Skip to main content
SpringerLink
Log in

Importance of the Bcl-2 family in cell death regulation

  • Multi-author Reviews
  • Published:
Experientia Aims and scope Submit manuscript

Abstract

Bcl-2 was first identified as a novel transcript associated with the t(14;18) chromosomal breakpoint which occurs in most follicular lymphomas. The deregulated expression of bcl-2 was found to contribute to multistep neoplasia through the suppression of cell death, or apoptosis, in transgenic mouse models. Bcl-2 was subsequently shown to be normally expressed in a variety of tissues and to significantly inhibit the induction of apoptosis in many experimental systems. Bcl-2 is now known to be structurally similar to other proteins, in particular within the domains referred to as BH1 and BH2. This multigene family of cell death regulators includes members which enhance rates of apoptosis, including bcl-xs and bax, and those which inhibit apoptosis, including MCL-1 and bcl-xl. Members of the bcl-2 family physically interact with other proteins, including other family members and these interactions appear to modulate their function. The mechanism(s) by which bcl-2 family members regulate cell death remain in large part unknown, although recent evidence suggests that bcl-2 may interfere with cellular signalling events involved in apoptosis induction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Literatur

  1. Kerr J. F., Wyllie A. H. and Currie A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer26: 239–257

    PubMed  Google Scholar 

  2. Camilleri-Broet S., Davi F., Feuillard J., Bourgeois C., Seilhean D., Hauw J. J. and Raphael M. (1985) Hight expression of latent membrane protein 1 of Epstein-Barr virus and BCL-2 oncoprotein in acquired immunodeficiency syndromerelated primary brain lymphomas. Blood86: 432–435

    Google Scholar 

  3. Behl C., Hovey L., Krajewski S., Schubert D. and Reed, J. C. (1993) BCL-2 prevents killing of neuronal cells by glutamate but not by amyloid beta protein. Biochem. Biophys. Res. Commun.197: 949–956

    Article  PubMed  Google Scholar 

  4. Migheli A., Cavalla P., Piva R., Giordana M. T. and Schiffer D. (1994) Bcl-2 protein expression in aged brain and neurodegenerative diseases. Neuroreport15: 1906–1908

    Google Scholar 

  5. McDonnell T. J. (1993) Cell division versus cell death: a functional model of multistep neoplasia. Mol. Carcinogen.8: 209–213

    Google Scholar 

  6. Bakhshi A., Jensen J. P., Goldman P., Wright J. J., McBride O. W., Epstein A. L. and Korsmeyer S. J. (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell41: 899–906

    Article  PubMed  Google Scholar 

  7. Cleary M. L., Smith S. D. and Sklar J. (1986) Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18). Cell47: 19–28

    Article  PubMed  Google Scholar 

  8. Cleary M. L. and Sklar J. (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl Acad. Sci. USA83: 7439–7443

    Google Scholar 

  9. Tsujimoto Y., Cossman J., Jaffe E. and Croce C. M. (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science228: 1440–1443

    PubMed  Google Scholar 

  10. Tsujimoto Y. and Croce C. M. (1986) Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl Acad. Sci. USA83: 5214–5218

    PubMed  Google Scholar 

  11. Hsu B., Marin M. C., Brisbay S., McConnell K. and McDonnell T. J. (1994) Bcl-2 gene expression confers multidrug resistance to chemotherapeutic induced cell death. Cancer Bull.46: 125–129

    Google Scholar 

  12. Olsen C. W., Kehren J. C., Dybdahl-Sissoko N. R. and Hinshaw V. S. (1996) Bcl-2 alters influenza virus yield, spread and hemagglutinin glycosylation. J. Virol.70: 663–666

    PubMed  Google Scholar 

  13. Vaux D. L., Weissman I. L. and Kim S. K. (1992) Prevention of programmed cell death inCaenorhaditis elegans by human bcl-2. Science258: 1955–1957

    PubMed  Google Scholar 

  14. Miyashita T. and Reed J. C. (1992) Bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to death and DNA fragmentation induced by glucocorticoids and multible chemotherapeutic drugs. Cancer Res.52: 5407–5411

    PubMed  Google Scholar 

  15. Strasser A. and Anderson R. L. (1995) Bcl-2 and thermotolerance cooperate in cell survival. Cell Growth Diff. 6: 799–805

    PubMed  Google Scholar 

  16. Levine B., Huang Q., Isaacs J. T., Reed J. C., Griffin D. E. and Hardwick J. M. (1993) Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature361: 739–742

