Apoptosis as a Stress Response

Lessons from an Insect Virus
  • Rollie J. Clem


Cells have evolved a number of protective mechanisms to help them withstand stressful external stimuli such as heat, toxic chemicals, anoxia, and infection by microorganisms. Despite these protective responses, if the level of stress is too great, cell death results. Kerr et al. (1972) were the first to emphasize the differences between cell death directed by the cell, or programmed cell death, and cell death beyond the control of the cell, or necrotic cell death. Whether the death of a cell is programmed or necrotic often depends on the severity of the stress signal. Cells have evolved the ability to respond to many physiological stimuli by assisting in their own death. However, if the level of stress is so great that it overwhelms the ability of the cell to function, necrosis is often the result.


Programme Cell Death Spinal Muscular Atrophy Ring Finger Nuclear Polyhedrosis Virus Occlusion Body 


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  1. Alnemri, E. S., Robertson, N. M., Fernandes, T. F., Croce, C. M., and Litwack, G., 1992, Overexpressed full-length human BCL2 extends the survival of baculovirus-infected Sf9 insect cells, Proc. Natl. Acad. Sci. USA 89: 7295–7299.PubMedCrossRefGoogle Scholar
  2. Ayres, M. D., Howard, S. C., Kuzio, J., Lopez-Ferber, M., and Possee, R. D., 1994, The complete DNA sequence of Autographa californica nuclear polyhedrosis virus, Virology 202: 586–605.PubMedCrossRefGoogle Scholar
  3. Barlow, P. N., Luisi, B., Milner, A., Elliott, M., and Everett, R., 1994, Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy, J. Mol. Biol. 2337: 201–211.CrossRefGoogle Scholar
  4. Beidler, D. R, Tewari, M., Friesen, P. D., Poirier, G., and Dixit, V. M., 1995, The baculovirus p35 protein inhibits fas-and tumor necrosis factor-induced apoptosis, J. Biol. Chem. 270: 16256–16258.CrossRefGoogle Scholar
  5. Berg, J. M., and Shi, Y., 1996, The galvanization of biology: A growing appreciation for the roles of zinc, Science 271: 1081–1085.PubMedCrossRefGoogle Scholar
  6. Bergqvist, A., and Magnusson, G., 1994, Apoptosis of Spodoptera frugiperda cells induced by okadaic acid is abrogated by baculovirus infection, Exp. Cell Res. 215: 223–227.PubMedCrossRefGoogle Scholar
  7. Birnbaum, M. J., Clem, R. J., and Miller, L. K., 1994, An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a peptide with cys/his sequence motifs, J. Virol. 68: 2521–2528.Google Scholar
  8. Borden, K. L. B., Boddy, M. N., Lally, J., O’Reilly, N. J., Martin, S., Howe, K., Solomon, E., and Freemont, P. S., 1995, The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML, EMBO J. 14: 1532–1541.Google Scholar
  9. Bump, N. J., Hackett, M., Hugunin, M., Seshagiri, S., Brady, K., Chen, P., Ferenz, C., Franklin, S., Ghayur, T., Li, P., Licari, P., Mankovich, J., Shi, L., Greenberg, A. H., Miller, L. K., and Wong, W. W., 1995, Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35, Science 269: 1885–1888.PubMedCrossRefGoogle Scholar
  10. Cartier, J. L., Hershberger, P. A., and Friesen, P. D., 1994, Suppression of apoptosis in insect cells stably transfected with baculovirus p35: Dominant interference by N-terminal sequences p351–76, J. Virol. 68: 7728–7737.PubMedGoogle Scholar
  11. Chacon, M. R., Almazan, F., Nogal, M. L., Vinuela, E., and Rodriguez, J. F.,1995, The African swine fever virus IAP homolog is a late structural polypeptide, Virology 214: 670–674.Google Scholar
