Skip to main content

Advertisement

Log in

The Bcl-2 family in autoimmune and degenerative disorders

  • Cell Death and Disease
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Members of the Bcl-2 family are essential regulators of programmed cell death and thus play a major role in the development and function of many tissues. The balance between pro-survival and pro-apoptotic members of the family decides whether a cell will live or die. This mechanism allows organisms to get rid of cells that are no longer needed or have become dangerous. Deregulation of apoptosis is a major contributing factor in the development of many diseases. A deeper understanding of how the Bcl-2 family proteins orchestrate death in normal and pathologic conditions is thus relevant not only for disease etiology, but also to try to prevent these various disorders. Experiments with transgenic and gene-ablated mice have helped elucidate the function of the different members of the Bcl-2 family and their physiological roles. The present review highlights the role of Bcl-2 family members in autoimmune and degenerative disorders, with a particular focus on the mouse models that have been used to study their function.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Schneider P, Tschopp J (2000) Apoptosis induced by death receptors. Pharm Acta Helv 74:281–286. doi:10.1016/S0031-6865(99)00038-2

    Article  PubMed  CAS  Google Scholar 

  2. Adams JM, Cory S (2007) The Bcl-2-regulated apoptosis switch: mechanism and therapeutic potential. Cur Opin Immunol 19:488–496 (in press)

    Article  CAS  Google Scholar 

  3. Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164. doi:10.1016/j.tcb.2008.01.007

    Article  PubMed  CAS  Google Scholar 

  4. Shi Y (2006) Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18:677–684. doi:10.1016/j.ceb.2006.09.006

    Article  PubMed  CAS  Google Scholar 

  5. Lacronique V, Mignon A, Fabre M et al (1996) Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med 2:80–86. doi:10.1038/nm0196-80

    Article  PubMed  CAS  Google Scholar 

  6. Chen L, Willis SN, Wei A et al (2005) Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403. doi:10.1016/j.molcel.2004.12.030

    Article  PubMed  CAS  Google Scholar 

  7. Willis SN, Fletcher JI, Kaufmann T et al (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856–859. doi:10.1126/science.1133289

    Article  PubMed  CAS  Google Scholar 

  8. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481–1486. doi:10.1101/gad.897601

    Article  PubMed  CAS  Google Scholar 

  9. van Delft MF, Huang DCS (2006) How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 16:203–213. doi:10.1038/sj.cr.7310028

    Article  PubMed  CAS  Google Scholar 

  10. Bouillet P, Metcalf D, Huang DCS et al (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286:1735–1738. doi:10.1126/science.286.5445.1735

    Article  PubMed  CAS  Google Scholar 

  11. Koralov SB, Muljo SA, Galler GR et al (2008) Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132:860–874. doi:10.1016/j.cell.2008.02.020

    Article  PubMed  CAS  Google Scholar 

  12. Ventura A, Young AG, Winslow MM et al (2008) Targeted deletion reveals essential and overlapping functions of the mIR-17 92 family of miRNA clusters. Cell 132:875–886. doi:10.1016/j.cell.2008.02.019

    Article  PubMed  CAS  Google Scholar 

  13. Xiao C, Srinivasan L, Calado DP et al (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nat Immunol 9:404–414. doi:10.1038/ni1575

    Article  CAS  Google Scholar 

  14. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838. doi:10.1038/nature03702

    Article  PubMed  CAS  Google Scholar 

  15. Tagawa H, Karnan S, Suzuki R et al (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24:1348–1358. doi:10.1038/sj.onc.1208300

    Article  PubMed  CAS  Google Scholar 

  16. Zhang L, Ming L, Yu J (2007) BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat 10:207–217. doi:10.1016/j.drup.2007.08.002

    Article  PubMed  CAS  Google Scholar 

  17. Ota A, Tagawa H, Karnan S et al (2004) Identification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma. Cancer Res 64:3087–3095. doi:10.1158/0008-5472.CAN-03-3773

    Article  PubMed  CAS  Google Scholar 

  18. Strasser A, Puthalakath H, O’Reilly LA, Bouillet P (2008) What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain. Immunol Cell Biol 86:57–66. doi:10.1038/sj.icb.7100141

    Article  PubMed  CAS  Google Scholar 

  19. Groves T, Parsons M, Miyamoto NG, Guidos CJ (1997) TCR engagement of CD4+CD8+ thymocytes in vitro induces early aspects of positive selection, but not apoptosis. J Immunol 158:65–75