    Article  PubMed  Google Scholar 

  17. Hengartner M. O. and Horvitz H. R. (1994)C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell76: 665–676

    Article  PubMed  Google Scholar 

  18. Kamada S., Shimono A., Shinto Y., Tsujimura T., Takahashi T., Noda T., Kitamura Y., Kondoh H. and Tsujimoto Y. (1995) 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

    PubMed  Google Scholar 

  19. Krajewski S., Tanaka S., Takayama S. Schibler M. J., Fenton W. and Reed J. C. (1993) 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

    PubMed  Google Scholar 

  20. 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

    PubMed  Google Scholar 

  21. 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. USA91: 6569–6573

    PubMed  Google Scholar 

  22. Marin M. C., Fernandez A., Bick R. J., Bick R. J., Brisbay S., Buja L. M., Snuggs M., McConkey D. J., von Eschenbasch A. C., Keating M. J. and McDonnell T. J. (1996) Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+. Oncogene12: 2259–2266

    PubMed  Google Scholar 

  23. Fernandez A., Marin M. C., McDonnell T. J. and Ananthaswamy H. N. (1994) Differential sensitivity of normal and Ha-ras-transformed C3H mouse embryo fibroblast to tumor necrosis factor: induction of bcl-2, c-myc and manganese superoxide dismutase in resistant cells. Oncogene9: 2009–2017

    PubMed  Google Scholar 

  24. Jaattela M., Benedict M., Tewari M., Shayman J. A. and Dixit V. M. (1995) Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells. Oncogene10: 2297–2305

    PubMed  Google Scholar 

  25. Talley A. K., Dewhurst S., Perry S. W., Dollard S. C., Gummuluru S., Fine S. M., New D., Epstein L. G., Gendelman H. E. and Gelbard H. A. (1995) Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidantN-acetylcysteine and the genes bcl-2 and crmA. Mol. Cell. Biol. 15: 2359–2366

    PubMed  Google Scholar 

  26. Vandenabeele P., Declercq W., Vanhaesebroeck B., Grooten J. and Fiers W. (1995) Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells. J. Immunol.154: 2904–2913

    PubMed  Google Scholar 

  27. Lotem J. and Sachs L. (1995) Regulation of bcl-2, bcl-xl and bax in the control of apoptosis by hematopoietic cytokines and dexamethasone. Cell Growth Diff.6: 647–653

    PubMed  Google Scholar 

  28. Vaux D. L., Aguila H. L. and Weissman I. L. (1992) Bcl-2 prevents death of factor- deprived cells but fails to prevent apoptosis in targets of cell mediated killing. Int. Immunol.4: 821–824

    PubMed  Google Scholar 

  29. Reed J. C. (1994) Bcl-2 and the regulation of programmed cell death. J. Cell. Biol.124: 1–6

    Article  PubMed  Google Scholar 

  30. Oltvai Z. N., Milliman C. L. and Korsmeyer S. J. (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell74: 609–619

    Article  PubMed  Google Scholar 

  31. Yin X. M., Oltvali Z. N. and Korsmeyer S. J. (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature369: 272–273

    Article  PubMed  Google Scholar 

  32. Boise L. H., Gonzalez-Garcia M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nunez G. and Thompson, C. B. (1993) Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell74: 597–608

    Article  PubMed  Google Scholar 

  33. Kozopas K. M., Yang T., Buchan H. L., Zhou P. and Craig R. W. (1993) MCL-1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc. Natl Acad. Sci. USA90: 3516–3520

    PubMed  Google Scholar 

  34. Yang E., Zha J., Jockel J., Boise L. H., Thompson C. B. and Korsmeyer S. J. (1995) Bad, a heterodimeric partner for Bcl-Xll and Bcl-2, displaces Bax and promotes cell death. Cell80: 285–291

    Article  PubMed  Google Scholar 

  35. Seto M., Jaeger U., Hockett R. D., Graninger W., Bennett S., Goldman P. and Korsmeyer S. J. (1988) Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J.7: 123–131

    PubMed  Google Scholar 

  36. Young R. L. and Korsmeyer S. J. (1993) A negative regulatory element in the bcl-2 5′-untranslated region inhibits expression from an upstream promoter. Mol. Cell. Biol.13: 3686–3697

    PubMed  Google Scholar 

  37. Hockenbery D. M., Nunez G., Milliman C., Schreiber R. D. and Korsmeyer S. J. (1990) Bcl-2 in inner mitochondrial membrane protein that blocks programmed cell death. Nature348: 334–336

