pines J. Cyclins and cancer. II. Cyclin D and CDK inhibitors come of age. Cell 1994, 79: 573–582.PubMedCrossRefGoogle Scholar
  11. 11.
    Sherr CJ. G1 phase progression: cycling on cue. Cell 1994, 79: 551–555.PubMedCrossRefGoogle Scholar
  12. 12.
    Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G. Cyclin Dl is a nuclear protein required for cell cycle progression in Gl. Genes Dev 1993, 7: 812–821.PubMedCrossRefGoogle Scholar
  13. 13.
    Quelle DE, Ashmun RA, Shurtleff SA, Kato JY, Bar-Sagi D, Roussel MF, Sherr CJ. Overexpression of mouse D-type cyclins accelerates Gl phase in rodent fibroblasts. Genes Dev 1993, 7: 1559–1571.PubMedCrossRefGoogle Scholar
  14. 14.
    Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the Gl-to-S phase transition. Mol Cell Biol 1995, 15: 2612–2624.PubMedGoogle Scholar
  15. 15.
    van den Heuvel S and Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 1993, 262: 2050–2054.PubMedCrossRefGoogle Scholar
  16. 16.
    Ohtsubo M, Roberts J.M. Cyclin-dependent regulation of Gl in mammalian fibroblasts. Science 1993, 259: 1908–1912.PubMedCrossRefGoogle Scholar
  17. 17.
    Girard F, Strausfeld U, Fernandez A, Lamb NJC. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 1991, 67: 1169–1179.PubMedCrossRefGoogle Scholar
  18. 18.
    King RW, Jackson KP, Kirschner MW. Mitosis in transition. Cell 1994, 79: 563–571.PubMedCrossRefGoogle Scholar
  19. 19.
    Sherr CJ and Roberts JM. Inhibitors of mammalian Gl cyclin-dependent kinases. Genes Dev 1995, 9: 1149–1163.PubMedCrossRefGoogle Scholar
  20. 20.
    Shim J, Lee H, Park J, Kim H, Choi E. A non-enzymatic p21 protein inhibitor of stress-activated protein kinases. Nature 1996, 381: 804–807.PubMedCrossRefGoogle Scholar
  21. 21.
    Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995, 81: 323–330.PubMedCrossRefGoogle Scholar
  22. 22.
    La Thangue NB. DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell-cycle control. Trends Biochem Sci 1994, 19: 108–114.PubMedCrossRefGoogle Scholar
  23. 23.
    Ucker DS. Death by suicide: one way to go in mammalian cellular development? New Biol 1991, 3: 103–109.PubMedGoogle Scholar
  24. 24.
    Lazebnik YA, Cole S, Cooke CA, Nelson WG, Earnshaw WC. Nuclear events of apoptosis in vitro in cell-free mitotic extracts: a model system for analysis of the active phase of apoptosis. J Cell Biol 1993, 123: 7–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Nigg EA. Targets of cyclin-dependent protein kinases. Curr Opin Cell Biol 1993, 5: 187–193.PubMedCrossRefGoogle Scholar
  26. 26.
    Lazebnik YA, Takahashi A, Moir RD, Goldman RD, Poirier GG, Kaufmann SH, Earnshaw WC. Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution. Proc Natl Acad Sci USA 1995, 92: 9042–9046.PubMedCrossRefGoogle Scholar
  27. 27.
    Demarcq C, Bunch RT, Creswell D, Eastman A. 1994, The role of cell cycle progression in cisplatin-induced apoptosis in Chinese hamster ovary cells. Cell Growth Differ 1994, 5: 983–993.PubMedGoogle Scholar
  28. 28.
    Shimizu T, O’Connor PM, Kohn KW, Pommier Y. Unscheduled activation of cyclin B 1/Cdc2 kinase in human promyelocytic leukemia cell line HL60 cells undergoing apoptosis induced by DNA damage. Cancer Res 1995, 55: 228–231.PubMedGoogle Scholar
  29. 29.
    Meikrantz W, Gisselbrecht S, Tarn SW, Schlegel R. Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci USA 1994, 91: 3754–3758.PubMedCrossRefGoogle Scholar
  30. 30.
    Wang Q, Worland PJ, Clark JL, Carlson BA, Sausville EA. Apoptosis in 7-hydroxy-staurospurine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 1995, 6: 927–936.PubMedGoogle Scholar
  31. 31.
    Donaldson KL, Goolsby G, Kiener PA, Wahl AF. Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Differ 1994, 5: 1041–1050.PubMedGoogle Scholar
  32. 32.
    Deckwerth TL and Johnson EM Jr. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor (NGF). J Cell Biol 1993, s123: 1207–1CrossRefGoogle Scholar
  33. 33.
    Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R, Johnson EM Jr. Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. J Cell Biol 1994, 127: 1717–1727.PubMedCrossRefGoogle Scholar
  34. 34.
    Freeman RS, Estus S, Johnson EM Jr. Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of cyclin Dl during programmed cell death. Neuron 1994, 12: 343–355.PubMedCrossRefGoogle Scholar
  35. 35.
