Skip to main content
SpringerLink
Log in
Book cover

Essentials of Apoptosis pp 25–61Cite as

The Bcl-2 Family Proteins

  • Chapter
  • First Online:

  • 1468 Accesses

Abstract

The Bcl-2 family proteins are a group of evolutionarily conserved molecules that regulate apoptosis mainly at the site of mitochondria. This family of proteins consists of both antideath and prodeath molecules. The latter are also composed of multidomain prodeath molecules and the BH3-only prodeath molecules. While the BH3-only molecules act at the distal, receiving the death signals, the multidomain prodeath and antideath molecules regulate the mitochondrial outer membrane’s permeability to control apoptosis. Protein interactions among the family members are important for their functions and have been explored for therapeutic purposes, as illustrated by the development of the BH3-only mimetics. Recent studies have also indicated that these molecules can act in other subcellular locations and their functions are beyond apoptosis regulation. Thus, the Bcl-2 family proteins also play important roles in autophagy, cell proliferation, and many other cellular functions.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 1984;226(4678):1097–9.

    Article  PubMed  CAS  Google Scholar 

  2. Cleary ML, Sklar J. 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 USA 1985;82(21):7439–43.

    Article  PubMed  CAS  Google Scholar 

  3. Bakhshi A, Jensen JP, Goldman P, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 1985;41(3):899–906.

    Article  PubMed  CAS  Google Scholar 

  4. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335(6189):440–2.

    Article  PubMed  CAS  Google Scholar 

  5. Nunez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol 1990;144(9):3602–10.

    PubMed  CAS  Google Scholar 

  6. Hardwick JM. Viral interference with apoptosis. Semin Cell Dev Biol 1998;9(3):339–49.

    Article  PubMed  CAS  Google Scholar 

  7. Youle RJ, Strasser A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008;9(1):47–59.

    Article  PubMed  CAS  Google Scholar 

  8. Hengartner MO, Horvitz HR. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene Bcl-2. Cell 1994;76(4):665–76.

    Article  PubMed  CAS  Google Scholar 

  9. Conradt B, Horvitz HR. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 1998;93(4):519–29.

    Article  PubMed  CAS  Google Scholar 

  10. Vernooy SY, Copeland J, Ghaboosi N, Griffin EE, Yoo SJ, Hay BA. Cell death regulation in Drosophila: Conservation of mechanism and unique insights. J Cell Biol 2000;150(2):F69–76.

    Article  PubMed  CAS  Google Scholar 

  11. Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax [see comments]. Nature 1994;369(6478):321–3.

    Article  PubMed  CAS  Google Scholar 

  12. Chittenden T, Flemington C, Houghton AB, et al. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 1995;14(22):5589–96.

    PubMed  CAS  Google Scholar 

  13. Hunter JJ, Bond BL, Parslow TG. Functional dissection of the human Bc12 protein: Sequence requirements for inhibition of apoptosis. Mol Cell Biol 1996;16(3):877–83.

    PubMed  CAS  Google Scholar 

  14. Huang DC, Adams JM, Cory S. The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. EMBO J 1998;17(4):1029–39.

    Article  PubMed  CAS  Google Scholar 

  15. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999;13:1899–911.

    Article  PubMed  CAS  Google Scholar 

  16. Cory S, Huang DC, Adams JM. The Bcl-2 family: Roles in cell survival and oncogenesis. Oncogene 2003;22(53):8590–607.

    Article  PubMed  CAS  Google Scholar 

  17. Wang K, Gross A, Waksman G, Korsmeyer SJ. Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 1998;18(10):6083-9.

    PubMed  CAS  Google Scholar 

  18. Levine B, Sinha S, Kroemer G. Bcl-2 family members: Dual regulators of apoptosis and autophagy. Autophagy 2008;4(5):600–6.

    PubMed  CAS  Google Scholar 

  19. Chen L, Willis SN, Wei A, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005;17(3):393–403.

    Article  PubMed  CAS  Google Scholar 

  20. Kuwana T, Bouchier-Hayes L, Chipuk JE, et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005;17(4):525–35.

    Article  PubMed  CAS  Google Scholar 

  21. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002;2(3):183–92.

