The ATP Switch in Apoptosis

  • David J. McConkey


As a result of the work outlined above and other studies, a clear-cut distinction between apoptosis and necrosis no longer exists at the biochemical level. The strongest evidence for overlap comes from studies in models of hypoxia showing that over-expression of Bcl2 or its homolog Bcl-xL can block necrosis. The effects of Bcl2 appear largely due to direct effects on mitochondria, including stabilization of membrane potential, preservation of ATP production, prevention of oxidative stress, and enhanced Ca2+ uptake. In addition, Bcl2 may exert similar effects on the ER and the nucleus by regulating Ca2+ and GSH fluxes. If Bcl2 is not linked solely to suppression of apoptosis, what molecular distinctions between apoptosis and necrosis are we left with? A particularly attractive conclusion is that apoptosis requires caspases whereas necrosis does not (Hirsch et al., 1997). This would explain the ATP requirement for apoptosis, because Apaf-1-mediated activation of caspase-9-requires ATP hydrolysis (Li et al., 1997), and oxidation of the caspase active site cysteine would explain why excessive oxidative stress or thiol depletion inhibit apoptosis and lead to necrosis. It should be noted, however, that viral caspase inhibitors (such as the cowpox virus crmA protein) can partially attenuate necrosis that is due to chemical hypoxia (Shimizu et al., 1996a, 1996b). Further work is needed to directly examine the activation status of particular caspases in additional models of necrosis.


Programme Cell Death Mitochondrial Permeability Transition Necrotic Cell Death Mitochondrial Transmembrane Potential Buthionine Sulfoximine 
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  1. Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., and Nicotera, P., 1995, Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function, Neuron 15:961–973.CrossRefPubMedGoogle Scholar
  2. Backway, K. L., McCulloch, E. A., Chow, S., and Hedley, D. W, 1997, Relationships between the mitochondrial permeability transition and oxidative stress during ara-C toxicity, Cancer Res. 57:2446–2451.PubMedGoogle Scholar
  3. Baffy, G., Miyashita, T., Williamson, J. R., and Reed, J. C., 1993, Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced BCL-2 oncoprotein production, J. Biol. Chem. 268:6511–6519.PubMedGoogle Scholar
  4. Baker, A., Payne, C. M., Briehl, M. M., and Powis, G., 1997, Thioredoxin, a gene found overexpressed in human cancer, inhibits apoptosis in vitro and in vivo. Cancer Res. 57:5162–5167.PubMedGoogle Scholar
  5. Bojes, H. K., Datta, K., Xu, J., Chin, A., Simonian, P., Nunez, G., and Kehrer, J. P., 1997, BCL-XL overexpression attenuates glutathione depletion in FL5.12 cells following interleukin-3 withdrawal, Biochem. J. 325:315–319.PubMedGoogle Scholar
  6. Bonfoco, E., Kraine, D., Ankarcrona, M., Nicotera, P., and Lipton, S. A., 1995, Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intenseinsults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures, Proc: Natl. Acad. Sci. USA 92:7162–7166.Google Scholar
  7. Chinnaiyan, A. M., O’Rourke, K., Lane, B. R., and Dixit, V. M., 1997, Interaction of ced-4 with ced-3 and ced-9: A molecular framework for cell death, Science 275:1122–1126.CrossRefPubMedGoogle Scholar
  8. Clement, M. V, and Stamenkovic, I., 1996, Superoxide anion is a natural inhibitor of Fas-mediated cell death, EMBOJ. 15:216–225.Google Scholar