    Kranenburg O, van der Eb AJ, Zantema A. Cyclin Dl is an essential mediator of apoptotic neuronal cell death. EMBO J 1996, 15: 46–54.PubMedGoogle Scholar
  36. 36.
    Herrup K and Busser JC. The induction of multiple cell cycle events precedes target-related neuronal death. Development 1995, 121: 2385–2395.PubMedGoogle Scholar
  37. 37.
    Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA. Cyclin Dl provides a link between development and oncogen-esis in the retina and breast. Cell 1995, 82: 621–630.PubMedCrossRefGoogle Scholar
  38. 38.
    Gao CY and Zelenka PS. Induction of cyclin B and H1 kinase activity in apoptotic PC12 cells. Exp Cell Res 1995, 219: 612–618.PubMedCrossRefGoogle Scholar
  39. 39.
    Farinelli SE and Greene LA. Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci 1996, 16: 1150–1162.PubMedGoogle Scholar
  40. 40.
    Park DS, Farinelli SE, Greene LA. Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. J Biol Chem 1996, 271: 8161–8169.PubMedCrossRefGoogle Scholar
  41. 41.
    Fotedar R, Flatt J, Gupta S, Margolis RL, Fitzgerald P, Messier H, Fotedar A. Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B. Mol Cell Biol 1995, 15: 932–942.PubMedGoogle Scholar
  42. 42.
    Li CJ, Friedman DJ, Wang C, Metelev V, Pardee AB. Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 1995, 268: 429–431.PubMedCrossRefGoogle Scholar
  43. 43.
    Shi L, Nishioka WK, Th’ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Science 1994, 263: 1143–1145.PubMedCrossRefGoogle Scholar
  44. 44.
    Martin SJ, McGahon AJ, Nishioka WK, La Face D. p34cdc2 and apoptosis. Science 1995, 269: 106–107.PubMedCrossRefGoogle Scholar
  45. 45.
    Ongkeko W, Ferguson DJP, Harris AL, Norbury C. Inactivation of Cdc2 increases the level of apoptosis induced by DNA damage. J Cell Sci 1995, 108: 2897–2904.PubMedGoogle Scholar
  46. 46.
    Meikrantz W and Schlegel R. Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases. J Biol Chem 1996, 271: 10205–10209.PubMedCrossRefGoogle Scholar
  47. 47.
    Galaktionov K, Chen X, Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 1996, 382: 511–517.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang J, Walsh K. Resistance to apoptosis conferred by Cdk inhibitors during myocyte differentiation. Science 1996, 273: 359–361.PubMedCrossRefGoogle Scholar
  49. 49.
    Poluha W, Poluha DK, Chang B, Crosbie NE, Schonhoff CM, Kilpatrick DL, Ross AH. The cyclin-dependent kinase inhibitor p21Wafl is required for survival of differentiating neuroblastoma cells. Mol Cell Biol 1996, 16: 1335–1341.PubMedGoogle Scholar
  50. 50.
    Waldman T, Lengauer C, Kinzler KW, Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 1996, 381: 713–716.PubMedCrossRefGoogle Scholar
  51. 51.
    Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E. The adenovirus El A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci USA 1992, 89: 7742–7746.PubMedCrossRefGoogle Scholar
  52. 52.
    White AE, Livanos EM, Tisty TD. Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 1994, 8: 666–677.PubMedCrossRefGoogle Scholar
  53. 53.
    Clarke AR, Maandag ER, van Roon M, van der Lugt NMT, van der Valk M, Hooper ML, Berns A, Riele HT. Requirement for a functional Rb-1 gene in murine development. Nature 1992, 359: 328–330.PubMedCrossRefGoogle Scholar
  54. 54.
    Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA. Effects of an Rb mutation in the mouse. Nature 1992, 359: 295–300.PubMedCrossRefGoogle Scholar
  55. 55.
    Lee EY HP, Chang C-Y, Hu N, Wang Y-CJ, Lai C-C, Herrup K, Lee W H, Bradley A. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992, 359: 288–294.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee EY HP, Hu N, Yuan S-SF, Cox LA, Bradley A, Lee W-H, Herrup K. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev 1994, 8: 2008–2021.PubMedCrossRefGoogle Scholar
  57. 57.
    Almasan A, Yin Y, Kelly RE, Lee EY-HP, Bradley A, Li W, Bertino JR, Wahl GM Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc Natl Acad Sci USA 1995, 92: 5436–5440.PubMedCrossRefGoogle Scholar
  58. 58.
    Haas-Koogan DA, Kogan SC, Levi D, Dazin P, T’Ang A, Fung Y, Israel MA. Inhibition of apoptosis by the retinoblastoma gene product. EMBO J 1995, 14: 461–472.Google Scholar
  59. 59.
    Berry DE, Lu Y, Schmidt B, Fallon PG, O’Connell C, Hu S-X, Xu H-J, Blanck G. Retinoblastoma protein inhibits interferon-y induced apoptosis. Oncogene 1996, 12: 1809–1819.PubMedGoogle Scholar
  60. 60.
