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BH3-Only Proteins in Cancer and Apoptosis

  • Fabio Ghiotto
  • Claudya Tenca
  • Franco Fais
  • Silvia BrunoEmail author
Chapter

Abstract

In multicellular organisms, an enormous number of cells die every day, because of stress, injury, infection, or natural turnover necessary for proper tissue homeostasis. In most of these events, cell death is orchestrated by the dying cell itself, a sort of cellular suicide called “apoptosis”. Malfunctioning of this death program at any stage leads to severe human diseases, including cancer and autoimmune disorders. Apoptosis is elicited by intracellular or extracellular stimuli that activate a common cell death machinery, culminating in permeabilization of the mitochondrial membrane. In this chapter we describe the state of the art of the knowledge of how cells execute “mitochondrial” or “intrinsic” apoptosis. A fundamental and crucial role as regulators of the cell’s commitment to apoptosis is assumed by BH3-only proteins, a class of small molecules belonging to the Bcl-2 family. They are both sensors of death signals and vectors of information to the core apoptotic machinery, exerting their activity by hierarchical and finely tuned interactions with the other Bcl-2 family members. We discuss the groundbreaking research from several laboratories that have contributed to disclosing the complex activity of BH3-only proteins and the efforts made to translate these results into novel tools for cancer therapy.

Keywords

Apoptosis Mitochondrial dysfunction Bcl-2 family BH3-only proteins BH3 mimetics in cancer therapy 