  9. Cohen, G. M., 1997, Caspases: The executioners of apoptosis, Biochem. J. 326:1–16.PubMedGoogle Scholar
  10. Cohen, J. J., and Duke, R. C., 1984, Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death, J. Immunol. 132:38–42.PubMedGoogle Scholar
  11. Dong, Z., Saikumar, P., Weinberg, J. M., and Venkatachalam, M. A., 1997, Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death, Am. J. Pathol. 151:1205–1213.PubMedGoogle Scholar
  12. Dybukt, J. M., Ankarcrona, M., Burkitt, M., Sjoholm, A., Strom, K.., Orrenius, S., and Nicotera, P., 1994, Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINmSF cells. The role of intracellular polyamines, J. Biol. Chem. 269:30553–30560.Google Scholar
  13. Eguchi, Y., Shimizu, S., and Tsujimoto, Y., 1997, Intracellular ATP levels determine cell death fate by apoptosis or necrosis, Cancer Res. 57:1835–1840.PubMedGoogle Scholar
  14. Ellis, H. M., and Horvitz, H. R., 1986, Genetic control of programmed cell death in the nematode C. elegans, Cell, 44:817–829.Google Scholar
  15. Fadok, V. A., Voelker, D. R., Campbell, P. A., Cohen, J. J., Bratton, D. L., and Henson, P. M., 1992, Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages, J. Immunol. 148:2207–2216.PubMedGoogle Scholar
  16. Fernandes, R. S., and Cotter, T. G., 1994, Apoptosis or necrosis: Intracellular levels of glutathione influence the mode of cell death, Biochem. Pharmacol. 48:675–681.CrossRefPubMedGoogle Scholar
  17. Fernandez, A., Kiefer, J., Fosdick, L., and McConkey, D. J., 1995, Oxygen radical production and thiol depletion are required for Ca2+-mediated endogenous endonuclease activation in apoptotic thymocytes, J. Immunol. 155:5133–5139.PubMedGoogle Scholar
  18. Friesen, C., Herr, I., Krammer, P. H., and Debatin, K. M., 1996, Involvement of the CD95(APO-1/Fas) receptor/ligand system in drug-inducedapoptosis in leukemia cells, Nature Medicine 2:574–577.CrossRefPubMedGoogle Scholar
  19. Gaal, J. C., Smith, K. R., and Pearson, C. K., 1987, Cellular euthanasia mediated by a nuclear enzyme: A central role for nuclear ADP-riboxylation in cellular metabolism, Trends Biochem. Sci. 12:129–130.CrossRefGoogle Scholar
  20. Hampton, M. B., and Orrenius, S., 1997, Dual regulation of caspase activity by hydrogen peroxide: Implications for apoptosis, FEBS Lett. 414:552–556.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. Hengartner, M. O., and Horvitz, H. R., 1994a, C. elegans cell survival gene ced-9 encodes a functional homolog of mammalian proto-oncogene bcl-2, Cell 76:665–676.CrossRefPubMedGoogle Scholar
  23. Hengartner, M. O., and Horvitz, H. R., 1994b, Programmed cell death in Caenorhabditis elegans. Curr. Opin. Genet. Dev. 4:581–586.Google Scholar
  24. Herzenberg, L. A., Rosa, S. C. D., Dubs, J. G., Roederer, M., Anderson, M. T., Ela, S. W., Deresinski, S. C., and Herzenberg, L. A., 1997, Glutathione deficiency is associated with impaired survival in HIV disease, Proc. Natl. Acad. Sci. USA 94:1967–1972.CrossRefPubMedGoogle Scholar
  25. Hirsch, T., Marchetti, P., Susin, S. A., Dallaporta, B., Zamzami, N., Marzo, I., Beuskens, M., and Kroemer, G., 1997, The apoptosis-necrosis paradox: Apoptogenic proteases activated after the mitochondrial permeability transition determine the mode of cell death, Oncogene 15:1573–1581.CrossRefPubMedGoogle Scholar