    Article  PubMed  CAS  Google Scholar 

  22. Kim H, Rafiuddin-Shah M, Tu HC, et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006;8(12):1348–58.

    Article  PubMed  CAS  Google Scholar 

  23. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74(4):609–19.

    Article  PubMed  CAS  Google Scholar 

  24. Hsu YT, Youle RJ. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 1998;273(17):10777–83.

    Article  PubMed  CAS  Google Scholar 

  25. Sedlak TW, Oltvai ZN, Yang E, et al. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci USA 1995;92(17):7834–8.

    Article  PubMed  CAS  Google Scholar 

  26. Hanada M, Aime-Sempe C, Sato T, Reed JC. Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J Biol Chem 1995;270(20):11962–9.

    Article  PubMed  CAS  Google Scholar 

  27. Leber B, Lin J, Andrews DW. Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 2007;12(5):897–911.

    Article  PubMed  CAS  Google Scholar 

  28. Nechushtan A, Smith CL, Hsu YT, Youle RJ. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 1999;18(9):2330–41.

    Article  PubMed  CAS  Google Scholar 

  29. Desagher S, Osen-Sand A, Nichols A, et al. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 1999;144(5):891–901.

    Article  PubMed  CAS  Google Scholar 

  30. Hinds MG, Smits C, Fredericks-Short R, et al. Bim, Bad and Bmf: Intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 2007;14(1):128–36.

    Article  PubMed  CAS  Google Scholar 

  31. Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ. BID: A novel BH3 domain-only death agonist. Genes Dev 1996;10(22):2859–69.

    Article  PubMed  CAS  Google Scholar 

  32. Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes [comment]. Cell 1994;79(2):189–92.

    Article  PubMed  CAS  Google Scholar 

  33. Willis SN, Fletcher JI, Kaufmann T, et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 2007;315(5813):856–9.

    Article  PubMed  CAS  Google Scholar 

  34. Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC. Differential regulation of Bax and Bak by anti-apoptotic Bcl-2 family proteins Bcl-B and Mcl-1. J Biol Chem 2008;283(15):9580-6.

    Article  PubMed  CAS  Google Scholar 

  35. Willis SN, Chen L, Dewson G, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005;19(11):1294–305.

    Article  PubMed  CAS  Google Scholar 

  36. Ke N, Godzik A, Reed JC. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J Biol Chem 2001;276(16):12481–4.

    Article  PubMed  CAS  Google Scholar 

  37. 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 1997;94(23):12401–6.

    Article  PubMed  CAS  Google Scholar 

  38. Wei MC, Lindsten T, Mootha VK, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000;14(16):2060–71.

    PubMed  CAS  Google Scholar 

  39. Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002;22(11):3577–89.

    Article  PubMed  CAS  Google Scholar 

  40. Diaz JL, Oltersdorf T, Horne W, et al. A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members. J Biol Chem 1997;272(17):11350–5.

    Article  PubMed  CAS  Google Scholar 

  41. Eskes R, Desagher S, Antonsson B, Martinou JC. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 2000;20(3):929–35.

    Article  PubMed  CAS  Google Scholar 

  42. Muchmore SW, Sattler M, Liang H, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 1996;381(6580):335–41.

    Article  PubMed  CAS  Google Scholar 

  43. Tan KO, Tan KM, Chan SL, et al. MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains. J Biol Chem 2001;276(4):2802–7.

    Article  PubMed  CAS  Google Scholar 

  44. Ray R, Chen G, Vande Velde C, et al. BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem 2000;275(2):1439–48.

    Article  PubMed  CAS  Google Scholar 

  45. Cheng EH, Levine B, Boise LH, Thompson CB, Hardwick JM. Bax-independent inhibition of apoptosis by Bcl-XL. Nature 1996;379(6565):554–6.

    Article  PubMed  CAS  Google Scholar 

  46. Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001;8(3):705–11.