  12. Chejanovsky, N., and Gershburg, E., 1995, The wild-type Autographa californica nuclear polyhedrosis virus induces apoptosis of Spodoptera littoralis cells, Virology 209: 519–525.PubMedCrossRefGoogle Scholar
  13. Clarke, A. R., Purdie, C. A., Harrison, D. J., Morris, R. G., Bird, C. C., Hooper, M. L., and Wyllie, A. H., 1993, Thymocyte apoptosis induced by p53-dependent and independent pathways, Nature 362: 849–852.PubMedCrossRefGoogle Scholar
  14. Clem, R. J., and Miller, L. K., 1993, Apoptosis reduces both the in vitro replication and the in vivo infectivity of a baculovirus, J. Virol. 67: 3730–3738.PubMedGoogle Scholar
  15. Clem, R. J., and Miller, L. K., 1994a, Control of programmed cell death by the baculovirus genes p35 and iap, Mol. Cell Biol. 14: 5212–5222.PubMedGoogle Scholar
  16. Clem, R. J., and Miller, L. K., 1994b, Induction and inhibition of apoptosis by insect viruses, in: Apoptosis II: The Molecular Basis of Cell Death ( F. O. Cope and L. D. Tomei, eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 89–110.Google Scholar
  17. Clem, R J., Fechheimer, M., and Miller, L. K., 1991, Prevention of apoptosis by a baculovirus gene during infection of insect cells, Science 254: 1388–1390.PubMedCrossRefGoogle Scholar
  18. Clem, R. J., Robson, M., and Miller, L. K., 1994, Influence of infection route on the infectivity of baculovirus mutants lacking the apoptosis-inhibiting gene p35 and the adjacent gene p94, J. Virol. 68: 6759–6762.PubMedGoogle Scholar
  19. Clem, R. J.. Hardwick, J. M., and Miller, L. K., 1996, Anti-apoptotic genes of baculoviruses, Cell Death Differ. 3: 9–16.Google Scholar
  20. Clouston, W. M., and Kerr, J. F. R., 1985, Apoptosis, lymphocytotoxicity and the containment of viral infections, Med. Hypoth. 18: 399–404.CrossRefGoogle Scholar
  21. Crook, N. E., Clem, R. J., and Miller, L. K., 1993, An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif, J. Virol. 67: 2168–2174.PubMedGoogle Scholar
  22. Duckett, C. S., Nava, V. E., Gedrich, R. W., Clem, R. J., Van Dongen, J. L., Gilfillan, M. C., Shiels, H., Hardwick, J. M., and Thompson, C. B., 1996, A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors, EMBO J. 15: 2685–2694.Google Scholar
  23. Ellis, R. E., Yuan, J., and Horvitz, H. R., 1991, Mechanisms and functions of cell death, Annu. Rev. Cell Biol. 7: 663–698.CrossRefGoogle Scholar
  24. Fernandes-Alnemri, T., Litwack, G., and Alnemri, E. S., 1994, CPP32, a novel human apoptotic protein with homology to Caenorhabditis eiegans cell death protein ced-3 and mammalian interleukin-lbeta-converting enzyme, J. Biol. Chem. 269: 30761–30764.PubMedGoogle Scholar
  25. Fernandes-Alnemri, T., Litwack, G., and Alnemri, E. S., 1995, Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family, Cancer Res. 55: 2737–2742.Google Scholar
  26. Freemont, P. S., Hanson, I. M., and Trowsdale, J., 1991, A novel cysteine-rich sequence motif, Cell 64: 483–484.PubMedCrossRefGoogle Scholar
  27. Giorgi, F., and Deri, P., 1976, Cell death in ovarian chambers of Drosophila melanogaster, J. Embryol. Exp. Morphol. 35: 521–533.Google Scholar
  28. Golstein, P., Marguet, D., and Depraetere, V., 1995, Homology between reaper and the cell death domains of Fas and TNFR1, Cell 81: 185–186.PubMedCrossRefGoogle Scholar