    Article  PubMed  Google Scholar 

  38. Nguyen M., Branton P. E., Walton P. A., Oltvai Z. N., Korsmeyer S. J. and Shore G. C. (1994) Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus. J. Biol. Chem.269: 16521–16524

    PubMed  Google Scholar 

  39. Nguyen M., Millar D. G., Yong V. M., Korsmeyer S. J. and Shore G. C. (1993) Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J. Biol. Chem.268: 25265–25268

    PubMed  Google Scholar 

  40. Borner C., Martinou I., Mattman C., Irmler M., Schaerer E., Martinou J. C. and Tschopp J. (1994) The protein bcl-2 alpha does not require membrane attachment, but two conserved domains to suppress apoptosis. J. Cell Biol.126: 1059–1068

    Article  PubMed  Google Scholar 

  41. 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. Cell75: 241–251

    PubMed  Google Scholar 

  42. Akao Y., Otsuki Y., Kataoka S., Ito Y. and Tsujimoto Y. (1994) Multiple subcellular localization of bcl-2: detection in nuclear outer membrane, endoplasmic of bcl-2: detection in nuclear outer membrane, endoplasmic reticulum membrane, and mitochondrial membranes. Cancer Res.54: 2468–2471

    PubMed  Google Scholar 

  43. Chen-Levy Z. and Cleary M. L. (1990) Membrane topology of the Bcl-2 proto-oncogenic protein demonstrated in vitro. J. Biol. Chem.265: 4929–4933

    PubMed  Google Scholar 

  44. Chen-Levy Z., Nourse J. and Cleary M. L. (1989) The bcl-2 candidate proto-oncogene product is a 24-kilodalton integralmembrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol. Cell Biol.9: 701–710

    PubMed  Google Scholar 

  45. de Jong D., Prins F. A., Mason D. Y., Reed J. C., van Ommen G. B. and Kluin P. M. (1994) Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells. Cancer Res.54: 256–260

    PubMed  Google Scholar 

  46. Givol I., Tsarfaty I., Resau J., Rulong S., da Silva P. P., Nasioulas G., Du Hadaway J., Hughes S. H. and Ewert D. L. (1994) Bcl-2 expressed using a retroviral vector is localized primarily in the nuclear membrane and the endoplasmic reticulum of chicken embryo fibroblasts. Cell Growth Diff.5: 419–429

    PubMed  Google Scholar 

  47. Janiak F., Leber B. and Andrews D. W. (1994) Assembly of Bcl-2 into microsomal and outer mitochondrial membranes. J. Biol. Chem.269: 9842–9849

    PubMed  Google Scholar 

  48. Lithgow T., van Driel R., Bertram J. F. and Strasser A. (1994) 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 Diff.5: 411–417

    PubMed  Google Scholar 

  49. Yin X. M., Oltvai Z. N. and Korsmeyer S. J. (1995) Heterodimerization with Bax is required for Bcl-2 to repress cell death. Curr. Top. Microbiol. Immunol.194: 331–338

    PubMed  Google Scholar 

  50. Hanada M., Aimé-Sempé C., Sato T. and Reed J. C. (1995) Structure-function analysis of Bcl-2 protein: identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J. Biol. Chem.270: 11962–11969

    Article  PubMed  Google Scholar 

  51. Tanaka S., Saito K. and Reed J. C. (1993) Structure-function analysis of the Bcl-2 oncoprotein: addition of a heterologous transmembrane domain to portions of the Bcl-2 beta protein restores function as a regulator of cell survival. J. Biol. Chem.268: 10920–10926

    PubMed  Google Scholar 

  52. Korsmeyer S. J., Shutter J. R., Veis D. J., Merry D. E. and Oltvai Z. N. (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Seminars in Cancer Biology4: 327–332

    PubMed  Google Scholar 

  53. Sedlak T. W., Oltvai Z. N., Yang E., Wang K., Boise L. H., Thompson C. B. and Korsmeyer S. J. (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc. Natl Acad. Sci. USA92: 7834–7838

    PubMed  Google Scholar 

  54. McDonnell T. J., Deane N., Platt F. M., Nunez G. Jaeger U., McKearn J. P. and Korsmeyer S. J. (1989) Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell57: 79–88