  26. Hockenbery, D. M., Nunez, G., Milliman, C., Schreiber, R. D., and Korsmeyer, S. J., 1990, BCL-2 is an inner mitochondrial membrane protein that blocks programmed cell death, Nature 348:334–336.CrossRefPubMedGoogle Scholar
  27. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L., and Korsmeyer, S. J., 1993, BCL-2 functions in an antioxidant pathway to prevent apoptosis, Cell 75:241–251.CrossRefPubMedGoogle Scholar
  28. Israel, N., and Gougerot-Pocidalo, M. A., 1997, Oxidative stress in human immunodeficiency virus infection, Cell Mol. Life Sci. 53:864–870.PubMedGoogle Scholar
  29. Jones, D. P., McConkey, D. J., Nicotera, P., and Orrenius, S., 1989, Calcium-activated DNA fragmentation in rat liver nuclei, J Biol. Chem. 264:6398–6403.PubMedGoogle Scholar
  30. Kane, D. J., Sarafian, T. A., Anton, R., Hahn, H., Gralla, E. B., Valentine, J. S., Ord, T., and Bredesen, D. E., 1993, BCL-2 inhibition of neural death: Decreased generation of reactive oxygen species, Science 262:1274–1277.PubMedGoogle Scholar
  31. Kazzaz, J. A., Xu, J., Palaia, T. A., Mantell, L., Fein, A. M., and Horowitz, S., 1996, Cellular oxygen toxicity: Oxidant injury without apoptosis, J. Biol. Chem 271:15182–15186.PubMedGoogle Scholar
  32. Kerr, J. F. R., Wyllie, A. H., and Currie, A. R., 1972, Apoptosis: A basic biological phenomenon with wideranging implications in tissue kinetics, Br. J. Cancer 26:239–257.PubMedGoogle Scholar
  33. Kim, Y. M., Talanian, R. V., and Billiar, T. R., 1997, Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms, J. Biol. Chem. 272:31138–31148.PubMedGoogle Scholar
  34. Kluck, R. M., Bossy-Wetzel, E., Green, D. R., and Newmeyer, D. D., 1997, The release of cytochrome c from mitochondria: A primary site for bcl-2 regulation of apoptosis, Science 275:1132–1136.CrossRefPubMedGoogle Scholar
  35. Kroemer, G., Zamzami, N., and Susin, S. A., 1997, Mitochondrial control of apoptosis, Immunol. Today 18:44–52.CrossRefPubMedGoogle Scholar
  36. Lam, M., Dubyak, G., and Distelhorst, C. W., 1993, Effect of glucocorticoid treatment on intraccllular calcium homeostasis in mouse lymphoma cells, Mol. Endocrinol. 7:686–693.CrossRefPubMedGoogle Scholar
  37. Lam, M., Dubyak, G., Chen, L., Nunez, G., Miesfeld, R. L., and Distelhorst, C. W., 1994, Evidence that bcl-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes, Proc. Natl. Acad. Sci. USA 91:6569–6573.PubMedGoogle Scholar
  38. Laster, S. M., Wood, J. G., and Gooding, L. R., 1988, Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis, J. Immunol. 141:2629–2634.PubMedGoogle Scholar
  39. Leist, M., Single, B., Castoldi, A. F., Kuhnle, S., and Nicotera, P., 1997, Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis, J. Exp. Med. 185:1484–1486.CrossRefGoogle Scholar
  40. Lelli, J. L., Becks, L. L., Dabrowska, M. I., and Hinshaw, D. B., 1998, ATP converts necrosis to apoptosis in oxidant-injured endothelial cells, Free Radical Biol. Med. 25:694–702.Google Scholar
  41. Lemasters, J. J., DiGuiseppi, J., Nieminen, A.-L., and Herman, B., 1987, Blebbing, free Ca2+ and mitochondrial membrane potential preceding cell death in hepatocytes, Nature 325:78–81.CrossRefPubMedGoogle Scholar
  42. Lennon, S. V., Martin, S. J., and Cotter, T. G., 1991, Dose-dependent induction of apoptosis in human tumour cell lines by widely divergent stimuli, Cell Prolif. 24:203–204.PubMedGoogle Scholar