  29. Grether, M. E., Abrams, J. M., Agapite, J., White, K., and Steller, H., 1995, The head involution defective gene of Drosophila melanogaster functions in programmed cell death, Genes Dey. 9: 1694–1708.CrossRefGoogle Scholar
  30. Hay, B. A., Wolff, T., and Rubin, G. M., 1994, Expression of baculovirus P35 prevents cell death in Drosophila, Development 120: 2121–2129.PubMedGoogle Scholar
  31. Hay, B. A., Wassarman, D. A., and Rubin, G. M., 1995, Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death, Cell 83: 1253–1262.Google Scholar
  32. Hengartner, M. O., and Horvitz, H. R., 1994, C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bd-2, Cell 76: 665–676.PubMedCrossRefGoogle Scholar
  33. Hengartner, M. O., Ellis, R. E., and Horvitz, H. R, 1992, Caenorhabditis elegans gene ced-9 protects cells from programmed cell death, Nature 356: 494–499.Google Scholar
  34. Hershberger, P. A., Dickson, J. A., and Friesen, P. D., 1992, Site-specific muta-genesis of the 35-kilodalton protein gene encoded by Autographa californica nuclear polyhedrosis virus: Cell line-specific effects on virus replication, J. Virol. 66: 5525–5533.PubMedGoogle Scholar
  35. Hershberger, P. A., LaCount, D. J., and Friesen, P. D., 1994, The apoptotic suppressor P35 is required early during baculovirus replication and is targeted to the cytosol of infected cells, J. Virol. 68: 3467–3477.PubMedGoogle Scholar
  36. Kamita, S. G., Majima, K., and Maeda, S., 1993, Identification and characterization of the p35 gene of Bombyx mori nuclear polyhedrosis virus that prevents virus-induced apoptosis, J. Virol. 67: 455–463.Google Scholar
  37. Kane, D.J., Sarafian, T. A., Anton, R., Hahn, H., Gralla, E. B., Valentine, J. S., Ord, T., and Bredesen, D. E., 1993, Bd-2 inhibition of neural death: Decreased generation of reactive oxygen species, Science 262: 1274–1277.PubMedCrossRefGoogle Scholar
  38. Kerr, J. F. R., and Harmon, B. V., 1991, Definition and incidence of apoptosis: An historical perspective, in: Apoptosis: The Molecular Basis of Cell Death ( L. D. Tomei and F. O. Cope. eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 5–29.Google Scholar
  39. Kerr, J. F. R., Wyllie, A. H., and Currie, A. R., 1972, Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics, Br. J. Cancer 26: 239–257.PubMedCrossRefGoogle Scholar
  40. Kool, M. and Vlak, J. M., 1993, The structural and functional organization of the Autographa californica nuclear polyhedrosis virus genome, Arch. Virol. 130: 1–16.PubMedCrossRefGoogle Scholar
  41. Kool, M., Ahrens, J. M., and Rohrmann, G. F., 1995, Replication of baculovirus DNA, J. Gen. Virol. 76: 2103–2118.PubMedCrossRefGoogle Scholar
  42. Koval, T. M., 1996, Moths: Myths and mysteries of stress resistance, BioEssays 18: 149–156.Google Scholar
  43. Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.-E., MacKenzie, A., and Korneluk, R. G., 1996, Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes, Nature 379: 349–353.PubMedCrossRefGoogle Scholar
  44. Lockshin, R. A., 1985, Programmed cell death, in: Comprehensive Insect Physiology, Biochemistry and Pharmacology (G. A. Kerkut and L. I. Gilbert, eds.), Pergamon Press, Elmsford, NY, Vol. 2, pp. 301–317.Google Scholar
  45. Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., and Jacks, T., 1993, p53 is required for radiation-induced apoptosis in mouse thymocytes, Nature 362: 847–849.Google Scholar
  46. Lu, A., and Miller, L. K., 1995, The roles of eighteen baculovirus late expression factor genes in transcription and DNA replication, J. Virol. 69: 975–982.Google Scholar