    PubMed  CAS  Google Scholar 

  20. Bouillet P, Purton JF, Godfrey DI et al (2002) BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415:922–926. doi:10.1038/415922a

    Article  PubMed  CAS  Google Scholar 

  21. von Boehmer H (1990) Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol 8:531–556. doi:10.1146/annurev.immunol.8.1.531

    Article  Google Scholar 

  22. Liston A, Lesage S, Gray DHD et al (2004) Generalized resistance to thymic deletion in the NOD mouse: a polygenic trait characterized by defective induction of Bim. Immunity 21:817–830

    PubMed  CAS  Google Scholar 

  23. Rathmell JC, Lindsten T, Zong W-X, Cinalli RM, Thompson CB (2002) Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 3:932–939. doi:10.1038/ni834

    Article  PubMed  CAS  Google Scholar 

  24. Lindsten T, Ross AJ, King A et al (2000) The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell 6:1389–1399. doi:10.1016/S1097-2765(00)00136-2

    Article  PubMed  CAS  Google Scholar 

  25. Ogilvy S, Metcalf D, Print CG, Bath ML, Harris AW, Adams JM (1999) Constitutive bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc Natl Acad Sci USA 96:14943–14948. doi:10.1073/pnas.96.26.14943

    Article  PubMed  CAS  Google Scholar 

  26. Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, Milbrandt J (1995) Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269:532–535. doi:10.1126/science.7624775

    Article  PubMed  CAS  Google Scholar 

  27. Ponnio T, Burton Q, Pereira FA, Wu DK, Conneely OM (2002) The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol 22:935–945

    PubMed  CAS  Google Scholar 

  28. Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367:277–281. doi:10.1038/367277a0

    Article  PubMed  CAS  Google Scholar 

  29. Calnan BJ, Szychowski S, Chan FK, Cado D, Winoto A (1995) A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3:273–282. doi:10.1016/1074-7613(95)90113-2

    Article  PubMed  CAS  Google Scholar 

  30. Zhou T, Cheng J, Yang P et al (1996) Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med 183:1879–1892. doi:10.1084/jem.183.4.1879

    Article  PubMed  CAS  Google Scholar 

  31. Lin B, Kolluri SK, Lin F et al (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116:527–540. doi:10.1016/S0092-8674(04)00162-X

    Article  PubMed  CAS  Google Scholar 

  32. Luciano F, Krajewska M, Ortiz-Rubio P et al (2007) Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 109:3849–3855. doi:10.1182/blood-2006-11-056879

    Article  PubMed  CAS  Google Scholar 

  33. Thompson J, Winoto A (2008) During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. J Exp Med 205:1029–1036. doi:10.1084/jem.20080101

    Article  PubMed  CAS  Google Scholar 

  34. Kolluri SK, Zhu X, Zhou X et al (2008) A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14:285–298. doi:10.1016/j.ccr.2008.09.002

    Article  PubMed  CAS  Google Scholar 

  35. Tiegs SL, Russell DM, Nemazee D (1993) Receptor editing in self-reactive bone marrow B cells. J Exp Med 177:1009–1020. doi:10.1084/jem.177.4.1009

    Article  PubMed  CAS  Google Scholar 

  36. Hartley SB, Cooke MP, Fulcher DA et al (1993) Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72:325–335. doi:10.1016/0092-8674(93)90111-3

    Article  PubMed  CAS  Google Scholar 

  37. Nisitani S, Tsubata T, Murakami M, Okamoto M, Honjo T (1993) The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow. J Exp Med 178:1247–1254. doi:10.1084/jem.178.4.1247

    Article  PubMed  CAS  Google Scholar 

  38. Fang W, Weintraub BC, Dunlap B et al (1998) Self-reactive B lymphocytes overexpressing Bcl-xL escape negative selection and are tolerized by clonal anergy and receptor editing. Immunity 9:35–45. doi:10.1016/S1074-7613(00)80586-5

    Article  PubMed  CAS  Google Scholar 

  39. Enders A, Bouillet P, Puthalakath H, Xu Y, Tarlinton DM, Strasser A (2003) Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreative B cells. J Exp Med 198:1119–1126. doi:10.1084/jem.20030411

    Article  PubMed  CAS  Google Scholar 

  40. Hernandez J, Aung S, Redmond WL, Sherman LA (2001) Phenotypic and functional analysis of CD8+ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J Exp Med 194:707–717. doi:10.1084/jem.194.6.707