    Article  PubMed  Google Scholar 

  55. McDonnell T. J., Nunez G., Platt F. M., Hockenbery D., London L., McKearn J. P. and Korsmeyer S. J. (1990) Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol. Cell. Biol.10: 1901–1907

    PubMed  Google Scholar 

  56. McDonnell T. J. and Korsmeyer S.J. (1991) Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature349: 254–256

    Article  PubMed  Google Scholar 

  57. Marin M. C., Hsu B., Stephens L. C., Brisbay S. and McDonnell T. J. (1995) The functional basis of c-myc and bcl-2 complementation during multistep lymphomagenesis in vivo. Exp. Cell Res.217: 240–247

    Article  PubMed  Google Scholar 

  58. McDonnell T. J. (1993) The bcl-2 immunoglobulin transgenic mouse: a model of the t(14;18) translocation in human follicular lymphoma. Transgene1 47–52

    Google Scholar 

  59. McDonnell T. J., Marin M. C., Hsu B., Brisbay S. M., McConnell K., Tu S.-M., Campbell M. L. and Rodriguz-Villanueva G. (1993) The bcl-2 oncogene: apoptosis and neoplasia. Radiat. Res.136: 307–312

    PubMed  Google Scholar 

  60. Nakayama K., Negishi I. Kuida K., Sawa H. and Loh D. Y. (1994) Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease and lymphocytopenia. Proc. Natl Acad. Sci. USA91: 3700–3704

    PubMed  Google Scholar 

  61. Veis D. J., Sorenson C. M., Shutter J. R. and Korsmeyer S. J. (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys and hypopigmented hair. Cell75: 229–240

    Article  PubMed  Google Scholar 

  62. Nicotera P., Zhivotovsky B. and Orrenius S. (1994) Nuclear calcium transport and the role of calcium in apoptosis. Cell Calcium16: 279–288

    Article  PubMed  Google Scholar 

  63. Kumar S., Kinoshita M., Noda M., Copeland N. G. and Jenkins N. A. (1994) Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of theCaenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme. Genes Dev.8: 1613–1626

    PubMed  Google Scholar 

  64. 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. Science262: 1274–1277

    PubMed  Google Scholar 

  65. Jacobson M. D. and Raff M. C. (1995) Programmed cell death and Bcl-2 protection in very low oxygen. Nature374: 814–816

    Article  PubMed  Google Scholar 

  66. Shimizu S., Eguchi Y., Kosaka H., Kamiike W., Matsuda H. and Tsujimoto Y. (1995) Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xl. Nature374: 811–813

    Article  PubMed  Google Scholar 

  67. Ellis H. M. and Horvitz H. R. (1986) Genetic control of programmed cell death in the nematodeC. elegans. Cell44: 817–829

    Article  PubMed  Google Scholar 

  68. Hengartner M. O., Ellis R. E. and Horvitz H. R. (1992)Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature356: 494–499

    Article  PubMed  Google Scholar 

  69. Hengartner M. O. and Horvitz H. R. (1994) Activation ofC. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature369: 318–320

    Article  PubMed  Google Scholar 

  70. Miura M., Zhu H., Rottelo R., Hartwieg E. A. and Yuan J. (1993) Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of theC. elegans cell death gene ced-3. Cell75: 653–660

    Article  PubMed  Google Scholar 

  71. Yuan J., Shaham S., Ledoux S., Ellis H. M. and Horvitz H. R. (1993) TheC. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell75: 641–652

    Article  PubMed  Google Scholar 

  72. Darmon A. J., Nicholson D. W. and Bleackley R. C. (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature377: 446–448

    Article  PubMed  Google Scholar 

  73. Fernandes-Alnemri T., Litwack G. and Alnemri E. S. (1994) CPP32, a novel human apoptotic protein with homology toCaenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J. Biol. Chem.269: 30761–30764

    PubMed  Google Scholar 

  74. Nicholson D. W., Ali A., Thornberry N. A., Vaillancourt J. P., Ding C. K., Gallant M., Gareau Y., Griffin P. R., Labelle M. and Lazebnik Y. A. (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature376: 37–43

    Article  PubMed  Google Scholar 

  75. Tewari M., Quan L. T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D. R., Poirier G. G., Salvesen G. S., Dixit V. M. (1995) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell81: 801–809

    Article  PubMed  Google Scholar 

  76. Chinnaiyan A. M., Orth K., O'Rourke K., Duan H., Poirier G. G. and Dixit V. M. (1996) 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