  47. Martin, S. J., and Green, D. R., 1995, Protease activation during apoptosis: Death by a thousand cuts? Cell 82: 349–352.PubMedCrossRefGoogle Scholar
  48. Martinou, I., Fernandez, P.-A., Missotten, M., White, E., Allet, B., Sadoul, R., and Martinou, J.-C., 1995, Viral proteins E1B19K and p35 protect sympathetic neurons from cell death induced by NGF deprivation, J. Cell Biol. 128: 201–208.PubMedCrossRefGoogle Scholar
  49. Martz, E., and Howell, D. M., 1989, CTL: Virus control cells first and cytolytic cells second? Immunol. Today 10: 79–86.PubMedCrossRefGoogle Scholar
  50. Miller, L. K., 1995, Genetically engineered insect virus pesticides: Present and future, J. Invert. Pathol. 65: 211–216.CrossRefGoogle Scholar
  51. Nagata, S., and Golstein, P., 1995, The Fas death factor, Science 267: 1449–1456.PubMedCrossRefGoogle Scholar
  52. Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffin, P. R, Labelle, M., Lazebnik, Y. A., Munday, N. A., Raju, S. M., Smulson, M. E., Yamin, T. T., Yu, V. L., and Miller, D. K., 1995, Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis, Nature 376: 37–43.PubMedCrossRefGoogle Scholar
  53. Oltvai, Z. N., and Korsmeyer, S. J., 1994, Checkpoints of dueling dimers foil death wishes, Cell 79: 189–192.PubMedCrossRefGoogle Scholar
  54. O’Reilly, D. R., Miller, L. K., and Luckow, V. A., 1992, Baculovirus Expression Vectors: A Laboratory Manual, Freeman, San Francisco.Google Scholar
  55. Pipan, N., and Rakovec, V., 1980, Cell death in the midgut epithelium of the worker honey bee (Apis mellifera carnica) during metamorphosis, Zoomorphologie 94: 217–224.CrossRefGoogle Scholar
  56. Prikhod’ko, E. A., and Miller, L. K., 1996, Induction of apoptosis by baculovirus transactivator IE-1, J. Virol. 70: 7116–7124.PubMedGoogle Scholar
  57. Pronk, G.J., Ramer, K., Amiri, P., and Williams, L. T., 1996, Requirement of an ICE-like protease for induction of apoptosis and ceramide generation by REAPER, Science 271: 808–810.PubMedCrossRefGoogle Scholar
  58. Quan, L. T., Caputo, A., Bleackley, R. C., Pickup, D. J., and Salvesen, G. S., 1995, Granzyme B is inhibited by the cowpox serpin cytokine response modifier A, J. Biol. Chem. 270: 10377–10379.PubMedCrossRefGoogle Scholar
  59. Rabizadeh, S., LaCount, D. J, Friesen, P. D., and Bredesen, D. E., 1993, Expression of the baculovirus p35 gene inhibits mammalian neural cell death, J. Neurochem. 61: 2318–2321.PubMedCrossRefGoogle Scholar
  60. Raff, M. C., Barres, B. A., Burne, J. F., Coles, H. S., Ishizaki, Y., and Jacobson, M. D., 1993, Programmed cell death and the control of cell survival: Lessons from the nervous system, Science 262: 695–700.PubMedCrossRefGoogle Scholar
  61. Rohrmann, G. F., 1992, Baculovirus structural proteins, J. Gen. Virol. 73: 749–761.PubMedCrossRefGoogle Scholar
  62. Rohrmann, G. F., and Leisy, D. J., 1995, Interactions of baculovirus replication proteins: Application of a yeast two-hybrid system, American Society for Virology Annual Meeting Abstracts, p. 105.Google Scholar
  63. Rothe, M., Pan, M.-G., Henzel, W. J., Ayres, T. M., and Goeddel, D. V., 1995, The TNFR2-TRAF signalling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins, Cell 83: 1243–1252.PubMedCrossRefGoogle Scholar