    Article  PubMed  CAS  Google Scholar 

  47. Petros AM, Medek A, Nettesheim DG, et al. Solution structure of the antiapoptotic protein Bcl-2. Proc Natl Acad Sci USA 2001;98(6):3012–7.

    Article  PubMed  CAS  Google Scholar 

  48. McDonnell J, Fushman D, Milliman C, Korsmeyer S, Cowburn D. Solution structure of the proapoptotic molecule BID: A structural basis for apoptotic agonist and antagonists. Cell 1999;96(5):625–34.

    Article  PubMed  CAS  Google Scholar 

  49. Chou J, Li H, Salvesen G, Yuan J, Wagner G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 1999;96(5):615–24.

    Article  PubMed  CAS  Google Scholar 

  50. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007;26(9):1324–37.

    Article  PubMed  CAS  Google Scholar 

  51. 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-X(L). Cell 1996;87(4):619–28.

    Article  PubMed  CAS  Google Scholar 

  52. Tsuruta F, Sunayama J, Mori Y, et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 2004;23(8):1889–99.

    Article  PubMed  CAS  Google Scholar 

  53. Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 2003;5(4):320–9.

    Article  PubMed  CAS  Google Scholar 

  54. Cohen HY, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 2004;13(5):627–38.

    Article  PubMed  CAS  Google Scholar 

  55. Puthalakath H, Villunger A, O'Reilly LA, et al. Bmf: A proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001;293(5536):1829–32.

    Article  PubMed  CAS  Google Scholar 

  56. 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 1999;3(3):287–96.

    Article  PubMed  CAS  Google Scholar 

  57. Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 2003;301(5632):513–7.

    Article  PubMed  CAS  Google Scholar 

  58. Leu JI, George DL. Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev 2007;21(23):3095–109.

    Article  PubMed  CAS  Google Scholar 

  59. Takahashi Y, Karbowski M, Yamaguchi H, et al. Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis. Mol Cell Biol 2005;25(21):9369–82.

    Article  PubMed  CAS  Google Scholar 

  60. Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004;303(5660):1010–4.

    Article  PubMed  CAS  Google Scholar 

  61. Leu JI, Dumont P, Hafey M, Murphy ME, George DL. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 2004;6(5):443–50.

    Article  PubMed  CAS  Google Scholar 

  62. Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 2005;309(5741):1732–5.

    Article  PubMed  CAS  Google Scholar 

  63. Jiang P, Du W, Heese K, Wu M. The Bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis. Mol Cell Biol 2006;26(23):9071–82.

    Article  PubMed  CAS  Google Scholar 

  64. Lin B, Kolluri SK, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 2004;116(4):527–40.

    Article  PubMed  CAS  Google Scholar 

  65. Luciano F, Krajewska M, Ortiz-Rubio P, et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 2007;109(9):3849–55.

    Article  PubMed  CAS  Google Scholar 

  66. Chen F, Hersh BM, Conradt B, et al. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 2000;287(5457):1485–9.

    Article  PubMed  CAS  Google Scholar 

  67. Zhang H, Xu Q, Krajewski S, et al. BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. Proc Natl Acad Sci USA 2000;97(6):2597–602.

    Article  PubMed  CAS  Google Scholar 

  68. Chau BN, Cheng EH, Kerr DA, Hardwick JM. Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. Mol Cell 2000;6(1):31–40.

    PubMed  CAS  Google Scholar 

  69. Ng FW, Nguyen M, Kwan T, et al. p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum. J Cell Biol 1997;139(2):327–38.

    Article  PubMed  CAS  Google Scholar 

  70. Brooks C, Wei Q, Feng L, et al. Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci USA 2007;104(28):11649–54.

    Article  PubMed  CAS  Google Scholar 

  71. Kim TH, Zhao Y, Ding WX, et al. Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome c release. Mol Biol Cell 2004;15(7):3061–72.

    Article  PubMed  CAS  Google Scholar 

  72. Shibasaki F, Kondo E, Akagi T, McKeon F. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature 1997;386(6626):728–31.

