Advertisement

Overview of BCL-2 Family Proteins and Therapeutic Potentials

  • Jason D. Huska
  • Heather M. Lamb
  • J. Marie Hardwick
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1877)

Abstract

BCL-2 family proteins interact in a network that regulates apoptosis. The BH3 amino acid sequence motif serves to bind together this conglomerate protein family, both literally and figuratively. BH3 motifs are present in antiapoptotic and proapoptotic BCL-2 homologs, and in a separate group of unrelated BH3-only proteins often appended to the BCL-2 family. BH3-containing helices mediate many of their physical interactions to determine cell death versus survival, leading to the development of BH3 mimetics as therapeutics. Here we provide an overview of BCL-2 family interactions, their relevance in health and disease, and the progress toward regulating their interactions therapeutically.

Key words

Apoptosis BCL-2 BCL-xL BAX BAK BH3-only BH3 mimetics Navitoclax Venetoclax 

Notes

Acknowledgments

Supported by the National Institutes of Health USA grants RO1 NS083373 (JMH), RO1 NS037402 (JMH), RO1 GM077875 (JMH), and F31 AI122613 (JDH).

References

  1. 1.
    Aouacheria A, Combet C, Tompa P, Hardwick JM (2015) Redefining the BH3 death domain as a ‘short linear motif’. Trends Biochem Sci 40(12):736–748.  https://doi.org/10.1016/j.tibs.2015.09.007CrossRefGoogle Scholar
  2. 2.
    Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226(4678):1097–1099CrossRefGoogle Scholar
  3. 3.
    Tsujimoto Y, Jaffe E, Cossman J, Gorham J, Nowell PC, Croce CM (1985) Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature 315(6017):340–343CrossRefGoogle Scholar
  4. 4.
    Cleary ML, Smith SD, 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) translocation. Cell 47(1):19–28CrossRefGoogle Scholar
  5. 5.
    Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335(6189):440–442.  https://doi.org/10.1038/335440a0CrossRefGoogle Scholar
  6. 6.
    Hengartner MO, Ellis RE, Horvitz HR (1992) Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356(6369):494–499.  https://doi.org/10.1038/356494a0CrossRefGoogle Scholar
  7. 7.
    Nunez G, Hockenbery D, McDonnell TJ, Sorensen CM, Korsmeyer SJ (1991) Bcl-2 maintains B cell memory. Nature 353(6339):71–73.  https://doi.org/10.1038/353071a0CrossRefGoogle Scholar
  8. 8.
    Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122(6):927–939.  https://doi.org/10.1016/j.cell.2005.07.002CrossRefGoogle Scholar
  9. 9.
    Yi CH, Pan H, Seebacher J, Jang IH, Hyberts SG, Heffron GJ, Vander Heiden MG, Yang R, Li F, Locasale JW, Sharfi H, Zhai B, Rodriguez-Mias R, Luithardt H, Cantley LC, Daley GQ, Asara JM, Gygi SP, Wagner G, Liu CF, Yuan J (2011) Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146(4):607–620.  https://doi.org/10.1016/j.cell.2011.06.050CrossRefGoogle Scholar
  10. 10.
    Berman SB, Chen YB, Qi B, McCaffery JM, Rucker EB 3rd, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM (2009) Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 184(5):707–719.  https://doi.org/10.1083/jcb.200809060CrossRefGoogle Scholar
  11. 11.
    Fannjiang Y, Kim CH, Huganir RL, Zou S, Lindsten T, Thompson CB, Mito T, Traystman RJ, Larsen T, Griffin DE, Mandir AS, Dawson TM, Dike S, Sappington AL, Kerr DA, Jonas EA, Kaczmarek LK, Hardwick JM (2003) BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. Dev Cell 4(4):575–585CrossRefGoogle Scholar
  12. 12.
    Jiao S, Li Z (2011) Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70(4):758–772.  https://doi.org/10.1016/j.neuron.2011.04.004CrossRefGoogle Scholar
  13. 13.
    Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278(5345):1966–1968CrossRefGoogle Scholar
  14. 14.
    Gross A, Katz SG (2017) Non-apoptotic functions of BCL-2 family proteins. Cell Death Differ.  https://doi.org/10.1038/cdd.2017.22CrossRefGoogle Scholar
  15. 15.
    Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM (2013) Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152(3):519–531.  https://doi.org/10.1016/j.cell.2012.12.031CrossRefGoogle Scholar
  16. 16.
    Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD (2008) BAX activation is initiated at a novel interaction site. Nature 455(7216):1076–1081.  https://doi.org/10.1038/nature07396CrossRefGoogle Scholar
  17. 17.