  64. Roy, N., Mahadevan, M. S., McLean, M., Shutler, G., Yaraghi, Z., Farahani, R., Baird, S., Besner-Johnston, A., Lefebvre, C., Kang, X., Salih, M., Aubry, A., Tamai, K., Guan, X., Ioannou, P., Crawford, T. O., de Jong, P. J., Surh, L., Ikeda, J. E., Korneluk, R. G., and MacKenzie, A., 1995, The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy, Cell 80: 167–178.PubMedCrossRefGoogle Scholar
  65. Schwartz, L. M., Smith, S. W., Jones, M. E., and Osborne, B. A., 1993, Do all programmed cell deaths occur via apoptosis?, Proc. Natl. Acad. Sci. USA 90: 980–984.PubMedCrossRefGoogle Scholar
  66. Steller, H., 1995, Mechanisms and genes of cellular suicide, Science 267: 1445 1449.Google Scholar
  67. Strasser, A., Harris, A. W., Jacks, T., and Cory, S., 1994, DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bd-2, Cell 79: 329–339.PubMedCrossRefGoogle Scholar
  68. Sugimoto, A., Friesen, P. D., and Rothman, J. H., 1994, Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans, EMBO J. 13: 2023–2028.Google Scholar
  69. Thompson, C. B., 1995, Apoptosis in the pathogenesis and treatment of disease, Science 267: 1456–1462.PubMedCrossRefGoogle Scholar
  70. Uren, A. G., Pakusch, M., Hawkins, C. J., Puls, K. L., and Vaux, D. L., 1996, Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors, Proc. Natl. Acad. Sci. USA 93: 4974–4978.PubMedCrossRefGoogle Scholar
  71. Vaux, D. L., and Hacker, G., 1995, Hypothesis: Apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular pathogens, Clin. Exp. Pharm. Physiol. 22: 861–863.CrossRefGoogle Scholar
  72. Vaux, D. L., and Strasser, A., 1996, The molecular biology of apoptosis, Proc. Natl. Acad. Sci. USA 93: 2239–2244.PubMedCrossRefGoogle Scholar
  73. Vaux, D. L., Weissman, I. L., and Kim, S. K., 1992, Prevention of programmed cell death in Caenorhabditis elegans by human bel-2, Science 258: 1955–1957.PubMedCrossRefGoogle Scholar
  74. Vaux, D. L., Hacker, G., and Strasser, A., 1994, An evolutionary perspective on apoptosis, Cell 76: 777–779.PubMedCrossRefGoogle Scholar
  75. Walker, N. I., Harmon, B. V., Gobe, G. C., and Kerr, J. F. R., 1988, Patterns of cell death, Methods Achiev. Exp. Pathol. 13: 18–54.PubMedGoogle Scholar
  76. White, K., Grether, M. E., Abrams, J. M., Young, L., Farrell, K., and Steller, H., 1994, Genetic control of programmed cell death in Drosophila, Science 264: 677–683.PubMedCrossRefGoogle Scholar
  77. White, K., Tahaoglu, E., and Steller, H., 1996, Cell killing by the Drosophila gene reaper, Science 271: 805–807.PubMedCrossRefGoogle Scholar
  78. Williams, G. T., and Smith, C. A., 1993, Molecular regulation of apoptosis: Genetic controls on cell death, Cell 74: 777–779.PubMedCrossRefGoogle Scholar
  79. Wolff, T., and Ready, D. F., 1991, Cell death in normal and rough eye mutants of Drosophila, Development 113: 825–839.PubMedGoogle Scholar
  80. Xue, D., and Horvitz, H. R., 1995, Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein, Nature 377: 248–251.PubMedCrossRefGoogle Scholar
  81. Yuan, J., and Horvitz, H. R., 1992, The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death, Development 116: 309–320.PubMedGoogle Scholar
  82. Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M., and Horvitz, H. R., 1993, The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-lbeta-converting enzyme, Cell 75: 641–652.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Rollie J. Clem
    • 1
  1. 1.Department of Molecular Microbiology and ImmunologyThe Johns Hopkins School of Hygiene and Public HealthBaltimoreUSA

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