    Article  PubMed  CAS  Google Scholar 

  73. Wang Q, Gao F, May WS, Zhang Y, Flagg T, Deng X. Bcl2 Negatively regulates DNA double-strand-break repair through a nonhomologous end-joining pathway. Mol Cell 2008;29(4):488–98.

    Article  PubMed  CAS  Google Scholar 

  74. Oakes SA, Scorrano L, Opferman JT, et al. Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc Natl Acad Sci USA 2005;102(1):105–10.

    Article  PubMed  CAS  Google Scholar 

  75. Hetz C, Bernasconi P, Fisher J, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 2006;312(5773):572–6.

    Article  PubMed  CAS  Google Scholar 

  76. Bruey JM, Bruey-Sedano N, Luciano F, et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 2007;129(1):45–56.

    Article  PubMed  CAS  Google Scholar 

  77. Danial NN, Gramm CF, Scorrano L, et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003;424(6951):952–6.

    Article  PubMed  CAS  Google Scholar 

  78. Huang Q, Petros AM, Virgin HW, Fesik SW, Olejniczak ET. Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus. Proc Natl Acad Sci USA 2002;99(6):3428–33.

    Article  PubMed  CAS  Google Scholar 

  79. Kvansakul M, van Delft MF, Lee EF, et al. A structural viral mimic of prosurvival Bcl-2: A pivotal role for sequestering proapoptotic Bax and Bak. Mol Cell 2007;25(6):933–42.

    Article  PubMed  CAS  Google Scholar 

  80. Schendel SL, Azimov R, Pawlowski K, Godzik A, Kagan BL, Reed JC. Ion channel activity of the BH3 only Bcl-2 family member, BID. J Biol Chem 1999;274(31):21932–6.

    Article  PubMed  CAS  Google Scholar 

  81. Cheng EH, Kirsch DG, Clem RJ, et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997;278(5345):1966–8.

    Article  PubMed  CAS  Google Scholar 

  82. Clem RJ, Cheng EH, Karp CL, et al. Modulation of cell death by Bcl-XL through caspase interaction. Proc Natl Acad Sci USA 1998;95(2):554–9.

    Article  PubMed  CAS  Google Scholar 

  83. Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 2000;288(5468):1053–8.

    Article  PubMed  CAS  Google Scholar 

  84. Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 2001;7(3):673–82.

    Article  PubMed  CAS  Google Scholar 

  85. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001;7(3):683–94.

    Article  PubMed  CAS  Google Scholar 

  86. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 2002;4(11):842–9.

    Article  PubMed  CAS  Google Scholar 

  87. Sanchez I, Yuan J. A convoluted way to die. Neuron 2001;29(3):563–6.

    Article  PubMed  CAS  Google Scholar 

  88. Chao JR, Wang JM, Lee SF, et al. mcl-1 is an immediate-early gene activated by the granulocyte- macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol 1998;18(8):4883–98.

    PubMed  CAS  Google Scholar 

  89. Moulding DA, Quayle JA, Hart CA, Edwards SW. Mcl-1 expression in human neutrophils: Regulation by cytokines and correlation with cell survival. Blood 1998;92(7):2495–502.

    PubMed  CAS  Google Scholar 

  90. Karsan A, Yee E, Kaushansky K, Harlan JM. Cloning of human Bcl-2 homologue: Inflammatory cytokines induce human A1 in cultured endothelial cells. Blood 1996;87(8):3089–96.

    PubMed  CAS  Google Scholar 

  91. Chuang PI, Yee E, Karsan A, Winn RK, Harlan JM. A1 is a constitutive and inducible Bcl-2 homologue in mature human neutrophils. Biochem Biophys Res Commun 1998;249(2):361–5.

    Article  PubMed  CAS  Google Scholar 

  92. Hu X, Yee E, Harlan JM, Wong F, Karsan A. Lipopolysaccharide induces the antiapoptotic molecules, A1 and A20, in microvascular endothelial cells. Blood 1998;92(8):2759–65.