    Fan G, Ma X, Kren BT, Steer CJ. The retinoblastoma gene product inhibits TGF-βl induced apoptosis in primary rat hepatocytes and human HuH-7 hepatoma cells. Oncogene 1996, 12: 1909–1919.PubMedGoogle Scholar
  61. 61.
    An B and Dou QP. Cleavage of retinoblastoma protein during apoptosis: an interleukin 1β-converting enzyme-like protease as candidate. Cancer Res 1996, 56: 438–442.PubMedGoogle Scholar
  62. 62.
    Qin X, Livingston DM, Kaelin WG Jr, Adams PD. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci USA 1994, 91: 10,918–10,922.PubMedCrossRefGoogle Scholar
  63. 63.
    Shan B and Lee W. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol 1994, 14: 8166–8173.PubMedGoogle Scholar
  64. 64.
    Kowalik TF, DeGregori J, Schwarz JK, Nevins JR. E2F-1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. J Virol 1995, 69: 2491–2500.PubMedGoogle Scholar
  65. 65.
    Wu X, Levine, AJ. p53 and E2F-l cooperate to mediate apoptosis. Proc Natl Acad Sci USA 1994, 91: 3602–3606.PubMedCrossRefGoogle Scholar
  66. 66.
    Shan B, Durfee T, Lee W-H. Disruption of RB/E2F-1 interaction by single point mutations in E2F-1 enhances S-phase entry and apoptosis. Proc Natl Acad Sci USA 1996, 93: 679–684.PubMedCrossRefGoogle Scholar
  67. 67.
    Hiebert SW, Packman G, Strom DK, Haffner R, Oren M, Zambetti G, Cleveland JL. E2F-1:DP-1 induces p53 and overrides survival factors to trigger apoptosis. Mol Cell Biol 1995, 15: 6864–6874.PubMedGoogle Scholar
  68. 68.
    Krek W, Xu G, Livingston DM. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint. Cell 1995, 83: 1149–1158.PubMedCrossRefGoogle Scholar
  69. 69.
    Field SJ, Tsai F, Kuo F, Zubiaga AM, Kaelin WG Jr, Livingston DM, Orkin SH, Greenberg ME. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 1996, 85: 549–561.PubMedCrossRefGoogle Scholar
  70. 70.
    Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 1996, 85: 537–548.PubMedCrossRefGoogle Scholar
  71. 71.
    Heintz N. Cell death and the cell cycle: a relationship between transformation and neurodegeneration? Trends Biochem Sci 1993, 18: 157–159.PubMedCrossRefGoogle Scholar
  72. 72.
    Al-Ubaidi MR, Hollyfield JG, Overbeek PA, Baehr W. Photoreceptor degeneration induced by the expression of simian virus 40 large tumor antigen in the retina of transgenic mice. Proc Natl Acad Sci USA 1992, 89: 1194–1198.PubMedCrossRefGoogle Scholar
  73. 73.
    Hammang JP, Behringer RR, Baetge EE, Palmiter RD, Brinster RL, Messing A. Oncogene expression in retinal horizontal cells of transgenic mice results in a cascade of neurodegeneration. Neuron 1993, 10: 1197–1209.PubMedCrossRefGoogle Scholar
  74. 74.
    Feddersen, R.M, Ehlenfeldt, R, Yunis, WS, Clark, HB, Orr, HT. Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron 1992, 9: 955–966.PubMedCrossRefGoogle Scholar
  75. 75.
    Feddersen RM, Clark HB, Yunis WS, Orr HT. In vivo viability of postmitotic Purkinje neurons requires pRb family member function. Mol Cell Neurosci 1995, 6: 153–167.PubMedCrossRefGoogle Scholar
  76. 76.
    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993, 362: 849–852.PubMedCrossRefGoogle Scholar
  77. 77.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993, 362: 847–849.PubMedCrossRefGoogle Scholar
  78. 78.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996, 379: 88–91.PubMedCrossRefGoogle Scholar
  79. 79.
    Hermeking H and Eick D. Mediation of c-Myc-induced apoptosis by p53. Science 1994, 265: 2091–2093.PubMedCrossRefGoogle Scholar
  80. 80.
    Gottlieb E, Haffner R, von Ruden T, Wagner EF, Oren M. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J 1994, 13: 1368–1374.PubMedGoogle Scholar
  81. 81.
    Morgenbesser SD, Williams BO, Jacks T, DePinho RA. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 1994, 371: 72–74.PubMedCrossRefGoogle Scholar
  82. 82.
    Fromm L, Shawlot W, Gunning K, Butel JS, Overbeek PA. The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice. Mol Cell Biol 1994, 14: 6743–6754.PubMedGoogle Scholar
  83. 83.
    Pan H and Griep AE. Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. Genes Dev 1994, 8: 1285–1299.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1999

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  • Robert S. Freeman

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