    Bleicken S, Jeschke G, Stegmueller C, Salvador-Gallego R, Garcia-Saez AJ, Bordignon E (2014) Structural model of active Bax at the membrane. Mol Cell 56(4):496–505.  https://doi.org/10.1016/j.molcel.2014.09.022CrossRefGoogle Scholar
  18. 18.
    Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435(7042):677–681.  https://doi.org/10.1038/nature03579CrossRefGoogle Scholar
  19. 19.
    Walensky LD, Pitter K, Morash J, Oh KJ, Barbuto S, Fisher J, Smith E, Verdine GL, Korsmeyer SJ (2006) A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 24(2):199–210.  https://doi.org/10.1016/j.molcel.2006.08.020CrossRefGoogle Scholar
  20. 20.
    Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Grave F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O (2016) The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538(7626):477–482.  https://doi.org/10.1038/nature19830CrossRefGoogle Scholar
  21. 21.
    Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16(4):273–284.  https://doi.org/10.1038/nrd.2016.253CrossRefGoogle Scholar
  22. 22.
    Chen HC, Kanai M, Inoue-Yamauchi A, Tu HC, Huang Y, Ren D, Kim H, Takeda S, Reyna DE, Chan PM, Ganesan YT, Liao CP, Gavathiotis E, Hsieh JJ, Cheng EH (2015) An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 17(10):1270–1281.  https://doi.org/10.1038/ncb3236CrossRefGoogle Scholar
  23. 23.
    Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, Dillon CP, Green DR (2011) A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 44(4):517–531.  https://doi.org/10.1016/j.molcel.2011.10.001CrossRefGoogle Scholar
  24. 24.
    Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A (2007) BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12(2):171–185.  https://doi.org/10.1016/j.ccr.2007.07.001CrossRefGoogle Scholar
  25. 25.
    Hsu YT, Youle RJ (1998) Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 273(17):10777–10783CrossRefGoogle Scholar
  26. 26.
    Cartron PF, Gallenne T, Bougras G, Gautier F, Manero F, Vusio P, Meflah K, Vallette FM, Juin P (2004) The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol Cell 16(5):807–818.  https://doi.org/10.1016/j.molcel.2004.10.028CrossRefGoogle Scholar
  27. 27.
    Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2006) Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8(12):1348–1358.  https://doi.org/10.1038/ncb1499CrossRefGoogle Scholar
  28. 28.
    Fletcher JI, Meusburger S, Hawkins CJ, Riglar DT, Lee EF, Fairlie WD, Huang DC, Adams JM (2008) Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax. Proc Natl Acad Sci U S A 105(47):18081–18087.  https://doi.org/10.1073/pnas.0808691105CrossRefGoogle Scholar
  29. 29.
    Czabotar PE, Lee EF, Thompson GV, Wardak AZ, Fairlie WD, Colman PM (2011) Mutation to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis. J Biol Chem 286(9):7123–7131.  https://doi.org/10.1074/jbc.M110.161281CrossRefGoogle Scholar
  30. 30.
    Ding J, Mooers BH, Zhang Z, Kale J, Falcone D, McNichol J, Huang B, Zhang XC, Xing C, Andrews DW, Lin J (2014) After embedding in membranes antiapoptotic Bcl-XL protein binds both Bcl-2 homology region 3 and helix 1 of proapoptotic Bax protein to inhibit apoptotic mitochondrial permeabilization. J Biol Chem 289(17):11873–11896.  https://doi.org/10.1074/jbc.M114.552562CrossRefGoogle Scholar
  31. 31.
    Peng R, Tong JS, Li H, Yue B, Zou F, Yu J, Zhang L (2013) Targeting Bax interaction sites reveals that only homo-oligomerization sites are essential for its activation. Cell Death Differ 20(5):744–754.  https://doi.org/10.1038/cdd.2013.4CrossRefGoogle Scholar
  32. 32.
    Nie C, Tian C, Zhao L, Petit PX, Mehrpour M, Chen Q (2008) Cysteine 62 of Bax is critical for its conformational activation and its proapoptotic activity in response to H2O2-induced apoptosis. J Biol Chem 283(22):15359–15369.  https://doi.org/10.1074/jbc.M800847200CrossRefGoogle Scholar
  33. 33.
    Wang K, Gross A, Waksman G, Korsmeyer SJ (1998) Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 18(10):6083–6089CrossRefGoogle Scholar
  34. 34.
    Zhang Z, Subramaniam S, Kale J, Liao C, Huang B, Brahmbhatt H, Condon SG, Lapolla SM, Hays FA, Ding J, He F, Zhang XC, Li J, Senes A, Andrews DW, Lin J (2016) BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes. EMBO J 35(2):208–236.  https://doi.org/10.15252/embj.201591552CrossRefGoogle Scholar
  35. 35.
    Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2009) Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36(3):487–499.  https://doi.org/10.1016/j.molcel.2009.09.030CrossRefGoogle Scholar
  36. 36.
    Kuwana T, Olson NH, Kiosses WB, Peters B, Newmeyer DD (2016) Pro-apoptotic Bax molecules densely populate the edges of membrane pores. Sci Rep 6:27299.  https://doi.org/10.1038/srep27299CrossRefGoogle Scholar
  37. 37.
    Szabo I, Soddemann M, Leanza L, Zoratti M, Gulbins E (2011) Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax- and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosis. Cell Death Differ 18(3):427–438.  https://doi.org/10.1038/cdd.2010.112CrossRefGoogle Scholar
  38. 38.
    Szabo I, Bock J, Grassme H, Soddemann M, Wilker B, Lang F, Zoratti M, Gulbins E (2008) Mitochondrial potassium channel Kv1.3 mediates Bax-induced apoptosis in lymphocytes. Proc Natl Acad Sci U S A 105(39):14861–14866.  https://doi.org/10.1073/pnas.0804236105CrossRefGoogle Scholar
  39. 39.
    Venturini E, Leanza L, Azzolini M, Kadow S, Mattarei A, Weller M, Tabatabai G, Edwards MJ, Zoratti M, Paradisi C, Szabo I, Gulbins E, Becker KA (2017) Targeting the potassium channel Kv1.3 kills glioblastoma cells. Neurosignals 25(1):26–38.  https://doi.org/10.1159/000480643CrossRefGoogle Scholar
  40. 40.
    Nechushtan A, Smith CL, Hsu YT, Youle RJ (1999) Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 18(9):2330–2341.  https://doi.org/10.1093/emboj/18.9.2330CrossRefGoogle Scholar
  41. 41.
    Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM (2004) Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem 279(20):21085–21095.  https://doi.org/10.1074/jbc.M400063200CrossRefGoogle Scholar
  42. 42.
    Wang Q, Sun SY, Khuri F, Curran WJ, Deng X (2010) Mono- or double-site phosphorylation distinctly regulates the proapoptotic function of Bax. PLoS One 5(10):e13393.  https://doi.org/10.1371/journal.pone.0013393CrossRefGoogle Scholar
  43. 43.
    Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24(44):9993–10002.  https://doi.org/10.1523/JNEUROSCI.2057-04.2004CrossRefGoogle Scholar
  44. 44.
    Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD (2010) BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 40(3):481–492.  https://doi.org/10.1016/j.molcel.2010.10.019CrossRefGoogle Scholar
  45. 45.
    Schinzel A, Kaufmann T, Schuler M, Martinalbo J, Grubb D, Borner C (2004) Conformational control of Bax localization and apoptotic activity by Pro168. J Cell Biol 164(7):1021–1032.  https://doi.org/10.1083/jcb.200309013CrossRefGoogle Scholar
  46. 46.
    Simonyan L, Legiot A, Lascu I, Durand G, Giraud MF, Gonzalez C, Manon S (2017) The substitution of Proline 168 favors Bax oligomerization and stimulates its interaction with LUVs and mitochondria. Biochim Biophys Acta 1859(6):1144–1155.  https://doi.org/10.1016/j.bbamem.2017.03.010CrossRefGoogle Scholar
  47. 47.
    Garner TP, Reyna DE, Priyadarshi A, Chen HC, Li S, Wu Y, Ganesan YT, Malashkevich VN, Cheng EH, Gavathiotis E (2016) An autoinhibited dimeric form of BAX regulates the BAX activation pathway. Mol Cell 64(2):431.  https://doi.org/10.1016/j.molcel.2016.10.005CrossRefGoogle Scholar
  48. 48.
    Liao C, Zhang Z, Kale J, Andrews DW, Lin J, Li J (2016) Conformational heterogeneity of Bax Helix 9 dimer for apoptotic pore formation. Sci Rep 6:29502.  https://doi.org/10.1038/srep29502CrossRefGoogle Scholar
  49. 49.
    Gahl RF, He Y, Yu S, Tjandra N (2014) Conformational rearrangements in the pro-apoptotic protein, Bax, as it inserts into mitochondria: a cellular death switch. J Biol Chem 289(47):32871–32882.  https://doi.org/10.1074/jbc.M114.593897CrossRefGoogle Scholar
  50. 50.
    Andreu-Fernandez V, Sancho M, Genoves A, Lucendo E, Todt F, Lauterwasser J, Funk K, Jahreis G, Perez-Paya E, Mingarro I, Edlich F, Orzaez M (2017) Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes. Proc Natl Acad Sci U S A 114(2):310–315.  https://doi.org/10.1073/pnas.1612322114CrossRefGoogle Scholar
  51. 51.