    PubMed  CAS  Google Scholar 

  93. Chao DT, Korsmeyer SJ. BCL-2 family: Regulators of cell death. Annu Rev Immunol 1998;16:395–419.

    Article  PubMed  CAS  Google Scholar 

  94. Boise LH, Minn AJ, Noel PJ, et al. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 1995;3(1):87–98.

    Article  PubMed  CAS  Google Scholar 

  95. Boise LH, Gonzalez-Garcia M, Postema CE, et al. Bcl-x, a Bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74(4):597–608.

    Article  PubMed  CAS  Google Scholar 

  96. Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MKB. Exon skipping in Mcl-1 results in a Bcl-2 Homology domain 3 only gene product that promotes cell death. J Biol Chem 2000;275(29):22136–46.

    Article  PubMed  CAS  Google Scholar 

  97. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993;75(2):241–51.

    Article  PubMed  CAS  Google Scholar 

  98. O'Connor L, Strasser A, O'Reilly LA, et al. Bim: A novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998;17(2):384–95.

    Article  PubMed  Google Scholar 

  99. Guo B, Godzik A, Reed JC. Bcl-G, a novel pro-apoptotic member of the Bcl-2 family. J Biol Chem 2001;276(4):2780–5.

    Article  PubMed  CAS  Google Scholar 

  100. Khaled AR, Kim K, Hofmeister R, Muegge K, Durum SK. Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH. Proc Natl Acad Sci USA 1999;96(25):14476–81.

    Article  PubMed  CAS  Google Scholar 

  101. Yin XM. Bid, a BH3-only multi-functional molecule, is at the cross road of life and death. Gene 2006;369:7–19.

    Article  PubMed  CAS  Google Scholar 

  102. Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 2000;290(5497):1761–5.

    Article  PubMed  CAS  Google Scholar 

  103. Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J 2004;23(5):1207–16.

    Article  PubMed  CAS  Google Scholar 

  104. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91(2):231–41.

    Article  PubMed  CAS  Google Scholar 

  105. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997;278(5338):687–9.

    Article  PubMed  CAS  Google Scholar 

  106. Harada H, Becknell B, Wilm M, et al. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 1999;3(4):413–22.

    Article  PubMed  CAS  Google Scholar 

  107. Wang HG, Pathan N, Ethell IM, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999;284(5412):339–43.

    Article  PubMed  CAS  Google Scholar 

  108. Fang G, Chang BS, Kim CN, Perkins C, Thompson CB, Bhalla KN. “Loop” domain is necessary for taxol-induced mobility shift and phosphorylation of Bcl-2 as well as for inhibiting taxol-induced cytosolic accumulation of cytochrome c and apoptosis. Cancer Res 1998;58(15):3202–8.

    PubMed  CAS  Google Scholar 

  109. Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 1999;19(12):8469–78.

    PubMed  CAS  Google Scholar 

  110. Poruchynsky MS, Wang EE, Rudin CM, Blagosklonny MV, Fojo T. Bcl-xL is phosphorylated in malignant cells following microtubule disruption. Cancer Res 1998;58(15):3331–8.

    PubMed  CAS  Google Scholar 

  111. Haldar S, Chintapalli J, Croce CM. Taxol induces Bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 1996;56(6):1253–5.

    PubMed  CAS  Google Scholar 

  112. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 2008;30(6):678–88.

    Article  PubMed  CAS  Google Scholar 

  113. Maiuri MC, Le Toumelin G, Criollo A, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007;26(10):2527–39.

    Article  PubMed  CAS  Google Scholar 

  114. Zhou XM, Liu Y, Payne G, Lutz RJ, Chittenden T. Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem 2000;275(32):25046–51.

    Article  PubMed  CAS  Google Scholar 

  115. Datta SR, Katsov A, Hu L, et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 2000;6(1):41–51.

    PubMed  CAS  Google Scholar 

  116. Yu C, Minemoto Y, Zhang J, et al. JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell 2004;13(3):329–40.

    Article  PubMed  CAS  Google Scholar 

  117. Deng H, Yu F, Chen J, Zhao Y, Xiang J, Lin A. Phosphorylation of bad at Thr201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. J Biol Chem 2008;283(30):20745–60.