  43. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X., 1997, Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell 91:479–489.CrossRefPubMedGoogle Scholar
  44. Lieberthal, W., Menza, S. A., and Levine, J. S., 1998, Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells, Am. J. Physiol. 274:F315–F327.PubMedGoogle Scholar
  45. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., 1996, Induction of the apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c., Cell 86:147–157.PubMedGoogle Scholar
  46. Lockshin, R. A., 1969, Programmed cell death: Activation of lysis by a mechanism involving the synthesis of protein, J. Insect Physiol. 15:1505–1516.CrossRefPubMedGoogle Scholar
  47. Macho, A., Hirsch, T., Marzo, I., Marchetti, P., Dallaporta, B., Susin, S. A., Zamzami, N., and Kroemer, G., 1997, Glutathione depletion is an early, and calcium elevation is a late, event of thymocyte apoptosis, J. Immunol. 158:4612–4619.PubMedGoogle Scholar
  48. Marin, M. C., Fernandez, A., Bick, R. J., Brisbay, S., Buja, M., Snuggs, M., McConkey, D. J., Eschenbach, A. C. V., Keating, M. J., and McDonnell, T. J., 1996, Apoptosis suppression by Bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+, Oncogene 12:2259–2266.PubMedGoogle Scholar
  49. Mayer, M., and Noble, M., 1994, N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro, Proc. Natl. Acad. Sci. USA 91:7496–7500.PubMedGoogle Scholar
  50. McCall, K., and Steller, H., 1997, Facing death in the fly: Genetic analysis of apoptosis in Drosophila, Trends Genet. 13:222–226.CrossRefPubMedGoogle Scholar
  51. McConkey, D. J., and Orrenius, S., 1996a, The role of calcium in the regulation of apoptosis, J. Leukocyte Biol. 59:775–783.PubMedGoogle Scholar
  52. McConkey, D. J., and Orrenius, S., 1996b, Signal transduction pathways in apoptosis, Stem Cell 14:619–631.Google Scholar
  53. McConkey, D. J., Hartzell, P., Nicotera, P., Wyllie, A. H., and Orrenius, S., 1988, Stimulation of endogenous endonuclease activity in hepatocytes exposed to oxidative stress, Toxicol. Lett. 42:123–130.CrossRefPubMedGoogle Scholar
  54. McConkey, D. J., Hartzell, P., Nicotera, P., and Orrenius, S.,1989, Calcium-activated DNA fragmentation kills immature thymocytes, FASEB J. 3:1843–1849.Google Scholar
  55. Meikrantz, W., Gisselbrecht, S., Tam, S. W., and Schlegel, R., 1994, Activation of cyclin A-dependent protein kinases during apoptosis, Proc. Natl. Acad. Sci. USA 91:3754–3758.PubMedGoogle Scholar
  56. Messmer, U. K., and Brune, B., 1996, Nitric oxide (NO) in apoptotic versus necrotic RAW 264.7 macrophage cell death: The role of NO-donor exposure, NAD+ content, and p53 accumulation, Arch. Biochem. Biophys. 327:1–10.PubMedGoogle Scholar
  57. Mirkovic, N., Voehringer, D. W., Story, M. D., McConkey, D. J., McDonnell, T. J., and Meyn, R. E., 1997, Resistance to radiation-induced apoptosis in BCL-2-expressing cells is reversed by depleting cellular thiols, Oncogene 15:1461–1470.CrossRefPubMedGoogle Scholar
  58. Murphy, A. N., Bredesen, D. E., Cortopassi, G., Wang, E., and Fiskum, G., 1996, BCL-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria, Proc. Natl. Acad. Sci. USA 93:9893–9898.PubMedGoogle Scholar
  59. Orrenius, S., McConkey, D. J., Bellomo, G., and Nicotera, P., 1989, Role of Ca2+ in toxic cell killing, Trends Pharmacol. Sci. 10:281–285.CrossRefPubMedGoogle Scholar