    Article  PubMed  CAS  Google Scholar 

  41. Davey GM, Kurts C, Miller JF et al (2002) Peripheral deletion of autoreactive CD8 T cells by cross presentation of self-antigen occurs by a Bcl-2-inhibitable pathway mediated by Bim. J Exp Med 196:947–955. doi:10.1084/jem.20020827

    Article  PubMed  CAS  Google Scholar 

  42. Redmond WL, Wei CH, Kreuwel HT, Sherman L (2008) A. The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen. J Immunol 180:5275–5282

    PubMed  CAS  Google Scholar 

  43. Erlacher M, Laabi V, Manzl C et al (2006) Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 203:2939–2951. doi:10.1084/jem.20061552

    Article  PubMed  CAS  Google Scholar 

  44. Matsuzaki Y, Nakayama K-I, Nakayama K et al (1997) Role of bcl-2 in the development of lymphoid cells from the hematopoietic stem cell. Blood 89:853–862

    PubMed  CAS  Google Scholar 

  45. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240. doi:10.1016/0092-8674(93)80065-M

    Article  PubMed  CAS  Google Scholar 

  46. Russell JH, Rush B, Weaver C, Wang R (1993) Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide. Proc Natl Acad Sci USA 90:4409–4413. doi:10.1073/pnas.90.10.4409

    Article  PubMed  CAS  Google Scholar 

  47. Russell JH, Wang R (1993) Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol 23:2379–2382. doi:10.1002/eji.1830230951

    Article  PubMed  CAS  Google Scholar 

  48. Brunner T, Mogil RJ, LaFace D et al (1995) Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:441–444. doi:10.1038/373441a0

    Article  PubMed  CAS  Google Scholar 

  49. Dhein J, Walczak H, Baumler C, Debatin K-M, Krammer PH (1995) Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:438–441. doi:10.1038/373438a0

    Article  PubMed  CAS  Google Scholar 

  50. Mogil RJ, Radvanyi L, Gonzalez-Quintial R et al (1995) Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int Immunol 7:1451–1458. doi:10.1093/intimm/7.9.1451

    Article  PubMed  CAS  Google Scholar 

  51. Van Parijs L, Ibraghimov A, Abbas AK (1996) The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 4:321–328. doi:10.1016/S1074-7613(00)80440-9

    Article  PubMed  Google Scholar 

  52. Strasser A, Harris AW, Cory S (1991) Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67:889–899. doi:10.1016/0092-8674(91)90362-3

    Article  PubMed  CAS  Google Scholar 

  53. Strasser A, Whittingham S, Vaux DL et al (1991) Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA 88:8661–8665. doi:10.1073/pnas.88.19.8661

    Article  PubMed  CAS  Google Scholar 

  54. Hildeman DA, Zhu Y, Mitchell TC et al (2002) Activated T cell death in vivo mediated by pro-apoptotic Bcl-2 family member, Bim. Immunity 16:759–767. doi:10.1016/S1074-7613(02)00322-9

    Article  PubMed  CAS  Google Scholar 

  55. Pellegrini M, Belz G, Bouillet P, Strasser A (2003) Shut down of an acute T cell immune response to viral infection is mediated by the pro-apoptotic Bcl-2 homology 3-only protein Bim. Proc Natl Acad Sci USA 100:14175–14180. doi:10.1073/pnas.2336198100

    Article  PubMed  CAS  Google Scholar 

  56. Hughes PD, Belz GT, Fortner K, Budd RC, Strasser A, Bouillet P (2008) Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 28:197–205. doi:10.1016/j.immuni.2007.12.017

    Article  PubMed  CAS  Google Scholar 

  57. Weant AE, Michalek RD, Khan IU, Holbrook BC, Willingham MC, Grayson JM (2008) Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 28:218–230. doi:10.1016/j.immuni.2007.12.014

    Article  PubMed  CAS  Google Scholar 

  58. Hutcheson J, Scatizzi JC, Siddiqui AM et al (2008) Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 28:206–217. doi:10.1016/j.immuni.2007.12.015

    Article  PubMed  CAS  Google Scholar 

  59. Rieux-Laucat F, Le Deist F, Hivroz C et al (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349. doi:10.1126/science.7539157

    Article  PubMed  CAS  Google Scholar 

  60. Snow AL, Oliveira JB, Zheng L, Dale JK, Fleisher TA, Lenardo MJ (2008) Critical role for BIM in T cell receptor restimulation-induced death. Biol Direct 3:34. doi:10.1186/1745-6150-3-34