    Article  PubMed  Google Scholar 

  77. Henderson S., Huen D., Rowe M., Dawson C., Johnson G. and Rickinson A. (1993) Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc. Natl Acad. Sci. USA90: 8479–8483

    PubMed  Google Scholar 

  78. Chiou S. K., Tseng C. C., Rao L. and White E. (1994) Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells. J. Virol.68: 6553–6566

    PubMed  Google Scholar 

  79. Apte S. S., Mattei M. G. and Olsen B. R. (1995) Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, BAX delta. Genomics26: 592–594

    Article  PubMed  Google Scholar 

  80. Cheng E. H.-Y., Levine B., Boise L. H., Thompson C. B. and Hardwick, J. M. (1996) Bax-independent inhibition of apoptosis by bcl-xl. Nature379: 554–556

    Article  PubMed  Google Scholar 

  81. Krajewski S., Krajewska M., Shabaik A. and Reed J. C. (1994) Immunohistochemical determination of in vivo distribution of bax, a dominant inhibitor of bcl-2. Am. J. Pathol.145: 1323–1336

    PubMed  Google Scholar 

  82. Knudson C. M., Tung K. S., Tourtellotte W. G., Brown G. A. and Korsmeyer S. J. (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science270: 96–99

    PubMed  Google Scholar 

  83. Miyashita T. and Reed J. C. (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell80: 293–299

    Article  PubMed  Google Scholar 

  84. Zhan Q., Fan S., Bae I., Guillouf C., Liebermann D., O'Connor P. and Fornace A. J. Jr. (1994) Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene9: 3743–3751

    PubMed  Google Scholar 

  85. Miyashita T., Krajewski S., Krajwaska M., Wang H. G., Lin H. K., Liebermann D. A., Hoffman B. and Reed J. C. (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene9: 1799–1805

    PubMed  Google Scholar 

  86. Miyashita T., Kitada S., Krajewski S., Horne W. A., Delia D. and Reed J. C. (1995) Overexpression of the bcl-2 protein increases the half-life of p21 (bax). J. Biol. Chem.270: 26049–26052

    Article  PubMed  Google Scholar 

  87. Bargou R. C., Daniel P. T., Mapara M. Y., Bommert K., Wagener C., Kallinich B., Royer H. D. and Dorken B. (1995) Expression of the bcl-2 gene family in normal and malignant breast tissue: low bax-alpha expression in tumor cells correlates with resistance towards apoptosis. Int. J. Cancer60: 854–859

    PubMed  Google Scholar 

  88. Krajewski S., Blomqvist C., Franssila K., Krajewska M., Wasenius V. M., Niskanen E., Nordling S. and Reed J. C. (1995) Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res.55: 4471–4478

    PubMed  Google Scholar 

  89. Sato T., Hanada M., Bodrug S., Irie S., Iwama N., Boise L. H., Thompson C. B., Golemis E., Fong L. and Wang H. G. (1994) Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hydrid system. Proc. Natl Acad. Sci. USA91: 9238–9242

    PubMed  Google Scholar 

  90. Gonzalez-Garcia M., Perez-Ballestro R., Ding L., Duan L., Boise L. H., Thompson C. B. and Nunez G. (1994) Bcl-x is the major mRNA form expressed during murine development and its product localizes to the mitochondria. Development120: 3033–3042

    PubMed  Google Scholar 

  91. Krajewski S., Krajwaska M., Shabaik A., Wang H. G., Irie S., Fong L. and Reed J. C. (1994) Immunohistochemical analysis of in vivo patterns of bcl-x expression. Cancer Res.54: 5501–5507

    PubMed  Google Scholar 

  92. Rouayrenc J. F., Boise L. H., Thompson C. B., Privat A. and Patey G. (1995) Presence of the long and the short forms of Bcl-X in several human and murine tissues. Life Sciences318: 537–540

    PubMed  Google Scholar 

  93. Park J. R., Bernstein I. D. and Hockenbery D. M. (1995) Primitive human hematopoietic precursors express bcl-x but not bcl-2. Blood86: 868–876

    PubMed  Google Scholar 

  94. Motoyama N., Wang F., Roth K. A., Sawa H., Nakayama K., Nakayama K., Negishi I., Senju S., Zhang Q., Fujii S. and Loh D. Y. (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science267: 1506–1510

    PubMed  Google Scholar 

  95. Choi M. S. and Boise L. H. (1995) The role of bcl-Xl in CD40-mediated rescue from anti-mu-induced apoptosis in WEHI-231 B lymphoma cells. Eur. J. Immunol.25: 1352–1357