  60. Pastorino, J. G., Simbula, G., Yamamoto, K., Glascott, P. A., Rothman, R. J., and Farber, J. L., 1996, The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition, J. Biol. Chem. 271:29792–29798.PubMedGoogle Scholar
  61. Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., and Vogelstein, B. A., 1997, A model for p53-induced apoptosis, Nature 389:300–305.CrossRefPubMedGoogle Scholar
  62. Reed, J. C., 1997, Double identity for proteins of the BCL-2 family, Nature 387:773–776.CrossRefPubMedGoogle Scholar
  63. Richter, C., 1993, Pro-oxidants and mitochondrial Ca2+: Their relationship to apoptosis and oncogenesis, FEBS Lett. 325:104–107.CrossRefPubMedGoogle Scholar
  64. Sata, N., Klonowski-Stumpe, H., Han, B., Haussinger, D., and Niederau, C., 1997, Menadione induces both necrosis and apoptosis in rat pancreatic acinar AR4-2J cells, Free Radical Biol. Med. 23:844–850.CrossRefGoogle Scholar
  65. Sato, N., Iwata, S., Nakamura, K., Hori, T., Mori, K., and Yodoi, J., 1995, Thiol-mediated redox regulation of apoptosis: Possible roles of cellular thiols other than glutathione in T cell apoptosis, J. Immunol. 154:3194–3203.PubMedGoogle Scholar
  66. Savill, J., Fadok, V., Henson, P., and Haslett, C., 1993, Phagocytic recognition of cells undergoing apoptosis, Immunol. Today 14:131–136.CrossRefPubMedGoogle Scholar
  67. Schwartz, L. M., and Truman, J. W., 1982, Peptide and steroid regulation of muscle degeneration in an insect, Science 215:1420–1424PubMedGoogle Scholar
  68. Shimizu, S., Eguchi, Y., Kamiike, W., Wuguri, S., Uchiyama, Y., Matsuda, H., and Tsujimoto, Y., 1996a, BCL-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors, Oncogene 13:21–29.PubMedGoogle Scholar
  69. Shimizu, S., Eguchi, Y., Kamiike, W., Waguri, S., Uchiyama, Y., Matsuda, H., and Tsujimoto, Y., 1996b, Retardation of chemical hypoxia-induccd necrotic cell death by BCL-2 and ICE inhibitors: Possible involvement of common mediators in apoptotic and necrotic signal transductions, Oncogene 12:2045–2050.PubMedGoogle Scholar
  70. Slater, A. F., Nobel, C. S., Maellaro, E., Bustamante, J., Kimland, M., and Orrenius, S., 1995, Nitrone spin traps and a nitroxide antioxidant inhibit a common pathway of thymocyte apoptosis, Biochem. J. 306:771–778.PubMedGoogle Scholar
  71. Squier, M. K. T., Miller, A. C. K.., Malkinson, A. M., and Cohen, J. J., 1994, Calpain activation in apoptosis, J. Cell Physiol. 159:229–237.CrossRefPubMedGoogle Scholar
  72. Tata, J. R., 1966, Requirement for RNA and protein synthesis for induced regression of the tadpole tail in organ culture, Dev. Biol. 13:77–94.CrossRefPubMedGoogle Scholar
  73. Thompson, C. B., 1995, Apoptosis in the pathogenesis and treatment of disease, Science 267:1456–1462.PubMedGoogle Scholar
  74. Thor, H., Smith, M. T., Hartzell, P., Bellomo, G., Jewell, S. A., and Orrenius, S., 1982, The metabolism of menadione (2-methyl-l, 4-naphthoquinone) by isolated hepatocytes, J. Biol. Chem. 257:12419–12425.PubMedGoogle Scholar
  75. Thornberry, N. A., Bull, H. G., Calaycay, J. R., Chapman, K. T., Howard, A. D., Kostura, M. J., Miller, D. K., Molineaux, S. M., Weidner, J. R., Aunins, J., Elliston, K. O., Ayala, J. M., Casano, F. J., Chin, J., Ding, G. J., Egger, L. A., Gaffney, E. P., Limjuco, G., Pahlha, O. C., Raju, S. M., Rolando, A. M., Salley, J. P., Yamin, T. T., Lee, T. D., Shively, J. E., MacCross, M., Mumford, R. A., Schmidt, J. A., and Tocci, M. J., 1992, A novel heterodimeric cysteine protease is required for interleukin-lb processing in monocytes, Nature 356:768–774.CrossRefPubMedGoogle Scholar