  61. Fischer SF, Bouillet P, O’Donnell K, Light A, Tarlinton DM, Strasser A (2007) Pro-apoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody forming cells. Blood 110:3978–3984. doi:10.1182/blood-2007-05-091306

    Article  PubMed  CAS  Google Scholar 

  62. Strasser A, Harris AW, Cory SE (1993) μ-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene 8:1–9

    PubMed  CAS  Google Scholar 

  63. Peschon JJ, Morrissey PJ, Grabstein KH et al (1994) Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180:1955–1960. doi:10.1084/jem.180.5.1955

    Article  PubMed  CAS  Google Scholar 

  64. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SEG, Murray R (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181:1519–1526. doi:10.1084/jem.181.4.1519

    Article  Google Scholar 

  65. Maraskovsky E, O’Reilly LA, Teepe M, Corcoran LM, Peschon JJ, Strasser A (1997) Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1 −/− mice. Cell 89:1011–1019. doi:10.1016/S0092-8674(00)80289-5

    Article  PubMed  CAS  Google Scholar 

  66. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL (1997) Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89:1033–1041. doi:10.1016/S0092-8674(00)80291-3

    Article  PubMed  CAS  Google Scholar 

  67. K-i Nakayama, Nakayama K, Izumi N et al (1993) Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261:1584–1588. doi:10.1126/science.8372353

    Article  Google Scholar 

  68. Kamada S, Shimono A, Shinto Y et al (1995) Bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus andspleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Res 55:354–359

    PubMed  CAS  Google Scholar 

  69. Motoyama N, Wang FP, Roth KA et al (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x deficient mice. Science 267:1506–1510. doi:10.1126/science.7878471

    Article  PubMed  CAS  Google Scholar 

  70. Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ (2003) Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426:671–676. doi:10.1038/nature02067

    Article  PubMed  CAS  Google Scholar 

  71. Opferman J, Iwasaki H, Ong CC et al (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101–1104. doi:10.1126/science.1106114

    Article  PubMed  CAS  Google Scholar 

  72. Akashi K, He X, Chen J et al (2003) Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 101:383–389. doi:10.1182/blood-2002-06-1780

    Article  PubMed  CAS  Google Scholar 

  73. Dzhagalov I, St John A, He YW (2007) The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 109:1620–1626. doi:10.1182/blood-2006-03-013771

    Article  PubMed  CAS  Google Scholar 

  74. Ma A, Pena JC, Chang B et al (1995) Bclx regulates the survival of double-positive thymocytes. Proc Natl Acad Sci USA 92:4763–4767. doi:10.1073/pnas.92.11.4763

    Article  PubMed  CAS  Google Scholar 

  75. Bouillet P, Cory S, Zhang L-C, Strasser A, Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency are prevented by loss of its BH3-only antagonist Bim. Dev Cell 1:645–653. doi:10.1016/S1534-5807(01)00083-1

    Article  PubMed  CAS  Google Scholar 

  76. Akhtar RS, Klocke BJ, Strasser A, Roth KA (2008) Loss of BH3-only protein Bim inhibits apoptosis of hemopoietic cells in the fetal liver and male germ cells but not neuronal cells in bcl-x-deficient mice. J Histochem Cytochem 56:921–927. doi:10.1369/jhc.2008.951749

    Article  PubMed  CAS  Google Scholar 

  77. Orlofsky A, Weiss LM, Kawachi N, Prystowsky MB (2002) Deficiency in the anti-apoptotic protein A1-a results in a diminished acute inflammatory response. J Immunol 168:1840–1846

    PubMed  CAS  Google Scholar 

  78. Hamasaki A, Sendo F, Nakayama K et al (1998) Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med 188:1985–1992. doi:10.1084/jem.188.11.1985

    Article  PubMed  CAS  Google Scholar 

  79. Xiang Z, Ahmed AA, Moller C, Nakayama K, Hatakeyama S, Nilsson G (2001) Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation. J Exp Med 194:1561–1569. doi:10.1084/jem.194.11.1561

    Article  PubMed  CAS  Google Scholar 

  80. Motoyama N, Kimura T, Takahashi T, Watanabe T, Nakano T (1999) bcl-x prevents apoptotic cell death of both primitive and definitive erythrocytes at the end of maturation. J Exp Med 189:1691–1698. doi:10.1084/jem.189.11.1691

    Article  PubMed  CAS  Google Scholar 

  81. Wagner KU, Claudio E, Rucker EB III et al (2000) Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly. Development 127:4949–4958