    PubMed  Google Scholar 

  96. Gottschalk A. R., Boise L. H., Thompson C. B. and Quintans J. (1994) Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by bcl-x but not bcl-2. Proc. Natl. Acad. Sci. USA91: 7350–4735

    PubMed  Google Scholar 

  97. Chittenden T., Harrington E. A., O'Connor R., Flemington C., Lutz R. J., Evan G. I. and Guild B. C. (1995) Induction of apoptosis by the Bcl-2 homologue Bak. Nature374: 733–736

    Article  PubMed  Google Scholar 

  98. Farrow S. N., White J. H., Martinou I., Raven T., Pun K. T., Grinham C. J., Martinou J. C. and Brown R. (1995) Cloning of a bcl-2 homologue by interaction with adenovirus E1B. Nature374: 731–733

    Article  PubMed  Google Scholar 

  99. Kiefer M. C., Brauer M. J., Powers V. C., Wu J. J., Umansky S. R., Tomei L. D. and Barr P. J. (1995) Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature374: 736–739

    Article  PubMed  Google Scholar 

  100. Lin E. Y., Orlofsky A., Berger M. S. and Prystowsky M. B. (1993) Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J. Immunol.151: 1979–1988

    PubMed  Google Scholar 

  101. Yang T., Kozopas K. M. and Craig R. W. (1995) The intracellular distribution and pattern of expression of MCL-1 overlap with, but are not identical to, those of Bcl-2. J. Cell Biol.128: 1173–1184

    Article  PubMed  Google Scholar 

  102. Craig R. W., Jabs E. W., Zhou P., Kozopas K. M., Hawkins A. L., Rochelle J. M., Seldin M. F. and Griffin C. A. (1994) Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL-1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease. Genomics23: 457–463

    Article  PubMed  Google Scholar 

  103. Atkin N. (1986) Chomosome 1 aberrations in cancer. Cancer Genet. Cytogenet.21: 279–285

    Article  PubMed  Google Scholar 

  104. Gendler S. J., Cohen E. P., Craston A., Duhig T., Johnstone G. and Barnes D. (1990) The locus of the polymorphic epithelial mucin (PEM) tumour antigen on chromosome 1q21 shows a high frequency of alteration in primary human breast cancer. Int. J. Cancer45: 431–435

    PubMed  Google Scholar 

  105. Testa J. R. (1990) Chromosome translocations in human cancer. Cell Growth Diff.1: 97–101

    PubMed  Google Scholar 

  106. Bodrug S. E., Aimé-Sempé C., Sato T., Krajewski S., Hanada M. and Reed, J. C. Biochemical and functional comparisons of MCL-1 and Bcl-2 proteins: evidence for a novel mechanism of regulating bcl-2 family function. Cell Death Diff. (in press)

  107. Reynolds J. E., Yang T., Qian L., Jenkinson J. D., Zhou P., Eastman A. and Craig R. W. (1994) MCL-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res.54: 6348–6352

    PubMed  Google Scholar 

  108. Lømo J., Smeland E. B., Krajewski S., Reed J. C. and Blomhoff H. K. (1996) Expression of the bcl-2 homologue MCL-1 correlates with survival of peripheral bloodB lymphocytes. Cancer Res.56: 40–43

    PubMed  Google Scholar 

  109. Krajewski S., Bodrug, S., Krajewska M., Shabaik A., Gascoyne R., Berean K. and Reed J. C. (1995) Immunohistochemical analysis of MCL-1 protein in human tissues: differential regulation of MCL-1 and Bcl-2 protein production suggests a unique role for MCL-1 in control of programmed cell death in vivo. Am. J. Pathol.146: 1309–1319

    PubMed  Google Scholar 

  110. Krajewski S., Bodrug S., Gascoyne R., Berean K., Krajewska M. and Reed J. C. (1994) Immunohistochemical analysis of MCL-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. Am. J. Pathol.145: 515–525

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 89, 77030, Houston, Texas, USA

    T. J. McDonnell, A. Beham, M. Sarkiss, M. M. Andersen & P. Lo

Authors
  1. T. J. McDonnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Beham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Sarkiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. M. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

McDonnell, T.J., Beham, A., Sarkiss, M. et al. Importance of the Bcl-2 family in cell death regulation. Experientia 52, 1008–1017 (1996). https://doi.org/10.1007/BF01920110

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01920110

Key words

Search

Navigation