    Google Scholar 

  118. Desagher S, Osen-Sand A, Montessuit S, et al. Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 2001;8(3):601–11.

    Article  PubMed  CAS  Google Scholar 

  119. Kamer I, Sarig R, Zaltsman Y, et al. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 2005;122(4):593–603.

    Article  PubMed  CAS  Google Scholar 

  120. Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ. A role for proapoptotic BID in the DNA-damage response. Cell 2005;122(4):579–91.

    Article  PubMed  CAS  Google Scholar 

  121. Kaufmann T, Tai L, Ekert PG, et al. The BH3-only protein bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 2007;129(2):423–33.

    Article  PubMed  CAS  Google Scholar 

  122. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999;15:269–90.

    Article  PubMed  CAS  Google Scholar 

  123. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007;87(1):99–163.

    Article  PubMed  CAS  Google Scholar 

  124. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 2008;18(4):157–64.

    Article  PubMed  CAS  Google Scholar 

  125. Lindsten T, Ross AJ, King A, et al. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell 2000;6(6):1389–99.

    Article  PubMed  CAS  Google Scholar 

  126. Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science 2001;292(5517):727–30.

    Article  PubMed  CAS  Google Scholar 

  127. Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001;15(12):1481–6.

    Article  PubMed  CAS  Google Scholar 

  128. Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B. Role of BAX in the apoptotic response to anticancer agents. Science 2000;290(5493):989–92.

    Article  PubMed  CAS  Google Scholar 

  129. LeBlanc H, Lawrence D, Varfolomeev E, et al. Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 2002;8(3):274–81.

    Article  CAS  Google Scholar 

  130. 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 1996;17(3):401–11.

    Article  PubMed  CAS  Google Scholar 

  131. Shimazu T, Degenhardt K, Nur EKA, et al. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes Dev 2007;21(8):929–41.

    Article  PubMed  CAS  Google Scholar 

  132. Letai AG. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer 2008;8(2):121–32.

    Article  PubMed  CAS  Google Scholar 

  133. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 2008;18(4):157–64.

    Article  PubMed  CAS  Google Scholar 

  134. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007;117(1):112–21.

    Article  PubMed  CAS  Google Scholar 

  135. Huang S, Sinicrope FA. BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res 2008;68(8):2944–51.

    Article  PubMed  CAS  Google Scholar 

  136. Konopleva M, Watt J, Contractor R, et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 2008;68(9):3413–20.

    Article  PubMed  CAS  Google Scholar 

  137. 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 Differ 1994;5(4):411–7.

    PubMed  CAS  Google Scholar 

  138. Zong WX, Li C, Hatzivassiliou G, et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 2003;162(1):59–69.

    Article  PubMed  CAS  Google Scholar 

  139. Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science 2003;300(5616):135–9.

    Article  PubMed  CAS  Google Scholar 

  140. Puthalakath H, O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007;129(7):1337–49.

    Article  PubMed  CAS  Google Scholar 

  141. Saunders JW, Jr. Death in embryonic systems. Science 1966;154(749):604–12.

    Article  PubMed  Google Scholar 

  142. Ranger AM, Malynn BA, Korsmeyer SJ. Mouse models of cell death. Nat Genet 2001;28(2):113–8.

    Article  PubMed  CAS  Google Scholar 

  143. Motoyama N, Wang F, Roth KA, et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 1995;267(5203):1506–10.

    Article  PubMed  CAS  Google Scholar 

  144. Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 2000;14(1):23–7.

    PubMed  CAS  Google Scholar 

  145. Opferman JT, Iwasaki H, Ong CC, et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 2005;307(5712):1101–4.

    Article  PubMed  CAS  Google Scholar 

  146. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993;75(2):229–40.

    Article  PubMed  CAS  Google Scholar 

  147. Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM. Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 2001;1(5):645–53.

    Article  PubMed  CAS  Google Scholar 

  148. Hamasaki A, Sendo F, Nakayama K, et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene [in process citation]. J Exp Med 1998;188(11):1985–92.