    PubMed  CAS  Google Scholar 

  82. Rhodes MM, Kopsombut P, Bondurant MC, Price JO, Koury MJ (2005) Bcl-x(L) prevents apoptosis of late-stage erythroblasts but does not mediate the antiapoptotic effect of erythropoietin. Blood 106:1857–1863. doi:10.1182/blood-2004-11-4344

    Article  PubMed  CAS  Google Scholar 

  83. Ismail M, Gibson FM, Gordon-Smith EC, Rutherford TR (2001) Bcl-2 and Bcl-x expression in the CD34+ cells of aplastic anaemia patients: relationship with increased apoptosis and upregulation of Fas antigen. Br J Haematol 113:706–712. doi:10.1046/j.1365-2141.2001.02810.x

    Article  PubMed  CAS  Google Scholar 

  84. Diwan A, Koesters AG, Odley AM et al (2007) Unrestrained erythroblast development in Nix−/− mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci USA 104:6794–6799. doi:10.1073/pnas.0610666104

    Article  PubMed  CAS  Google Scholar 

  85. Sorenson CM, Rogers SA, Korsmeyer SJ, Hammerman MR (1995) Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice. Am J Physiol 268:F73–F81

    PubMed  CAS  Google Scholar 

  86. Bouillet P, Robati M, Bath ML, Strasser A (2005) Polycystic kidney disease prevented by transgenic RNA interference. Cell Death Differ 12:831–833. doi:10.1038/sj.cdd.4401603

    Article  PubMed  CAS  Google Scholar 

  87. Lu W, Peissel B, Babakhanlou H et al (1997) Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nat Genet 17:179–181. doi:10.1038/ng1097-179

    Article  PubMed  CAS  Google Scholar 

  88. Hughes P, Robati M, Lu W, Zhou J, Strasser A, Bouillet P (2006) Loss of PKD1 and loss of Bcl-2 elicit polycystic kidney disease through distinct mechanisms. Cell Death Differ 13:1123–1127. doi:10.1038/sj.cdd.4401815

    Article  PubMed  CAS  Google Scholar 

  89. Orth JM, Gunsalus GL, Lamperti AA (1988) Evidence from Sertoli Cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli Cells produced during perinatal development. Endocrinology 122:787–794

    Article  PubMed  CAS  Google Scholar 

  90. Furuchi T, Masuko K, Nishimune Y, Obinata M, Matsui Y (1996) Inhibition of testicular germ cell apoptosis and differentiation in mice misexpressing Bcl-2 in spermatogonia. Development 122:1703–1709

    PubMed  CAS  Google Scholar 

  91. Rodriguez I, Ody C, Araki K, Garcia I, Vassalli P (1997) An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. EMBO J 16:2262–2270. doi:10.1093/emboj/16.9.2262

    Article  PubMed  CAS  Google Scholar 

  92. Knudson CM, Tung KSK, Tourtellotte WG, Brown GAJ, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270:96–99. doi:10.1126/science.270.5233.96

    Article  PubMed  CAS  Google Scholar 

  93. Russell LD, Chiarini-Garcia H, Korsmeyer SJ, Knudson CM (2002) Bax-dependent spermatogonia apoptosis is required for testicular development and spermatogenesis. Biol Reprod 66:950–958. doi:10.1095/biolreprod66.4.950

    Article  PubMed  CAS  Google Scholar 

  94. Ross AJ, Waymire KG, Moss JE et al (1998) Testicular degeneration in Bclw-deficient mice. Nat Genet 18:251–256. doi:10.1038/ng0398-251

    Article  PubMed  CAS  Google Scholar 

  95. Print CG, Loveland KL, Gibson L et al (1998) Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci USA 95:12424–12431. doi:10.1073/pnas.95.21.12424

    Article  PubMed  CAS  Google Scholar 

  96. Ross AJ, Amy SP, Mahar PL et al (2001) BCLW mediates survival of postmitotic Sertoli cells by regulating BAX activity. Dev Biol 239:295–308. doi:10.1006/dbio.2001.0445

    Article  PubMed  CAS  Google Scholar 

  97. Kasai S, Chuma S, Motoyama N, Nakatsuji N (2003) Haploinsufficiency of Bcl-x leads to male-specific defects in fetal germ cells: differential regulation of germ cell apoptosis between the sexes. Dev Biol 264:202–216. doi:10.1016/S0012-1606(03)00400-7

    Article  PubMed  CAS  Google Scholar 

  98. Rucker EB III, Dierisseau P, Wagner KU et al (2000) Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis. Mol Endocrinol 14:1038–1052. doi:10.1210/me.14.7.1038