  76. Tyurina, Y. Y, Tyurina, V A., Carta, G., Quinn, P. J., Schor, N. F., and Kagan, V. E., 1997, Direct evidence for antioxidant effect of BCL-2 in PC 12 rat pheochromocytoma cells, Arch. Biochem. Biophys. 344:413–123.CrossRefPubMedGoogle Scholar
  77. Vanderbilt, J. N., Bloom, K. S., and Anderson, J. N., 1982, Endogenous nuclease: Properties and effects on transcribed genes in chromatin, J. Biol. Chem. 257:13009–13017.PubMedGoogle Scholar
  78. Vaux, D. L., Weissman, I. L., and Kim, S. K., 1992, Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 258:1955–1957.PubMedGoogle Scholar
  79. Voehringer, D., McConkey, D. J., McDonnell, T, Brisbay, S., and Meyn, R. E., 1998, BCL-2 causes redistribution of glutathione to the nucleus, tProc. Natl. Acad. Sci. USA 95:2956–2960.Google Scholar
  80. Waters, S. L., Sarang, S. S., Wang, K. K. W., and Schnellmann, R. G., 1997, Calpains mediate calcium and chloride influx during the late phase of cell injury, J. Pharmacol. Exp. Ther. 283:1177–1184.PubMedGoogle Scholar
  81. Weil, M., Jacobson, M. D., Coles, H. S. R., Davies, T. J., Gardner, R. L., Raff, K. D., and Raff, M. C., 1996, Constitutive expression of the machinery for programmed cell death, J. Cell Biol. 133:1053–1059.CrossRefPubMedGoogle Scholar
  82. Williams, G. T., Smith, C. A., Spooncer, E., Dexter, T. M., and Taylor, D. R., 1990, Hacrnopoietic colony stimulating factors promote cell survival by suppressing apoptosis, Nature 343:76–79.PubMedGoogle Scholar
  83. Wu, D., Wallen, H. D., and Nunez, G., 1997, Interaction and regulation of subcellular localization of ced-4 by ced-9, Science 275:1126–1129.CrossRefPubMedGoogle Scholar
  84. Wyllie, A. H., 1980a, Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonucleasc activation, Nature 284:555–556.CrossRefPubMedGoogle Scholar
  85. Wyllie, A. H., Kerr, J. F. R., and Currie, A. R., 1980b, Cell death: The significance of apoptosts, Int. Rev. Cytol. 68:251–305.PubMedGoogle Scholar
  86. Wyllie, A. H., Morris, R. G., Smith, A. L., and Dunlop, D., 1984, Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis, J. Pathol. 142:67–77.CrossRefPubMedGoogle Scholar
  87. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, I). P., and Wang, X., 1997, Prevention of apoptosis by bcl-2: Release of cytochrome c from mitochondria blocked. Science 275:1129–1132.CrossRefPubMedGoogle Scholar
  88. Yuan, J., Shaham, S., Ledoux, S., Eills, H. M., and Horvitz, H. R., 1993, The C elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-lb-convcrting enzyme. Cell 75:641–652.CrossRefPubMedGoogle Scholar
  89. Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T, Susin, S. A., Petit, P. X., Mignotte, B., and Kroemer, G., 1995, Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death, J. Exp. Med. 182:367–377.CrossRefPubMedGoogle Scholar
  90. Zou, H., Henzel, W. J., Liu, X., Lutschg, A., and Wang, X., 1997, Apaf-1, a human protein homologous to C. elegans ced-4, participates in cytochrome c-dependent activation of caspasc-3, Cell 90:405–413.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • David J. McConkey
    • 1
  1. 1.Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, and Program in ToxicologyUniversity of Texas-Houston Graduate School of Biomedical SciencesHouston

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