    Article  PubMed  CAS  Google Scholar 

  149. Xiang Z, Ahmed AA, Moller C, Nakayama K, Hatakeyama S, Nilsson G. Essential role of the prosurvival Bcl-2 homologue A1 in mast cell survival after allergic activation. J Exp Med 2001;194(11):1561–69.

    Article  PubMed  CAS  Google Scholar 

  150. Print CG, Loveland KL, Gibson L, et al. Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci USA 1998;95(21):12424–31.

    Article  PubMed  CAS  Google Scholar 

  151. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995;270(5233):96–9.

    Article  PubMed  CAS  Google Scholar 

  152. Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins PUMA and Noxa. Science 2003;302(5647):1036–8.

    Article  PubMed  CAS  Google Scholar 

  153. Jeffers JR, Parganas E, Lee Y, et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 2003;4(4):321–8.

    Article  PubMed  CAS  Google Scholar 

  154. Naik E, Michalak EM, Villunger A, Adams JM, Strasser A. Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 2007;176(4):415–24.

    Article  PubMed  CAS  Google Scholar 

  155. Michalak EM, Villunger A, Adams JM, Strasser A. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 2008;15(6):1019–29.

    Article  PubMed  CAS  Google Scholar 

  156. Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999;286(5445):1735–8.

    Article  PubMed  CAS  Google Scholar 

  157. Erlacher M, Labi V, Manzl C, et al. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 2006;203(13):2939–51.

    Article  PubMed  CAS  Google Scholar 

  158. Yin XM, Wang K, Gross A, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 1999;400(6747):886–91.

    Article  PubMed  CAS  Google Scholar 

  159. Zinkel SS, Ong CC, Ferguson DO, et al. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev 2003;17(2):229–39.

    Article  PubMed  CAS  Google Scholar 

  160. Danial NN, Walensky LD, Zhang CY, et al. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 2008;14(2):144–53.

    Article  PubMed  CAS  Google Scholar 

  161. Labi V, Erlacher M, Kiessling S, et al. Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates {gamma} irradiation-induced thymic lymphoma development. J Exp Med 2008;205(3):641–55.

    Google Scholar 

  162. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by Beclin1. Nature 1999;402(6762):672–6.

    Article  PubMed  CAS  Google Scholar 

  163. Maiuri MC, Criollo A, Tasdemir E, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin1 and Bcl-2/Bcl-X(L). Autophagy 2007;3(4):374-6.

    PubMed  CAS  Google Scholar 

  164. Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin1-dependent autophagy. Cell 2005;122(6):927-39.

    Article  PubMed  CAS  Google Scholar 

  165. Sandoval H, Thiagarajan P, Dasgupta SK, et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 2008;454(7201):232–5.

    Article  PubMed  CAS  Google Scholar 

  166. Schweers RL, Zhang J, Randall MS, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci USA 2007;104(49):19500–5.

    Article  PubMed  CAS  Google Scholar 

  167. Tracy K, Macleod KF. Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. Autophagy 2007;3(6):616–9.

    PubMed  CAS  Google Scholar 

  168. Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 2008;27(10):1366–75.

    Article  PubMed  CAS  Google Scholar 

  169. Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA. Apolipoprotein l1, a novel BH3-only lipid binding protein, induces autophagic cell death. J Biol Chem 2008.

    Google Scholar 

  170. Knudson CM, Johnson GM, Lin Y, Korsmeyer SJ. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res 2001;61(2):659–65.

    PubMed  CAS  Google Scholar 

  171. Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene 2001;20(33):4507–18.

    Article  PubMed  CAS  Google Scholar 

  172. Bai L, Ni HM, Chen X, Difrancesca D, Yin XM. Deletion of bid impedes cell proliferation and hepatic carcinogenesis. Am J Pathol 2005;166(5):1523–32.

    Article  PubMed  CAS  Google Scholar 

  173. Bonnefoy-Berard N, Aouacheria A, Verschelde C, Quemeneur L, Marcais A, Marvel J. Control of proliferation by Bcl-2 family members. Biochim Biophys Acta 2004;1644(2–3):159-68.