    Article  PubMed  CAS  Google Scholar 

  99. Coultas L, Bouillet P, Loveland KL et al (2005) Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. EMBO J 24:3963–3973. doi:10.1038/sj.emboj.7600857

    Article  PubMed  CAS  Google Scholar 

  100. Abe-Dohmae S, Harada N, Yamada K, Tanaka R (1993) bcl-2 gene is highly expressed during neurogenesis in the central nervous system. Biochem Biophys Res Commun 191:915–921. doi:10.1006/bbrc.1993.1304

    Article  PubMed  CAS  Google Scholar 

  101. Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ (1994) bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development 120:301–311

    PubMed  CAS  Google Scholar 

  102. Nakayama K, Nakayama K-I, Negishi I, Kuida K, Sawa H, Loh DY (1994) Targeted disruption of bcl-2αβ in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci USA 91:3700–3704. doi:10.1073/pnas.91.9.3700

    Article  PubMed  CAS  Google Scholar 

  103. Michaelidis TM, Sendtner M, Cooper JD et al (1996) Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17:75–89. doi:10.1016/S0896-6273(00)80282-2

    Article  PubMed  CAS  Google Scholar 

  104. Allsopp TE, Wyatt S, Paterson HF, Davies AM (1993) The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73:295–307. doi:10.1016/0092-8674(93)90230-N

    Article  PubMed  CAS  Google Scholar 

  105. Garcia I, Martinou I, Tsujimoto Y, Martinou J-C (1992) Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science 258:302–304. doi:10.1126/science.1411528

    Article  PubMed  CAS  Google Scholar 

  106. Farlie PG, Dringen R, Rees SM, Kannourakis G, Bernard O (1995) bcl-2 transgene expression can protect neurons against developmental and induced cell death. Proc Natl Acad Sci USA 92:4397–4401. doi:10.1073/pnas.92.10.4397

    Article  PubMed  CAS  Google Scholar 

  107. Martinou J-C, Dubois-Dauphin M, Staple JK et al (1994) Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030. doi:10.1016/0896-6273(94)90266-6

    Article  PubMed  CAS  Google Scholar 

  108. Gibson L, Holmgreen S, Huang DCS et al (1996) bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 13:665–675

    PubMed  CAS  Google Scholar 

  109. Minami M, Jin KL, Li W, Nagayama T, Henshall DC, Simon RP (2000) Bcl-w expression is increased in brain regions affected by focal cerebral ischemia in the rat. Neurosci Lett 279:193–195. doi:10.1016/S0304-3940(99)00987-8

    Article  PubMed  CAS  Google Scholar 

  110. Hamner S, Arumae U, Li-Ying Y, Sun YF, Saarma M, Lindholm D (2001) Functional characterization of two splice variants of rat bad and their interaction with Bcl-w in sympathetic neurons. Mol Cell Neurosci 17:97–106. doi:10.1006/mcne.2000.0905

    Article  PubMed  CAS  Google Scholar 

  111. Korhonen L, Belluardo N, Mudo G, Lindholm D (2003) Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. Eur J NeuroSci 18:1121–1134. doi:10.1046/j.1460-9568.2003.02826.x

    Article  PubMed  Google Scholar 

  112. Akhtar RS, Ness JM, Roth KA (2004) Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta 1644:189–203. doi:10.1016/j.bbamcr.2003.10.013

    Article  PubMed  CAS  Google Scholar 

  113. Sasaki T, Kitagawa K, Yagita Y et al (2006) Bcl2 enhances survival of newborn neurons in the normal and ischemic hippocampus. J Neurosci Res 84:1187–1196. doi:10.1002/jnr.21036

    Article  PubMed  CAS  Google Scholar 

  114. Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S (1997) Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277:559–562. doi:10.1126/science.277.5325.559

    Article  PubMed  CAS  Google Scholar 

  115. Heaton MB, Moore DB, Paiva M, Gibbs T, Bernard O (1999) Bcl-2 overexpression protects the neonatal cerebellum from ethanol neurotoxicity. Brain Res 817:13–18. doi:10.1016/S0006-8993(98)01173-1

    Article  PubMed  CAS  Google Scholar 

  116. Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17:401–411. doi:10.1016/S0896-6273(00)80173-7

    Article  PubMed  CAS  Google Scholar 

  117. White FA, Keller-Peck CR, Knudson CM, Korsmeyer SJ, Snider WD (1998) Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J Neurosci 18:1428–1439

    PubMed  CAS  Google Scholar 

  118. Deshmukh M, Johnson EM Jr (1998) Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21:695–705. doi:10.1016/S0896-6273(00)80587-5

    Article  PubMed  CAS  Google Scholar 

  119. Middleton G, Davies AM (2001) Populations of NGF-dependent neurones differ in their requirement for BAX to undergo apoptosis in the absence of NGF/TrkA signalling in vivo. Development 128:4715–4728

    PubMed  CAS  Google Scholar 

  120. Shindler KS, Latham CB, Roth KA (1997) Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. J Neurosci 17:3112–3119

    PubMed  CAS  Google Scholar 

  121. Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N (1997) Neurodegeneration in Lurcher mice caused by mutation in δ2 glutamate receptor gene. Nature 388:769–773. doi:10.1038/42009

    Article  PubMed  CAS  Google Scholar 

  122. Doughty ML, De Jager PL, Korsmeyer SJ, Heintz N (2000) Neurodegeneration in Lurcher mice occurs via multiple cell death pathways. J Neurosci 20:3687–3694

    PubMed  CAS  Google Scholar 

  123. Sun YF, Yu LY, Saarma M, Timmusk T, Arumae U (2001) Neuron-specific Bcl-2 homology 3 domain-only splice variant of Bak is anti-apoptotic in neurons, but pro-apoptotic in non-neuronal cells. J Biol Chem 276:16240–16247. doi:10.1074/jbc.M010419200

    Article  PubMed  CAS  Google Scholar 

  124. Uo T, Kinoshita Y, Morrison RS (2005) Neurons exclusively express N-Bak, a BH3 domain-only Bak isoform that promotes neuronal apoptosis. J Biol Chem 280:9065–9073. doi:10.1074/jbc.M413030200

    Article  PubMed  CAS  Google Scholar 

  125. Putcha GV, Harris CA, Moulder KL, Easton RM, Thompson CB, Johnson EM Jr (2002) Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice. J Cell Biol 157:441–453. doi:10.1083/jcb.200110108

    Article  PubMed  CAS  Google Scholar 

  126. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf-1 (CED-4 homologue) regulates programmed cell death in mammalian development. Cell 94:727–737. doi:10.1016/S0092-8674(00)81732-8

    Article  PubMed  CAS  Google Scholar 

  127. Hakem R, Hakem A, Duncan GS et al (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352. doi:10.1016/S0092-8674(00)81477-4

    Article  PubMed  CAS  Google Scholar 

  128. Kuida K, Haydar TF, Kuan C-Y et al (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337. doi:10.1016/S0092-8674(00)81476-2

    Article  PubMed  CAS  Google Scholar 

  129. Kuida K, Zheng TS, Na S et al (1996) Decreased apoptosis in the brain and premature lethality in CPP32- deficient mice. Nature 384:368–372. doi:10.1038/384368a0

    Article  PubMed  CAS  Google Scholar 

  130. Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M (1997) Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 272:18842–18848. doi:10.1074/jbc.272.30.18842

    Article  PubMed  CAS  Google Scholar 

  131. Imaizumi K, Morihara T, Mori Y et al (1999) The cell death-promoting gene DP5, which interacts with the Bcl-2 family, is induced during neuronal apoptosis following exposure to amyloid β protein. J Biol Chem 274:7975–7981. doi:10.1074/jbc.274.12.7975

    Article  PubMed  CAS  Google Scholar 

  132. Imaizumi K, Benito A, Kiryu-Seo S et al (2004) Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death. J Neurosci 24:3721–3725. doi:10.1523/JNEUROSCI.5101-03.2004

    Article  PubMed  CAS  Google Scholar 

  133. Coultas L, Terzano S, Thomas T et al (2007) Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis. J Cell Sci 120:2044–2052. doi:10.1242/jcs.002063

    Article  PubMed  CAS  Google Scholar 

  134. Steckley D, Karajgikar M, Dale LB et al (2007) Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci 27:12989–12999. doi:10.1523/JNEUROSCI.3400-07.2007

    Article  PubMed  CAS  Google Scholar 

  135. Wyttenbach A, Tolkovsky AM (2006) The BH3-only protein Puma is both necessary and sufficient for neuronal apoptosis induced by DNA damage in sympathetic neurons. J Neurochem 96:1213–1226. doi:10.1111/j.1471-4159.2005.03676.x

    Article  PubMed  CAS  Google Scholar 

  136. Akhtar RS, Geng Y, Klocke BJ et al (2006) BH3-only proapoptotic Bcl-2 family members Noxa and Puma mediate neural precursor cell death. J Neurosci 26:7257–7264. doi:10.1523/JNEUROSCI.0196-06.2006

    Article  PubMed  CAS  Google Scholar 

  137. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J (2001) Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29:629–643. doi:10.1016/S0896-6273(01)00239-2

    Article  PubMed  CAS  Google Scholar 

  138. Harris CA, Johnson EM Jr (2001) BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons. J Biol Chem 276:37754–37760

    PubMed  CAS  Google Scholar 

  139. Miller TM, Moulder KL, Knudson CM et al (1997) Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J Cell Biol 139:205–217. doi:10.1083/jcb.139.1.205

    Article  PubMed  CAS  Google Scholar 

  140. Linseman DA, Phelps RA, Bouchard RJ et al (2002) Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. J Neurosci 22:9287–9297

    PubMed  CAS  Google Scholar 

  141. Biswas SC, Greene LA (2002) Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem 277:49511–49516. doi:10.1074/jbc.M208086200

    Article  PubMed  CAS  Google Scholar 

  142. Perier C, Bove J, Wu DC et al (2007) Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 104:8161–8166. doi:10.1073/pnas.0609874104

    Article  PubMed  CAS  Google Scholar 

  143. Bouillet P, Robati M, Adams JM, Strasser A (2003) Loss of pro-apoptotic BH3-only Bcl-2 family member Bim does not protect mutant Lurcher mice from neurodegeneration. J Neurosci Res 74:777–781. doi:10.1002/jnr.10805

    Article  PubMed  CAS  Google Scholar 

  144. Shimohama S, Fujimoto S, Sumida Y, Tanino H (1998) Differential expression of rat brain bcl-2 family proteins in development and aging. Biochem Biophys Res Commun 252:92–96. doi:10.1006/bbrc.1998.9577

    Article  PubMed  CAS  Google Scholar 

  145. Orike N, Middleton G, Borthwick E, Buchman V, Cowen T, Davies AM (2001) Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. J Biol Chem 154:995–1005

    CAS  Google Scholar 

  146. Shindler KS, Yunker AMR, Cahn R, Zha J, Korsmeyer SJ, Roth KA (1998) Trophic support promotes survival of bcl-x-deficient telencephalic cells in vitro. Cell Death Differ 5:901–910. doi:10.1038/sj.cdd.4400421

    Article  PubMed  CAS  Google Scholar 

  147. Ranger AM, Zha J, Harada H et al (2003) Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci USA 100:9324–9329. doi:10.1073/pnas.1533446100

    Article  PubMed  Google Scholar 

  148. Datta SR, Ranger AM, Lin MZ et al (2002) Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3:631–643. doi:10.1016/S1534-5807(02)00326-X

    Article  PubMed  CAS  Google Scholar 

  149. Reed JC (2003) Apoptosis-targeted therapies for cancer. Cancer Cell 3(1):17–22. doi:10.1016/s1535-6108(02)00241-6

    Article  PubMed  CAS  Google Scholar 

  150. Danial NN, Walensky LD, Zhang CY et al (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144–153. doi:10.1038/nm1717

    Article  PubMed  CAS  Google Scholar 

  151. Philipson LH, Roe MW (2008) When BAD is good for beta cells. Cell Metab 7:280–281. doi:10.1016/j.cmet.2008.03.009

    Article  PubMed  CAS  Google Scholar 

  152. Scarabelli TM, Knight R, Stephanou A et al (2006) Clinical implications of apoptosis in ischemic myocardium. Curr Probl Cardiol 31:181–264. doi:10.1016/j.cpcardiol.2005.11.002

    Article  PubMed  Google Scholar 

  153. Doonan F, Donovan M, Gomez-Vicente V, Bouillet P, Cotter TG (2007) Bim expression indicates the pathway to retinal cell death in development and degeneration. J Neurosci 27:10887–10894. doi:10.1523/JNEUROSCI.0903-07.2007

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the NH&MRC (Program Grant, Career Development Award and Project Grant), and the Charles and Sylvia Viertel Charitable Foundation. We are grateful to our colleagues at WEHI for their input in our work and their insightful comments. We apologize to the authors whose contributions have not been cited due to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Philippe Bouillet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mérino, D., Bouillet, P. The Bcl-2 family in autoimmune and degenerative disorders. Apoptosis 14, 570–583 (2009). https://doi.org/10.1007/s10495-008-0308-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-008-0308-4

Keywords

Navigation