    Zhang M, Zheng J, Nussinov R, Ma B (2016) Oncogenic mutations differentially affect Bax monomer, dimer, and Oligomeric pore formation in the membrane. Sci Rep 6:33340.  https://doi.org/10.1038/srep33340CrossRefGoogle Scholar
  52. 52.
    Zhang Z, Zhu W, Lapolla SM, Miao Y, Shao Y, Falcone M, Boreham D, McFarlane N, Ding J, Johnson AE, Zhang XC, Andrews DW, Lin J (2010) Bax forms an oligomer via separate, yet interdependent, surfaces. J Biol Chem 285(23):17614–17627.  https://doi.org/10.1074/jbc.M110.113456CrossRefGoogle Scholar
  53. 53.
    Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 1(5):645–653CrossRefGoogle Scholar
  54. 54.
    Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB (2000) The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6(6):1389–1399CrossRefGoogle Scholar
  55. 55.
    Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270(5233):96–99CrossRefGoogle Scholar
  56. 56.
    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(12):1481–1486.  https://doi.org/10.1101/gad.897601CrossRefGoogle Scholar
  57. 57.
    Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8(3):705–711CrossRefGoogle Scholar
  58. 58.
    Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330(6009):1390–1393.  https://doi.org/10.1126/science.1190217CrossRefGoogle Scholar
  59. 59.
    Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ (1997) 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 U S A 94(23):12401–12406CrossRefGoogle Scholar
  60. 60.
    Ke F, Grabow S, Kelly GL, Lin A, O'Reilly LA, Strasser A (2015) Impact of the combined loss of BOK, BAX and BAK on the hematopoietic system is slightly more severe than compound loss of BAX and BAK. Cell Death Dis 6:e1938.  https://doi.org/10.1038/cddis.2015.304CrossRefGoogle Scholar
  61. 61.
    Llambi F, Wang YM, Victor B, Yang M, Schneider DM, Gingras S, Parsons MJ, Zheng JH, Brown SA, Pelletier S, Moldoveanu T, Chen T, Green DR (2016) BOK is a non-canonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 165(2):421–433.  https://doi.org/10.1016/j.cell.2016.02.026CrossRefGoogle Scholar
  62. 62.
    Carpio MA, Michaud M, Zhou W, Fisher JK, Walensky LD, Katz SG (2015) BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc Natl Acad Sci U S A 112(23):7201–7206.  https://doi.org/10.1073/pnas.1421063112CrossRefGoogle Scholar
  63. 63.
    Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S et al (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267(5203):1506–1510CrossRefGoogle Scholar
  64. 64.
    Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ (2000) Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 14(1):23–27Google Scholar
  65. 65.
    Akhtar RS, Ness JM, Roth KA (2004) Bcl-2 family regulation of neuronal development and neurodegeneration. Biochim Biophys Acta 1644(2-3):189–203.  https://doi.org/10.1016/j.bbamcr.2003.10.013CrossRefGoogle Scholar
  66. 66.
    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(9):3112–3119CrossRefGoogle Scholar
  67. 67.
    Akhtar RS, Geng Y, Klocke BJ, Latham CB, Villunger A, Michalak EM, Strasser A, Carroll SL, Roth KA (2006) BH3-only proapoptotic Bcl-2 family members Noxa and Puma mediate neural precursor cell death. J Neurosci 26(27):7257–7264.  https://doi.org/10.1523/JNEUROSCI.0196-06.2006CrossRefGoogle Scholar
  68. 68.
    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(10):921–927.  https://doi.org/10.1369/jhc.2008.951749CrossRefGoogle Scholar
  69. 69.
    Nakamura A, Swahari V, Plestant C, Smith I, McCoy E, Smith S, Moy SS, Anton ES, Deshmukh M (2016) Bcl-xL is essential for the survival and function of differentiated neurons in the cortex that control complex behaviors. J Neurosci 36(20):5448–5461.  https://doi.org/10.1523/JNEUROSCI.4247-15.2016CrossRefGoogle Scholar
  70. 70.
    Qi B, Hardwick JM (2007) A Bcl-xL timer sets platelet life span. Cell 128(6):1035–1036.  https://doi.org/10.1016/j.cell.2007.03.002CrossRefGoogle Scholar
  71. 71.
    Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT (2007) Programmed anuclear cell death delimits platelet life span. Cell 128(6):1173–1186.  https://doi.org/10.1016/j.cell.2007.01.037CrossRefGoogle Scholar
  72. 72.
    Nakayama K, Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie MC, Fields LE, Lucas PJ, Stewart V, Alt FW et al (1993) Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261(5128):1584–1588CrossRefGoogle Scholar
  73. 73.
    Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75(2):229–240CrossRefGoogle Scholar
  74. 74.
    O'Reilly LA, Print C, Hausmann G, Moriishi K, Cory S, Huang DC, Strasser A (2001) Tissue expression and subcellular localization of the pro-survival molecule Bcl-w. Cell Death Differ 8(5):486–494.  https://doi.org/10.1038/sj.cdd.4400835CrossRefGoogle Scholar
  75. 75.
    Liu QA, Shio H (2008) Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2. PLoS Genet 4(6):e1000097.  https://doi.org/10.1371/journal.pgen.1000097CrossRefGoogle Scholar
  76. 76.
    Print CG, Loveland KL, Gibson L, Meehan T, Stylianou A, Wreford N, de Kretser D, Metcalf D, Kontgen F, Adams JM, Cory S (1998) Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc Natl Acad Sci U S A 95(21):12424–12431CrossRefGoogle Scholar
  77. 77.
    Russell LD, Warren J, Debeljuk L, Richardson LL, Mahar PL, Waymire KG, Amy SP, Ross AJ, MacGregor GR (2001) Spermatogenesis in Bclw-deficient mice. Biol Reprod 65(1):318–332CrossRefGoogle Scholar
  78. 78.
    Ottina E, Tischner D, Herold MJ, Villunger A (2012) A1/Bfl-1 in leukocyte development and cell death. Exp Cell Res 318(11):1291–1303.  https://doi.org/10.1016/j.yexcr.2012.01.021CrossRefGoogle Scholar
  79. 79.
    Hamasaki A, Sendo F, Nakayama K, Ishida N, Negishi I, Nakayama K, Hatakeyama S (1998) Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med 188(11):1985–1992CrossRefGoogle Scholar
  80. 80.
    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(11):1561–1569CrossRefGoogle Scholar
  81. 81.
    Hatakeyama S, Hamasaki A, Negishi I, Loh DY, Sendo F, Nakayama K, Nakayama K (1998) Multiple gene duplication and expression of mouse bcl-2-related genes, A1. Int Immunol 10(5):631–637CrossRefGoogle Scholar
  82. 82.
    Schenk RL, Tuzlak S, Carrington EM, Zhan Y, Heinzel S, Teh CE, Gray DH, Tai L, Lew AM, Villunger A, Strasser A, Herold MJ (2017) Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment. Cell Death Differ 24(3):534–545.  https://doi.org/10.1038/cdd.2016.156CrossRefGoogle Scholar
  83. 83.
    Hardwick JM, Chen YB, Jonas EA (2012) Multipolar functions of BCL-2 proteins link energetics to apoptosis. Trends Cell Biol 22(6):318–328.  https://doi.org/10.1016/j.tcb.2012.03.005CrossRefGoogle Scholar
  84. 84.
    Nakajima A, Nishimura K, Nakaima Y, Oh T, Noguchi S, Taniguchi T, Tamura T (2009) Cell type-dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene. Proc Natl Acad Sci U S A 106(30):12448–12452.  https://doi.org/10.1073/pnas.0905702106CrossRefGoogle Scholar
  85. 85.
    Bonneau B, Ando H, Kawaai K, Hirose M, Takahashi-Iwanaga H, Mikoshiba K (2016) IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact. Elife 5.  https://doi.org/10.7554/eLife.19896
  86. 86.
    Otsu K, Murakawa T, Yamaguchi O (2015) BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. Autophagy 11(10):1932–1933.  https://doi.org/10.1080/15548627.2015.1084459CrossRefGoogle Scholar
  87. 87.
    Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302(5647):1036–1038.  https://doi.org/10.1126/science.1090072CrossRefGoogle Scholar
  88. 88.
    Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP, Kutok JL, Le Beau MM, Greenberg ME, Korsmeyer SJ (2003) Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci U S A 100(16):9324–9329.  https://doi.org/10.1073/pnas.1533446100CrossRefGoogle Scholar
  89. 89.
    Coultas L, Bouillet P, Loveland KL, Meachem S, Perlman H, Adams JM, Strasser A (2005) Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. EMBO J 24(22):3963–3973.  https://doi.org/10.1038/sj.emboj.7600857CrossRefGoogle Scholar
  90. 90.
    Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286(5445):1735–1738CrossRefGoogle Scholar
  91. 91.
    Hubner A, Cavanagh-Kyros J, Rincon M, Flavell RA, Davis RJ (2010) Functional cooperation of the proapoptotic Bcl2 family proteins Bmf and Bim in vivo. Mol Cell Biol 30(1):98–105.  https://doi.org/10.1128/MCB.01155-09CrossRefGoogle Scholar
  92. 92.
    Imaizumi K, Benito A, Kiryu-Seo S, Gonzalez V, Inohara N, Lieberman AP, Kiyama H, Nunez G (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(15):3721–3725.  https://doi.org/10.1523/JNEUROSCI.5101-03.2004CrossRefGoogle Scholar
  93. 93.
    Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ (1999) Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400(6747):886–891.  https://doi.org/10.1038/23730CrossRefGoogle Scholar
  94. 94.
    Naik E, Michalak EM, Villunger A, Adams JM, Strasser A (2007) Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 176(4):415–424.  https://doi.org/10.1083/jcb.200608070CrossRefGoogle Scholar
  95. 95.
    Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN, McKinnon PJ, Cleveland JL, Zambetti GP (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4(4):321–328CrossRefGoogle Scholar
  96. 96.
    Erlacher M, Labi V, Manzl C, Bock G, Tzankov A, Hacker G, Michalak E, Strasser A, Villunger A (2006) Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 203(13):2939–2951.  https://doi.org/10.1084/jem.20061552CrossRefGoogle Scholar
  97. 97.
    Delbridge AR, Grabow S, Strasser A, Vaux DL (2016) Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 16(2):99–109.  https://doi.org/10.1038/nrc.2015.17CrossRefGoogle Scholar
  98. 98.
    Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50(4):641–662.  https://doi.org/10.1021/jm061152tCrossRefGoogle Scholar
  99. 99.
    Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (1997) Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275(5302):983–986CrossRefGoogle Scholar
  100. 100.
    Lessene G, Czabotar PE, Colman PM (2008) BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7(12):989–1000.  https://doi.org/10.1038/nrd2658CrossRefGoogle Scholar
  101. 101.
    Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68(9):3421–3428.  https://doi.org/10.1158/0008-5472.CAN-07-5836CrossRefGoogle Scholar
  102. 102.
    Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL, Cui Y, Busman T, Elmore SW, Rosenberg SH, Krivoshik AP, Enschede SH, Humerickhouse RA (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11(12):1149–1159.  https://doi.org/10.1016/S1470-2045(10)70261-8CrossRefGoogle Scholar
  103. 103.
    Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30(5):488–496.  https://doi.org/10.1200/JCO.2011.34.7898CrossRefGoogle Scholar
  104. 104.
    Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18(11):3163–3169.  https://doi.org/10.1158/1078-0432.CCR-11-3090CrossRefGoogle Scholar
  105. 105.
    Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, Dyagil IS, Yalamanchili S, Chai A, Sahasranaman S, Punnoose E, Hurst D, Pylypenko H (2015) A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma 56(10):2826–2833.  https://doi.org/10.3109/10428194.2015.1030638CrossRefGoogle Scholar
  106. 106.
    Debrincat MA, Pleines I, Lebois M, Lane RM, Holmes ML, Corbin J, Vandenberg CJ, Alexander WS, Ng AP, Strasser A, Bouillet P, Sola-Visner M, Kile BT, Josefsson EC (2015) BCL-2 is dispensable for thrombopoiesis and platelet survival. Cell Death Dis 6:e1721.  https://doi.org/10.1038/cddis.2015.97CrossRefGoogle Scholar
  107. 107.
    Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Bottcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17(6):768–778.  https://doi.org/10.1016/S1470-2045(16)30019-5CrossRefGoogle Scholar
  108. 108.
    Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF (2016) Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic Leukemia. N Engl J Med 374(4):311–322.  https://doi.org/10.1056/NEJMoa1513257CrossRefGoogle Scholar
  109. 109.
    Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19(2):202–208.  https://doi.org/10.1038/nm.3048CrossRefGoogle Scholar
  110. 110.
    AbbVie (2016) Venetoclax receives 3rd breakthrough therapy designation from the FDA for the combination treatment of patients with untreated acute myeloid leukemia not eligible for standard induction chemotherapy. https://www.prnewswire.com/news-releases/venetoclax-receives-3rd-breakthrough-therapy-designation-from-the-fda-for-the-combination-treatment-of-patients-with-untreated-acute-myeloid-leukemia-not-eligible-for-standard-induction-chemotherapy-300211208.html. Accessed 30th Nov 2017
  111. 111.
    Tahir SK, Smith ML, Hessler P, Rapp LR, Idler KB, Park CH, Leverson JD, Lam LT (2017) Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer 17(1):399.  https://doi.org/10.1186/s12885-017-3383-5CrossRefGoogle Scholar
  112. 112.
    Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, Belmont LD, Nimmer P, Xiao Y, Ma XM, Lowes KN, Kovar P, Chen J, Jin S, Smith M, Xue J, Zhang H, Oleksijew A, Magoc TJ, Vaidya KS, Albert DH, Tarrant JM, La N, Wang L, Tao ZF, Wendt MD, Sampath D, Rosenberg SH, Tse C, Huang DC, Fairbrother WJ, Elmore SW, Souers AJ (2015) Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med 7(279):279ra240.  https://doi.org/10.1126/scitranslmed.aaa4642CrossRefGoogle Scholar
  113. 113.
    Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG (2013) Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol 9(6):390–397.  https://doi.org/10.1038/nchembio.1246CrossRefGoogle Scholar
  114. 114.
    Koehler MF, Bergeron P, Choo EF, Lau K, Ndubaku C, Dudley D, Gibbons P, Sleebs BE, Rye CS, Nikolakopoulos G, Bui C, Kulasegaram S, Kersten WJ, Smith BJ, Czabotar PE, Colman PM, Huang DC, Baell JB, Watson KG, Hasvold L, Tao ZF, Wang L, Souers AJ, Elmore SW, Flygare JA, Fairbrother WJ, Lessene G (2014) Structure-guided rescaffolding of selective antagonists of BCL-XL. ACS Med Chem Lett 5(6):662–667.  https://doi.org/10.1021/ml500030pCrossRefGoogle Scholar
  115. 115.
    Tao ZF, Hasvold L, Wang L, Wang X, Petros AM, Park CH, Boghaert ER, Catron ND, Chen J, Colman PM, Czabotar PE, Deshayes K, Fairbrother WJ, Flygare JA, Hymowitz SG, Jin S, Judge RA, Koehler MF, Kovar PJ, Lessene G, Mitten MJ, Ndubaku CO, Nimmer P, Purkey HE, Oleksijew A, Phillips DC, Sleebs BE, Smith BJ, Smith ML, Tahir SK, Watson KG, Xiao Y, Xue J, Zhang H, Zobel K, Rosenberg SH, Tse C, Leverson JD, Elmore SW, Souers AJ (2014) Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med Chem Lett 5(10):1088–1093.  https://doi.org/10.1021/ml5001867CrossRefGoogle Scholar
  116. 116.
    Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905.  https://doi.org/10.1038/nature08822CrossRefGoogle Scholar
  117. 117.
    Wei G, Margolin AA, Haery L, Brown E, Cucolo L, Julian B, Shehata S, Kung AL, Beroukhim R, Golub TR (2012) Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell 21(4):547–562.  https://doi.org/10.1016/j.ccr.2012.02.028CrossRefGoogle Scholar
  118. 118.
    Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O'Rourke KM, Pujara K, Kohli PB, Johnson AR, Chiu ML, Lill JR, Jackson PK, Fairbrother WJ, Seshagiri S, Ludlam MJ, Leong KG, Dueber EC, Maecker H, Huang DC, Dixit VM (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471(7336):110–114.  https://doi.org/10.1038/nature09779CrossRefGoogle Scholar
  119. 119.
    Lee EF, Czabotar PE, van Delft MF, Michalak EM, Boyle MJ, Willis SN, Puthalakath H, Bouillet P, Colman PM, Huang DC, Fairlie WD (2008) A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J Cell Biol 180(2):341–355.  https://doi.org/10.1083/jcb.200708096CrossRefGoogle Scholar
  120. 120.
    Lee EF, Czabotar PE, Yang H, Sleebs BE, Lessene G, Colman PM, Smith BJ, Fairlie WD (2009) Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands. J Biol Chem 284(44):30508–30517.  https://doi.org/10.1074/jbc.M109.040725CrossRefGoogle Scholar
  121. 121.
    Belmar J, Fesik SW (2015) Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther 145:76–84.  https://doi.org/10.1016/j.pharmthera.2014.08.003CrossRefGoogle Scholar
  122. 122.
    Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J, Nimmer P, Jin S, Smith M, Xiao Y, Kovar P, Tanaka A, Bruncko M, Sheppard GS, Wang L, Gierke S, Kategaya L, Anderson DJ, Wong C, Eastham-Anderson J, Ludlam MJ, Sampath D, Fairbrother WJ, Wertz I, Rosenberg SH, Tse C, Elmore SW, Souers AJ (2015) Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis 6:e1590.  https://doi.org/10.1038/cddis.2014.561CrossRefGoogle Scholar
  123. 123.
    Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, Souers AJ (2015) Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J Med Chem 58(5):2180–2194.  https://doi.org/10.1021/jm501258mCrossRefGoogle Scholar
  124. 124.
    Liu X, He Y, Li F, Huang Q, Kato TA, Hall RP, Li CY (2015) Caspase-3 promotes genetic instability and carcinogenesis. Mol Cell 58(2):284–296.  https://doi.org/10.1016/j.molcel.2015.03.003CrossRefGoogle Scholar
  125. 125.
    Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E, Delgado ME, Haller M, Riley JS, Mason SM, Athineos D, Parsons MJ, van de Kooij B, Bouchier-Hayes L, Chalmers AJ, Rooswinkel RW, Oberst A, Blyth K, Rehm M, Murphy DJ, Tait SW (2015) Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol Cell 57(5):860–872.  https://doi.org/10.1016/j.molcel.2015.01.018CrossRefGoogle Scholar
  126. 126.
    Tang HL, Tang HM, Fung MC, Hardwick JM (2015) In vivo caspasetracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Rep 5:9015.  https://doi.org/10.1038/srep09015CrossRefGoogle Scholar
  127. 127.
    Tang HL, Tang HM, Mak KH, Hu S, Wang SS, Wong KM, Wong CS, Wu HY, Law HT, Liu K, Talbot CC Jr, Lau WK, Montell DJ, Fung MC (2012) Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol Biol Cell 23(12):2240–2252.  https://doi.org/10.1091/mbc.E11-11-0926CrossRefGoogle Scholar
  128. 128.
    Najafov A, Chen H, Yuan J (2017) Necroptosis and cancer. Trends Cancer 3(4):294–301.  https://doi.org/10.1016/j.trecan.2017.03.002CrossRefGoogle Scholar
  129. 129.
    Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proics E, Rubio-Patino C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert ML, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, Tait SWG (2017) Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol 19(9):1116–1129.  https://doi.org/10.1038/ncb3596CrossRefGoogle Scholar
  130. 130.
    Yatim N, Jusforgues-Saklani H, Orozco S, Schulz O, Barreira da Silva R, Reise Sousa C, Green DR, Oberst A, Albert ML (2015) RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells. Science 350(6258):328–334.  https://doi.org/10.1126/science.aad0395CrossRefGoogle Scholar
  131. 131.
    Aaes TL, Kaczmarek A, Delvaeye T, De Craene B, De Koker S, Heyndrickx L, Delrue I, Taminau J, Wiernicki B, De Groote P, Garg AD, Leybaert L, Grooten J, Bertrand MJ, Agostinis P, Berx G, Declercq W, Vandenabeele P, Krysko DV (2016) Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep 15(2):274–287.  https://doi.org/10.1016/j.celrep.2016.03.037CrossRefGoogle Scholar
  132. 132.
    Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, Kim SI, Kim SJ, Son MK, Hong SS, Levy JM, Pollyea DA, Jordan CT, Yan P, Frankhouser D, Nicolet D, Maharry K, Marcucci G, Choi KS, Cho H, Thorburn A, Kim YS (2015) Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res 25(6):707–725.  https://doi.org/10.1038/cr.2015.56CrossRefGoogle Scholar
  133. 133.
    Gallenne T, Gautier F, Oliver L, Hervouet E, Noel B, Hickman JA, Geneste O, Cartron PF, Vallette FM, Manon S, Juin P (2009) Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol 185(2):279–290.  https://doi.org/10.1083/jcb.200809153CrossRefGoogle Scholar
  134. 134.
    Edlich F, Banerjee S, Suzuki M, Cleland MM, Arnoult D, Wang C, Neutzner A, Tjandra N, Youle RJ (2011) Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol. Cell 145(1):104–116.  https://doi.org/10.1016/j.cell.2011.02.034CrossRefGoogle Scholar
  135. 135.
    Salvador-Gallego R, Mund M, Cosentino K, Schneider J, Unsay J, Schraermeyer U, Engelhardt J, Ries J, Garcia-Saez AJ (2016) Bax assembly into rings and arcs in apoptotic mitochondria is linked to membrane pores. EMBO J 35(4):389–401.  https://doi.org/10.15252/embj.201593384CrossRefGoogle Scholar
  136. 136.
    Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Sloetjes AW, de Witte T, Waksman G, Korsmeyer SJ (1998) Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 91(8):2991–2997Google Scholar
  137. 137.
    Garner TP, Reyna DE, Priyadarshi A, Chen HC, Li S, Wu Y, Ganesan YT, Malashkevich VN, Almo SS, Cheng EH, Gavathiotis E (2016) An autoinhibited dimeric form of BAX regulates the BAX activation pathway. Mol Cell 63(3):485–497.  https://doi.org/10.1016/j.molcel.2016.06.010CrossRefGoogle Scholar
  138. 138.
    Catalogue of somatic mutations in cancer. http://cancer.sanger.ac.uk/cosmic/search?q=BAX%2C+T174P

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jason D. Huska
    • 1
  • Heather M. Lamb
    • 1
  • J. Marie Hardwick
    • 1
  1. 1.Department of Molecular Microbiology and ImmunologyJohns Hopkins University Bloomberg School of Public HealthBaltimoreUSA

Personalised recommendations