    Article  PubMed  CAS  Google Scholar 

  174. Vail ME, Chaisson ML, Thompson J, Fausto N. Bcl-2 expression delays hepatocyte cell cycle progression during liver regeneration. Oncogene 2002;21(10):1548–55.

    Article  PubMed  CAS  Google Scholar 

  175. Janumyan YM, Sansam CG, Chattopadhyay A, et al. Bcl-xL/Bcl-2 coordinately regulates apoptosis, cell cycle arrest and cell cycle entry. EMBO J 2003;22(20):5459–70.

    Article  PubMed  CAS  Google Scholar 

  176. Cheng N, Janumyan YM, Didion L, Van Hofwegen C, Yang E, Knudson CM. Bcl-2 inhibition of T-cell proliferation is related to prolonged T-cell survival. Oncogene 2004;23(21):3770–80.

    Article  PubMed  CAS  Google Scholar 

  177. Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 2005;121(7):1085-95.

    Article  PubMed  CAS  Google Scholar 

  178. Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 2005;121(7):1071–83.

    Article  PubMed  CAS  Google Scholar 

  179. Yang E, Korsmeyer SJ. Molecular thanatopsis: A discourse on the BCL2 family and cell death. Blood 1996;88(2):386–401.

    PubMed  CAS  Google Scholar 

  180. Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 2005;5(11):876–85.

    Article  PubMed  CAS  Google Scholar 

  181. Korsmeyer SJ. Bcl-2: A repressor of lymphocyte death. Immunol Today 1992;13(8):285–8.

    Article  PubMed  CAS  Google Scholar 

  182. Walensky LD, Kung AL, Escher I, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004;305(5689):1466–70.

    Article  PubMed  CAS  Google Scholar 

  183. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435(7042):677–81.

    Article  PubMed  CAS  Google Scholar 

  184. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006;10(5):375–88.

    Article  PubMed  CAS  Google Scholar 

  185. Mott JL and Gores GJ. Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death. Hepatology 2007;46(3):906–11.

    Google Scholar 

  186. Zhai D, Jin C, Satterthwait AC, Reed JC. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ 2006;13(8):1419–21.

    Article  PubMed  CAS  Google Scholar 

  187. Wang G, Nikolovska-Coleska Z, Yang CY, et al. Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem 2006;49(21):6139–42.

    Article  PubMed  CAS  Google Scholar 

  188. Mohammad RM, Goustin AS, Aboukameel A, et al. Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin Cancer Res 2007;13(7):2226–35.

    Article  PubMed  CAS  Google Scholar 

  189. Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 2007;104(49):19512–7.

    Article  PubMed  CAS  Google Scholar 

  190. Inohara N, Ekhterae D, Garcia I, 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 1998;273(15):8705–10.

    Article  PubMed  CAS  Google Scholar 

  191. Mund T, Gewies A, Schoenfeld N, Bauer MK, Grimm S. Spike, a novel BH3-only protein, regulates apoptosis at the endoplasmic reticulum. FASEB J 2003;17(6):696–8.

    PubMed  CAS  Google Scholar 

  192. Reed JC, Doctor K, Rojas A, et al. Comparative analysis of apoptosis and inflammation genes of mice and humans. Genome Res 2003;13(6B):1376–88.

    Article  PubMed  CAS  Google Scholar 

  193. Coultas L, Pellegrini M, Visvader JE, et al. Bfk: A novel weakly proapoptotic member of the Bcl-2 protein family with a BH3 and a BH2 region. Cell Death Differ 2003;10(2):185–92.

    Article  PubMed  CAS  Google Scholar 

  194. Suzuki M, Youle RJ, Tjandra N. Structure of Bax: Coregulation of dimer formation and intracellular localization. Cell 2000;103(4):645–54.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, USA

    Wen-Xing Ding

Authors
  1. Wen-Xing Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Ming Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Ding, WX., Yin, XM. (2009). The Bcl-2 Family Proteins. In: Dong, Z., Yin, XM. (eds) Essentials of Apoptosis. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-381-7_2

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation