Journal of Clinical Immunology

, Volume 19, Issue 6, pp 365–377 | Cite as

A Portrait of the Bcl-2 Protein Family: Life, Death, and the Whole Picture

  • Marc Pellegrini
  • Andreas Strasser


The Bcl-2 family of proteins are important regulators of cell death. They are comprised of two opposing factions, the proapoptotic versus the antiapoptotic members. Both are required for normal development and cellular homeostasis of the immune system and other tissues. However, in certain circumstances they may participate in the development of disease.

Bcl-2 family of proteins apoptosis cancer autoimmunity infection 


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  1. 1.
    Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257, 1972Google Scholar
  2. 2.
    Raff MC: Social controls on cell survival and cell death. Nature 356:397–400, 1992Google Scholar
  3. 3.
    Vaux DL, Korsmeyer SJ: Cell death in development. Cell 96:245–254, 1999Google Scholar
  4. 4.
    Vaux DL, Haecker G, Strasser A: An evolutionary perspective on apoptosis. Cell 76:777–779, 1994Google Scholar
  5. 5.
    Barr PJ, Tomei LD: Apoptosis and its role in human disease. Biotechnology (NY) 12:487–493, 1994Google Scholar
  6. 6.
    Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462, 1995Google Scholar
  7. 7.
    Strasser A, Huang DC, Vaux DL: The role of the bcl-2/ced-9 gene family in cancer and general implications of defects in cell death control for tumourigenesis and resistance to chemotherapy. Biochim Biophys Acta 1333:F151-F178, 1997Google Scholar
  8. 8.
    Thornberry NA, Lazebnik Y: Caspases: Enemies within. Science 281:1312–1316, 1998Google Scholar
  9. 9.
    Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S: A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50, 1998Google Scholar
  10. 10.
    Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L: Granzyme B directly and efficiently cleaves several downstream caspase substrates: Implications for CTL-induced apoptosis. Immunity 8:451–460, 1998Google Scholar
  11. 11.
    Scaffidi C, Kirchhoff S, Krammer PH, Peter ME: Apoptosis signaling in lymphocytes. Curr Opin Immunol 11:277–285, 1999Google Scholar
  12. 12.
    Ashkenazi A, Dixit VM: Death receptors: Signaling and modulation. Science 281:1305–1308, 1998Google Scholar
  13. 13.
    Smith CA, Farrah T, Goodwin RG: The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death. Cell 76:959–962, 1994Google Scholar
  14. 14.
    Nagata S: Apoptosis by death factor. Cell 88:355–365, 1997Google Scholar
  15. 15.
    Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM: FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512, 1995Google Scholar
  16. 16.
    Hsu H, Xiong J, Goeddel DV: The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell 81:495–504, 1995Google Scholar
  17. 17.
    Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D: A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798, 1995Google Scholar
  18. 18.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D: Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 85:803–815, 1996Google Scholar
  19. 19.
    Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, et al.: FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827, 1996Google Scholar
  20. 20.
    Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM: An induced proximity model for caspase-8 activation. J Biol Chem 273:2926–2930, 1998Google Scholar
  21. 21.
    Martin DA, Siegel RM, Zheng L, Lenardo MJ: Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHα1) death signal. J Biol Chem 273:4345–4349, 1998Google Scholar
  22. 22.
    Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, et al.: Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352, 1998Google Scholar
  23. 23.
    Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, et al.: Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337, 1998Google Scholar
  24. 24.
    Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, et al.: Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739–750, 1998Google Scholar
  25. 25.
    Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P: Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:727–737, 1998Google Scholar
  26. 26.
    Strasser A, Harris AW, Huang DC, Krammer PH, Cory S: Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J 14:6136–6147, 1995Google Scholar
  27. 27.
    Memon SA, Moreno MB, Petrak D, Zacharchuk CM: Bcl-2 blocks glucocorticoid-but not Fas-or activation-induced apoptosis in a T cell hybridoma. J Immunol 155:4644–4652, 1995Google Scholar
  28. 28.
    Huang DC, Cory S, Strasser A: Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. Oncogene 14:405–414, 1997Google Scholar
  29. 29.
    Wallach D, Kovalenko AV, Varfolomeev EE, Boldin MP: Death-inducing functions of ligands of the tumor necrosis factor family: A Sanhedrin verdict. Curr Opin Immunol 10:279–288, 1998Google Scholar
  30. 30.
    Tartaglia LA, Goeddel DV: Tumor necrosis factor receptor signaling. A dominant negative mutation suppresses the activation of the 55-kDa tumor necrosis factor receptor. J Biol Chem 267:4304–4307, 1992Google Scholar
  31. 31.
    Malinin NL, Boldin MP, Kovalenko AV, Wallach D: MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 385:540–544, 1997Google Scholar
  32. 32.
    Yin Foo S, Nolan GP: NF-κB to the rescue: RELs, apoptosis and cellular transformation. Trends Genet 15:229–235, 1999Google Scholar
  33. 33.
    Zhang J, Cado D, Chen A, Kabra NH, Winoto A: Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392:296–300, 1998Google Scholar
  34. 34.
    Newton K, Harris AW, Bath ML, Smith KGC, Strasser A: A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J 17:706–718, 1998Google Scholar
  35. 35.
    Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, et al.: FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279:1954–1958, 1998Google Scholar
  36. 36.
    Smith KG, Strasser A, Vaux DL: CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J 15:5167–5176, 1996Google Scholar
  37. 37.
    Chinnaiyan AM, Orth K, O'Rourke K, Duan H, Poirier GG, Dixit VM: Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. J Biol Chem 271:4573–4576, 1996Google Scholar
  38. 38.
    Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, et al.: Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apol, and DR3 and is lethal prenatally. Immunity 9:267–276, 1998Google Scholar
  39. 39.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T: p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849, 1993Google Scholar
  40. 40.
    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, et al.: Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852, 1993Google Scholar
  41. 41.
    Clarke AR, Gledhill S, Hooper ML, Bird CC, Wyllie AH: p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following γ-irradiation. Oncogene 9:1767–1773, 1994Google Scholar
  42. 42.
    Strasser A, Harris AW, Jacks T, Cory S: DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329–339, 1994Google Scholar
  43. 43.
    Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299, 1995Google Scholar
  44. 44.
    McCurrach ME, Connor TM, Knudson CM, Korsmeyer SJ, Lowe SW: bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci USA 94:2345–2349, 1997Google Scholar
  45. 45.
    Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T: Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385:637–640, 1997Google Scholar
  46. 46.
    Soengas MS, Alarcon RM, Yoshida H, Giaccia AJ, Hakem R, Mak TW, et al.: Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 284:156–159, 1999Google Scholar
  47. 47.
    Miyashita T, Reed JC: bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 52:5407–5411, 1992Google Scholar
  48. 48.
    Adams JM, Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science 281:1322–1326, 1998Google Scholar
  49. 49.
    Tsujimoto Y, Cossman J, Jaffe E, Croce CM: Involvement of the bcl-2 gene in human follicular lymphoma. Science 228:1440–1443, 1985Google Scholar
  50. 50.
    Vaux DL, Cory S, Adams JM: Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442, 1988Google Scholar
  51. 51.
    Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, et al.: bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597–608, 1993Google Scholar
  52. 52.
    Gibson L, Holmgreen SP, Huang DC, Bernard O, Copeland NG, Jenkins NA, et al.: bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 13:665–675, 1996Google Scholar
  53. 53.
    Song Q, Kuang Y, Dixit VM, Vincenz C: Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J 18:167–178, 1999Google Scholar
  54. 54.
    Lin EY, Orlofsky A, Wang HG, Reed JC, Prystowsky MB: A1, a Bcl-2 family member, prolongs cell survival and permits myeloid differentiation. Blood 87:983–992, 1996Google Scholar
  55. 55.
    Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW: MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to bcl-2. Proc Natl Acad Sci USA 90:3516–3520, 1993Google Scholar
  56. 56.
    Chao DT, Linette GP, Boise LH, White LS, Thompson CB, Korsmeyer SJ: Bcl-xL and Bcl-2 repress a common pathway of cell death. J Exp Med 182:821–828, 1995Google Scholar
  57. 57.
    Zhou P, Qian L, Bieszczad CK, Noelle R, Binder M, Levy NB, et al.: Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92:3226–3239, 1998Google Scholar
  58. 58.
    Grillot DA, Merino R, Nunez G: Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J Exp Med 182:1973–1983, 1995Google Scholar
  59. 59.
    Strasser A, Harris AW, Cory S: bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67:889–899, 1991Google Scholar
  60. 60.
    Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ: bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67:879–888, 1991Google Scholar
  61. 61.
    Nguyen M, Millar DG, Yong VW, Korsmeyer SJ, Shore GC: Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J Biol Chem 268:25265–25268, 1993Google Scholar
  62. 62.
    Lithgow T, van Driel R, Bertram JF, Strasser A: The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Different 5:411–417, 1994Google Scholar
  63. 63.
    Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W, Reed JC: Investigation of the subcellular distribution of the Bcl-2 oncoprotein: Residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 53:4701–4714, 1993Google Scholar
  64. 64.
    Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619, 1993Google Scholar
  65. 65.
    Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, et al.: Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374:733–736, 1995Google Scholar
  66. 66.
    Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, et al.: Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature 374:736–739, 1995Google Scholar
  67. 67.
    Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, et al.: Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature 374:731–733, 1995Google Scholar
  68. 68.
    Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ: Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc Natl Acad Sci USA 94:12401–12406, 1997Google Scholar
  69. 69.
    Inohara N, Ekhterae D, Garcia I, Carrio R, Merino J, Merry A, et al.: Mtd, a novel Bcl-2 family member activates apoptosis in the absence of heterodimerization with Bcl-2 and Bcl-xL. J Biol Chem 273:8705–8710, 1998Google Scholar
  70. 70.
    Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ: Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291, 1995Google Scholar
  71. 71.
    Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ, et al.: Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11:1921–1928, 1995Google Scholar
  72. 72.
    Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ: BID: A novel BH3 domain-only death agonist. Genes Dev 10:2859–2869, 1996Google Scholar
  73. 73.
    Inohara N, Ding L, Chen S, Nunez G: Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16:1686–1694, 1997Google Scholar
  74. 74.
    Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M: Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 272:18842–18848, 1997Google Scholar
  75. 75.
    Hegde R, Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES: Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J Biol Chem 273:7783–7786, 1998Google Scholar
  76. 76.
    O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, et al.: Bim: A novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17:384–395, 1998Google Scholar
  77. 77.
    Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, et al.: A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 14:5589–5596, 1995Google Scholar
  78. 78.
    Kelekar A, Thompson CB: Bcl-2-family proteins: The role of the BH3 domain in apoptosis. Trends Cell Biol 8:324–330, 1998Google Scholar
  79. 79.
    Hsu YT, Youle RJ: Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 273:10777–10783, 1998Google Scholar
  80. 80.
    Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ: Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292, 1997Google Scholar
  81. 81.
    Hsu YT, Wolter KG, Youle RJ: Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA 94:3668–3672, 1997Google Scholar
  82. 82.
    Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A: The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296, 1999Google Scholar
  83. 83.
    Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ: BH3 domain of BAD is required for heterodimerization with BCL-xL and pro-apoptotic activity. J Biol Chem 272:24101–24104, 1997Google Scholar
  84. 84.
    Oltvai ZN, Korsmeyer SJ: Checkpoints of dueling dimers foil death wishes. Cell 79:189–192, 1994Google Scholar
  85. 85.
    Yin XM, Oltvai ZN, Korsmeyer SJ: BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323, 1994Google Scholar
  86. 86.
    Hu Y, Benedict MA, Wu D, Inohara N, Nunez G: Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 95:4386–4391, 1998Google Scholar
  87. 87.
    Pan G, O'Rourke K, Dixit VM: Caspase-9, Bcl-xL, and Apaf-1 form a ternary complex. J Biol Chem 273:5841–5845, 1998Google Scholar
  88. 88.
    Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM: Interaction of CED-4 with CED-3 and CED-9: A molecular framework for cell death. Science 275:1122–1126, 1997Google Scholar
  89. 89.
    Martinou JC: Apoptosis. Key to the mitochondrial gate. Nature 399:411–412, 1999Google Scholar
  90. 90.
    Green DR, Reed JC: Mitochondria and apoptosis. Science 281:1309–1312, 1998Google Scholar
  91. 91.
    Spector MS, Desnoyers S, Hoeppner DJ, Hengartner MO: Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature 385:653–656, 1997Google Scholar
  92. 92.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X: Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490, 1998Google Scholar
  93. 93.
    Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, et al.: Bcl-xL forms an ion channel in synthetic lipid membranes. Nature 385:353–357, 1997Google Scholar
  94. 94.
    Shimizu S, Narita M, Tsujimoto Y: Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487, 1999Google Scholar
  95. 95.
    Mannella CA: Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications. J Struct Biol 121:207–218, 1998Google Scholar
  96. 96.
    Colombini M, Blachly-Dyson E, Forte M: Ion Channels. New York, Plenum Press, 1996Google Scholar
  97. 97.
    Hengartner MO: Apoptosis. Death cycle and Swiss army knives. Nature 391:441–442, 1998Google Scholar
  98. 98.
    Raff M: Cell suicide for beginners. Nature 396:119–122, 1998Google Scholar
  99. 99.
    Li H, Zhu H, Xu CJ, Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501, 1998Google Scholar
  100. 100.
    von Freeden-Jeffry U, Solvason N, Howard M, Murray R: The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7:147–154, 1997Google Scholar
  101. 101.
    Maraskovsky E, O'Reilly LA, Teepe M, Corcoran LM, Peschon JJ, Strasser A: Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/-mice. Cell 89:1011–1019, 1997Google Scholar
  102. 102.
    Lagasse E, Weissman IL: Enforced expression of Bcl-2 in monocytes rescues macrophages and partially reverses osteopetrosis in op/op mice. Cell 89:1021–1031, 1997Google Scholar
  103. 103.
    Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL: Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89:1033–1041, 1997Google Scholar
  104. 104.
    Iwahashi H, Hanafusa T, Eguchi Y, Nakajima H, Miyagawa J, Itoh N, et al.: Cytokine-induced apoptotic cell death in a mouse pancreatic β-cell line: inhibition by Bcl-2. Diabetologia 39:530–536, 1996Google Scholar
  105. 105.
    Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ: Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3–3 not Bcl-xL. Cell 87:619–628, 1996Google Scholar
  106. 106.
    Cory S, Harris AW, Strasser A: Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells. Philos Trans R Soc Lond B Biol Sci 345:289–295, 1994Google Scholar
  107. 107.
    McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al.: bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88, 1989Google Scholar
  108. 108.
    Yang E, Korsmeyer SJ: Molecular thanatopsis: A discourse on the BCL2 family and cell death. Blood 88:386–401, 1996Google Scholar
  109. 109.
    Chao DT, Korsmeyer SJ: BCL-2 family: Regulators of cell death. Annu Rev Immunol 16:395–419, 1998Google Scholar
  110. 110.
    Print CG, Loveland KL, Gibson L, Meehan T, Stylianou A, Wreford N, et al.: Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci USA 95:12424–12431, 1998Google Scholar
  111. 111.
    Ross AJ, Waymire KG, Moss JE, Parlow AF, Skinner MK, Russell LD, et al.: Testicular degeneration in Bclw-deficient mice. Nature Genet 18:251–256, 1998Google Scholar
  112. 112.
    Michaelidis TM, Sendtner M, Cooper JD, Airaksinen MS, Holtmann B, Meyer M, et al.: Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17:75–89, 1996Google Scholar
  113. 113.
    Kamada S, Shimono A, Shinto Y, Tsujimura T, Takahashi T, Noda T, et al.: Bcl-2 deficiency in mice leads to pleiotropic abnormalities: Accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res 55:354–359, 1995Google Scholar
  114. 114.
    Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240, 1993Google Scholar
  115. 115.
    Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Negishi I, et al.: Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510, 1995Google Scholar
  116. 116.
    Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ: Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96–99, 1995Google Scholar
  117. 117.
    Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ: BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17:401–411, 1996Google Scholar
  118. 118.
    Brady HJ, Gil-Gomez G, Kirberg J, Berns AJ: Bax α perturbs T cell development and affects cell cycle entry of T cells. EMBO J 15:6991–7001, 1996Google Scholar
  119. 119.
    Brady HJ, Salomons GS, Bobeldijk RC, Berns AJ: T cells from baxα transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. gene product in. EMBO J 15:1221–1230, 1996Google Scholar
  120. 120.
    Shindler KS, Latham CB, Roth KA: Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. J Neurosci 17:3112–3119, 1997Google Scholar
  121. 121.
    Knudson CM, Korsmeyer SJ: Bcl-2 and Bax function independently to regulate cell death. Nature Genet 16:358–363, 1997Google Scholar
  122. 122.
    Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al.: Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275:967–969, 1997Google Scholar
  123. 123.
    Strasser A, Harris AW, Bath ML, Cory S: Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348:331–333, 1990Google Scholar
  124. 124.
    McDonnell TJ, Korsmeyer SJ: Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 349:254–256, 1991Google Scholar
  125. 125.
    Strasser A, Harris AW, Cory S: Eμ-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene 8:1–9, 1993Google Scholar
  126. 126.
    Linette GP, Hess JL, Sentman CL, Korsmeyer SJ: Peripheral T-cell lymphoma in lck pr -bcl-2 transgenic mice. Blood 86:1255–1260, 1995Google Scholar
  127. 127.
    Strasser A, Elefanty AG, Harris AW, Cory S: Progenitor tumours from Eμ-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival. EMBO J 15:3823–3834, 1996Google Scholar
  128. 128.
    Jager R, Herzer U, Schenkel J, Weiher H: Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene 15:1787–1795, 1997Google Scholar
  129. 129.
    Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR: Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257:212–214, 1992Google Scholar
  130. 130.
    Sakamuro D, Eviner V, Elliott KJ, Showe L, White E, Prendergast GC: c-myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. Oncogene 11:2411–2418, 1995Google Scholar
  131. 131.
    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, et al.: Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128, 1992Google Scholar
  132. 132.
    Tamiya S, Etoh K, Suzushima H, Takatsuki K, Matsuoka M: Mutation of CD95 (Fas/Apo-1) gene in adult T-cell leukemia cells. Blood 91:3935–3942, 1998Google Scholar
  133. 133.
    Beltinger C, Kurz E, Bohler T, Schrappe M, Ludwig WD, Debatin KM: CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia. Blood 91:3943–3951, 1998Google Scholar
  134. 134.
    Peng SL, Robert ME, Hayday AC, Craft J: A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice. J Exp Med 184:149–154, 1996Google Scholar
  135. 135.
    Davidson WF, Giese T, Fredrickson TN: Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions. J Exp Med 187:1825–1838, 1998Google Scholar
  136. 136.
    Zornig M, Grzeschiczek A, Kowalski MB, Hartmann KU, Moroy T: Loss of Fas/Apo-1 receptor accelerates lymphomagenesis in Eμ L-MYC transgenic mice but not in animals infected with MoMuLV. Oncogene 10:2397–2401, 1995Google Scholar
  137. 137.
    O'Connell J, Bennett MW, O'Sullivan GC, Collins JK, Shanahan F: The Fas counterattack: cancer as a site of immune privilege. Immunol Today 20:46–52, 1999Google Scholar
  138. 138.
    Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, et al.: Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366, 1996Google Scholar
  139. 139.
    Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, et al.: Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells-a mechanism of immune evasion? Nat Med 2:1361–1366, 1996Google Scholar
  140. 140.
    Fisher DE: Apoptosis in cancer therapy: crossing the threshold. Cell 78:539–542, 1994Google Scholar
  141. 141.
    Levine AJ: p53, the cellular gatekeeper for growth and division. Cell 88:323–331, 1997Google Scholar
  142. 142.
    Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene. Nature 351:453–456, 1991Google Scholar
  143. 143.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253:49–53, 1991Google Scholar
  144. 144.
    Lowe SW, Ruley HE, Jacks T, Housman DE: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967, 1993Google Scholar
  145. 145.
    Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, et al.: High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096, 1993Google Scholar
  146. 146.
    Brown JM, Wouters BG: Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59:1391–1399, 1999Google Scholar
  147. 147.
    Nossal GJ: Negative selection of lymphocytes. Cell 76:229–239, 1994Google Scholar
  148. 148.
    Murphy KM, Heimberger AB, Loh DY: Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250:1720–1723, 1990Google Scholar
  149. 149.
    Swat W, Ignatowicz L, von Boehmer H, Kisielow P: Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature 351:150–153, 1991Google Scholar
  150. 150.
    Clayton LK, Ghendler Y, Mizoguchi E, Patch RJ, Ocain TD, Orth K, et al.: T-Cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: the molecular basis of negative selection. EMBO J 16:2282–2293, 1997Google Scholar
  151. 151.
    Strasser A, Harris AW, von Boehmer H, Cory S: Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene. Proc Natl Acad Sci USA 91:1376–1380, 1994Google Scholar
  152. 152.
    Izquierdo M, Grandien A, Criado LM, Robles S, Leonardo E, Albar JP, et al.: Blocked negative selection of developing T cells in mice expressing the baculovirus p35 caspase inhibitor. EMBO J 18:156–166, 1999Google Scholar
  153. 153.
    Villa P, Kaufmann SH, Earnshaw WC: Caspases and caspase inhibitors. Trends Biochem Sci 22:388–393, 1997Google Scholar
  154. 154.
    Nicholson DW, Thornberry NA: Caspases: Killer proteases. Trends Biochem Sci 22:299–306, 1997Google Scholar
  155. 155.
    Brunner T, Mueller C: Is autoimmunity coming to a Fas(t) end?. Nat Med 5:19–20, 1999Google Scholar
  156. 156.
    Alderson MR, Tough TW, Davis-Smith T, Braddy S, Falk B, Schooley KA, et al.: Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med 181:71–77, 1995Google Scholar
  157. 157.
    Dhein J, Walczak H, Baumler C, Debatin KM, Krammer PH: Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:438–441, 1995Google Scholar
  158. 158.
    Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, et al.: Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373:444–448, 1995Google Scholar
  159. 159.
    Strasser A: Apoptosis. Death of a T cell. Nature 373:385–386, 1995Google Scholar
  160. 160.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317, 1992Google Scholar
  161. 161.
    Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, et al.: Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935–946, 1995Google Scholar
  162. 162.
    Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, et al.: Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349, 1995Google Scholar
  163. 163.
    Kasahara Y, Wada T, Niida Y, Yachie A, Seki H, Ishida Y. et al.: Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder. Int Immunol 10:195–202, 1998Google Scholar
  164. 164.
    Sneller MC, Wang J, Dale JK, Strober W, Middelton LA, Choi Y, et al.: Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89:1341–1348, 1997Google Scholar
  165. 165.
    Puck JM, Sneller MC: ALPS: An autoimmune human lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Semin Immunol 9:77–84, 1997Google Scholar
  166. 166.
    Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB: Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 335:1643–1649, 1996Google Scholar
  167. 167.
    Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S, et al.: Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA 88:8661–8665, 1991Google Scholar
  168. 168.
    Zhou T, Song L, Yang P, Wang Z, Lui D, Jope RS: Bisindolylmaleimide VIII facilitates Fas-mediated apoptosis and inhibits T cell-mediated autoimmune diseases. Nat Med 5:42–48, 1999Google Scholar
  169. 169.
    Strasser A, O'Connor L: Fas ligand—Caught between Scylla and Charybdis. Nat Med 4:21–22, 1998Google Scholar
  170. 170.
    Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ: Bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development 120:301–311, 1994Google Scholar
  171. 171.
    Farlie PG, Dringen R, Rees SM, Kannourakis G, Bernard O: bcl-2 transgene expression can protect neurons against developmental and induced cell death. Proc Natl Acad Sci USA 92:4397–4401, 1995Google Scholar
  172. 172.
    Dubois-Dauphin M, Frankowski H, Tsujimoto Y, Huarte J, Martinou JC: Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death. Proc Natl Acad Sci USA 91:3309–3313, 1994Google Scholar
  173. 173.
    Chen DF, Schneider GE, Martinou JC, Tonegawa S: Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385:434–439, 1997Google Scholar
  174. 174.
    Allsopp TE, Wyatt S, Paterson HF, Davies AM: The protooncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73:295–307, 1993Google Scholar
  175. 175.
    Greenlund LJ, Korsmeyer SJ, Johnson EM Jr: Role of BCL-2 in the survival and function of developing and mature sympathetic neurons. Neuron 15:649–661, 1995Google Scholar
  176. 176.
    Jenner P, Olanow CW: Understanding cell death in Parkinson's disease. Ann Neurol 44:S72-S84, 1998Google Scholar
  177. 177.
    Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD: Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1:1269, 1989Google Scholar
  178. 178.
    Olanow CW, Tatton WG: Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci 22:123–144, 1999Google Scholar
  179. 179.
    Marsden CD, Olanow CW: The causes of Parkinson's disease are being unraveled and rational neuroprotective therapy is close to reality. Ann Neurol 44:S189-S196, 1998Google Scholar
  180. 180.
    Blomer U, Kafri T, Randolph-Moore L, Verma IM, Gage FH: Bcl-xL protects adult septal cholinergic neurons from axotomized cell death. Proc Natl Acad Sci USA 95:2603–2608, 1998Google Scholar
  181. 181.
    Barinaga M: Stroke-damaged neurons may commit cellular suicide. Science 281:1302–1303, 1998Google Scholar
  182. 182.
    MacManus JP, Buchan AM, Hill IE, Rasquinha I, Preston E: Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett 164:89–92, 1993Google Scholar
  183. 183.
    Nicholls D, Attwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468, 1990Google Scholar
  184. 184.
    Choi DW: Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11:465–469, 1988Google Scholar
  185. 185.
    Choi DW: Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 6:667–672, 1996Google Scholar
  186. 186.
    Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, et al.: Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030, 1994Google Scholar
  187. 187.
    Kitagawa K, Matsumoto M, Tsujimoto Y, Ohtsuki T, Kuwabara K, Matsushita K, et al.: Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice. Stroke 29:2616–2621, 1998Google Scholar
  188. 188.
    Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischaemic brain injury mechanisms. Nature 399:A7-A14, 1999Google Scholar
  189. 189.
    Ma J, Endres M, Moskowitz MA: Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 124:756–762, 1998Google Scholar
  190. 190.
    Forloni G, Bugiani O, Tagliavini F, Salmona M: Apoptosis-mediated neurotoxicity induced by β-amyloid and PrP fragments. Mol Chem Neuropathol 28:163–171, 1996Google Scholar
  191. 191.
    Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, et al.: Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-β precursor protein and amyloidogenic A β peptide formation. Cell 97:395–406, 1999Google Scholar
  192. 192.
    Barinaga M: Is apoptosis key in Alzheimer's disease? Science 281:1303–1304, 1998Google Scholar
  193. 193.
    Wolozin B, Iwasaki K, Vito P, Ganjei JK, Lacana E, Sunderland T, et al.: Participation of presenilin 2 in apoptosis: Enhanced basal activity conferred by an Alzheimer mutation. Science 274:1710–1713, 1996Google Scholar
  194. 194.
    Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399:A23-A31, 1999Google Scholar
  195. 195.
    Everett H, McFadden G: Apoptosis: An innate immune response to virus infection. Trends Microbiol 7:160–165, 1999Google Scholar
  196. 196.
    Meinl E, Fickenscher H, Thome M, Tschopp J, Fleckenstein B: Anti-apoptotic strategies of lymphotropic viruses. Immunol Today 19:474–479, 1998Google Scholar
  197. 197.
    Barry M, McFadden G: Apoptosis regulators from DNA viruses. Curr Opin Immunol 10:422–430, 1998Google Scholar
  198. 198.
    Teodoro JG, Branton PE: Regulation of apoptosis by viral gene products. J Virol 71:1739–1746, 1997Google Scholar
  199. 199.
    Kaplan D, Sieg S: Role of the Fas/Fas ligand apoptotic pathway in human immunodeficiency virus type 1 disease. J Virol 72:6279–6282, 1998Google Scholar
  200. 200.
    Berndt C, Mopps B, Angermuller S, Gierschik P, Krammer PH: CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4(+) T cells. Proc Natl Acad Sci USA 95:12556–12561, 1998Google Scholar
  201. 201.
    Guillerm C, Coudronniere N, Robert-Hebmann V, Devaux C: Delayed human immunodeficiency virus type 1-induced apoptosis in cells expressing truncated forms of CD4. J Virol 72:1754–1761, 1998Google Scholar
  202. 202.
    Ohnimus H, Heinkelein M, Jassoy C: Apoptotic cell death upon contact of CD4+ T lymphocytes with HIV glycoprotein-expressing cells is mediated by caspases but bypasses CD95 (Fas/Apo-1) and TNF receptor 1. J Immunol 159:5246–5252, 1997Google Scholar
  203. 203.
    McCloskey TW, Ott M, Tribble E, Khan SA, Teichberg S, Paul MO, et al.: Dual role of HIV Tat in regulation of apoptosis in T cells. J Immunol 158:1014–1019, 1997Google Scholar
  204. 204.
    Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, et al.: Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37, 1994Google Scholar
  205. 205.
    Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, et al.: Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265:528–530, 1994Google Scholar
  206. 206.
    Lowin B, Hahne M, Mattmann C, Tschopp J: Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370:650–652, 1994Google Scholar
  207. 207.
    Gooding LR, Ranheim TS, Tollefson AE, Aquino L, Duerksen-Hughes P, Horton TM, et al.: The 10,400-and 14,500-dalton proteins encoded by region E3 of adenovirus function together to protect many but not all mouse cell lines against lysis by tumor necrosis factor. J Virol 65:4114–4123, 1991Google Scholar
  208. 208.
    Shisler J, Yang C, Walter B, Ware CF, Gooding LR: The adenovirus E3–10.4K/14.5K complex mediates loss of cell surface Fas (CD95) and resistance to Fas-induced apoptosis. J Virol 71:8299–8306, 1997Google Scholar
  209. 209.
    Ploegh HL: Viral strategies of immune evasion. Science 280:248–253, 1998Google Scholar
  210. 210.
    Tollefson AE, Hermiston TW, Lichtenstein DL, Colle CF, Tripp RA, Dimitrov T, et al.: Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 392:726–730, 1998Google Scholar
  211. 211.
    Li Y, Kang J, Horwitz MS: Interaction of an adenovirus E3 14.7-kilodalton protein with a novel tumor necrosis factor α-inducible cellular protein containing leucine zipper domains. Mol Cell Biol 18:1601–1610, 1998Google Scholar
  212. 212.
    Li Y, Kang J, Horwitz MS: Interaction of an adenovirus 14.7-kilodalton protein inhibitor of tumor necrosis factor α cytolysis with a new member of the GTPase superfamily of signal transducers. J Virol 71:1576–1582, 1997Google Scholar
  213. 213.
    Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, et al.: Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521, 1997Google Scholar
  214. 214.
    Hardwick JM: Viral interference with apoptosis. Semin Cell Dev Biol 9:339–949, 1998Google Scholar
  215. 215.
    Tschopp J, Thome M, Hofmann K, Meinl E: The fight of viruses against apoptosis. Curr Opin Genet Dev 8:82–87, 1998Google Scholar
  216. 216.
    O'Brien V: Viruses and apoptosis. J Gen Virol 79:1833–1845, 1998Google Scholar
  217. 217.
    Sarid R, Sato T, Bohenzky RA, Russo JJ, Chang Y: Kaposi's sarcoma-associated herpesvirus encodes a functional Bcl-2 homologue. Nat Med 3:293–298, 1997Google Scholar
  218. 218.
    Henderson S, Huen D, Rowe M, Dawson C, Johnson G, Rickinson A: Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci USA 90:8479–8483, 1993Google Scholar
  219. 219.
    Cheng EH, Nicholas J, Bellows DS, Hayward GS, Guo HG, Reitz MS, et al.: A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci USA 94:690–694, 1997Google Scholar
  220. 220.
    Zauli G, Gibellini D, Caputo A, Bassini A, Negrini M, Monne M, et al.: The human immunodeficiency virus type-1 Tat protein upregulates bcl-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Blood 86:3823–3834, 1995Google Scholar
  221. 221.
    Neil JC, Cameron ER, Baxter EW: p53 and tumour viruses: Catching the guardian off-guard. Trends Microbiol 5:115–120, 1997Google Scholar
  222. 222.
    Evan G, Littlewood T: A matter of life and cell death. Science 281:1317–1322, 1998Google Scholar
  223. 223.
    Greenway A, Azad A, McPhee D: Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. J Virol 69:1842–1850, 1995Google Scholar
  224. 224.
    Li CJ, Friedman DJ, Wang C, Metelev V, Pardee AB: Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 268:429–431, 1995Google Scholar
  225. 225.
    Griffin DE, Hardwick JM: Perspective: virus infections and the death of neurons. Trends Microbiol 7:155–160, 1999Google Scholar
  226. 226.
    Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, et al.: Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor ζ chain. J Exp Med 189:1489–1496, 1999Google Scholar
  227. 227.
    Ayyavoo V, Mahboubi A, Mahalingam S, Ramalingam R, Kudchodkar S, Williams WV, et al.: HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor κβ. Nat Med 3:1117–1123, 1997Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  1. 1.The Walter and Eliza Hall Institute of Medical ResearchMelbourneAustralia

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