References

  1. Adachi M, Zhao X, Imai K (2005) Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms. Cell Death Differ 12:192–193PubMedGoogle Scholar
  2. Adams JM (2003) Ways of dying: multiple pathways to apoptosis. Genes Dev 17:2481–2495PubMedGoogle Scholar
  3. Ahn CH, Jeong EG, Kim SS, Lee JW, Lee SH, Kim SH, Kim MS, Yoo NJ (2008) Expressional and mutational analysis of pro-apoptotic Bcl-2 member PUMA in hepatocellular carcinomas. Dig Dis Sci 53:1395–1399PubMedGoogle Scholar
  4. Akiyama T, Bouillet P, Miyazaki T, Kadono Y, Chikuda H, Chung UI, Fukuda A, Hikita A, Seto H, Okada T, Inaba T, Sanjay A, Baron R, Kawaguchi H, Oda H, Nakamura K, Strasser A, Tanaka S (2003) Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J 22:6653–6664PubMedGoogle Scholar
  5. Albershardt TC, Salerni BL, Soderquist RS, Bates DJ, Pletnev AA, Kisselev AF, Eastman A (2011) Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 286:24882–24895PubMedGoogle Scholar
  6. Anderton E, Yee J, Smith P, Crook T, White RE, Allday MJ (2008) Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt’s lymphoma. Oncogene 27:421–433PubMedGoogle Scholar
  7. Anding AL, Chapman JS, Barnett DW, Curley RW Jr, Clagett-Dame M (2007) The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis that is caspase- dependent and independent of the retinoic acid receptor. Cancer Res 67:6270–6277PubMedGoogle Scholar
  8. Annis MG, Soucie EL, Dlugosz PJ, Cruz-Aguado JA, Penn LZ, Leber B, Andrews DW (2005) Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 24:2096–2103PubMedGoogle Scholar
  9. Ayllon V, Martinez AC, Garcia A, Cayla X, Rebollo A (2000) Protein phosphatase 1alpha is a ras-activated bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J 19:2237–2246PubMedGoogle Scholar
  10. Ayllon V, Fleischer A, Cayla X, Garcia A, Rebollo A (2002) Segregation of bad from lipid rafts is implicated in the induction of apoptosis. J Immunol 168:3387–3393PubMedGoogle Scholar
  11. Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R, Mayo Phase C, California C (2011) A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol 6:1757–1760PubMedGoogle Scholar
  12. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ (1985) Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899–906PubMedGoogle Scholar
  13. Balakrishnan K, Burger JA, Wierda WG, Gandhi V (2009) AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 113:149–153PubMedGoogle Scholar
  14. Barrera-Vilarmau S, Obregon P, de Alba E (2011) Intrinsic order and disorder in the bcl-2 member harakiri: insights into its proapoptotic activity. PLoS One 6:e21413PubMedGoogle Scholar
  15. Barry M, Heibein JA, Pinkoski MJ, Lee SF, Moyer RW, Green DR, Bleackley RC (2000) Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol 20:3781–3794PubMedGoogle Scholar
  16. Bernabeu A, Guillen J, Perez-Berna AJ, Moreno MR, Villalain J (2007) Structure of the C-terminal domain of the pro-apoptotic protein Hrk and its interaction with model membranes. Biochim Biophys Acta 1768:1659–1670PubMedGoogle Scholar
  17. Billen LP, Kokoski CL, Lovell JF, Leber B, Andrews DW (2008a) Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol 6:e147PubMedGoogle Scholar
  18. Billen LP, Shamas-Din A, Andrews DW (2008b) Bid: a Bax-like BH3 protein. Oncogene 27(Suppl 1):S93–S104PubMedGoogle Scholar
  19. Bleicken S, Garcia-Saez AJ, Conte E, Bordignon E (2012) Dynamic interaction of cBid with detergents, liposomes and mitochondria. PLoS One 7:e35910PubMedGoogle Scholar
  20. 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 286:1735–1738PubMedGoogle Scholar
  21. Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A (2002) BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415:922–926PubMedGoogle Scholar
  22. Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ, Ebb RG, Subramanian T, Chittenden T, Lutz RJ et al (1995) Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11:1921–1928PubMedGoogle Scholar
  23. Bruno S, Ghiotto F, Tenca C, Mazzarello A, Bono M, Luzzi P, Casciaro S, Recchia A, Decensi A, Morabito F, Fais F (2012) N-(4-Hydroxyphenyl) retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity. Leukemia 26:2260–2268Google Scholar
  24. 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 16:807–818PubMedGoogle Scholar
  25. Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic Bcl-2 family members. Cancer Cell 9:351–365PubMedGoogle Scholar
  26. Chen GG, Lai PB, Chak EC, Xu H, Lee KM, Lau WY (2001) Immunohistochemical analysis of pro-apoptotic Bid level in chronic hepatitis, hepatocellular carcinoma and liver metastases. Cancer Lett 172:75–82PubMedGoogle Scholar
  27. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403PubMedGoogle Scholar
  28. Chen S, Lee JM, Zeng C, Chen H, Hsu CY, Xu J (2006) Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes. J Neurochem 97:631–640PubMedGoogle Scholar
  29. Chiang CW, Harris G, Ellig C, Masters SC, Subramanian R, Shenolikar S, Wadzinski BE, Yang E (2001) Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 97:1289–1297PubMedGoogle Scholar
  30. Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR (2005) PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309:1732–1735PubMedGoogle Scholar
  31. Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ (1995) A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 14:5589–5596PubMedGoogle Scholar
  32. Choy EY, Siu KL, Kok KH, Lung RW, Tsang CM, To KF, Kwong DL, Tsao SW, Jin DY (2008) An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med 205:2551–2560PubMedGoogle Scholar
  33. Cleary ML, Sklar J (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 82:7439–7443PubMedGoogle Scholar
  34. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656PubMedGoogle Scholar
  35. Coultas L, Bouillet P, Stanley EG, Brodnicki TC, Adams JM, Strasser A (2004) Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Mol Cell Biol 24:1570–1581PubMedGoogle Scholar
  36. 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 24:3963–3973PubMedGoogle Scholar
  37. Coultas L, Terzano S, Thomas T, Voss A, Reid K, Stanley EG, Scott CL, Bouillet P, Bartlett P, Ham J, Adams JM, Strasser A (2007) Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis. J Cell Sci 120:2044–2052PubMedGoogle Scholar
  38. Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A (2007) Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 4:1681–1689; discussion 1690Google Scholar
  39. Cragg MS, Jansen ES, Cook M, Harris C, Strasser A, Scott CL (2008) Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest 118:3651–3659PubMedGoogle Scholar
  40. Cragg MS, Harris C, Strasser A, Scott CL (2009) Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat Rev Cancer 9:321–326PubMedGoogle Scholar
  41. Cullen SP, Adrain C, Luthi AU, Duriez PJ, Martin SJ (2007) Human and murine granzyme B exhibit divergent substrate preferences. J Cell Biol 176:435–444PubMedGoogle Scholar
  42. Czabotar PE, Lee EF, van Delft MF, Day CL, Smith BJ, Huang DC, Fairlie WD, Hinds MG, Colman PM (2007) Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA 104:6217–6222PubMedGoogle Scholar
  43. Dai H, Smith A, Meng XW, Schneider PA, Pang YP, Kaufmann SH (2011) Transient binding of an activator BH3 domain to the Bak BH3-binding groove initiates Bak oligomerization. J Cell Biol 194:39–48PubMedGoogle Scholar
  44. Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM, Datta SR, Greenberg ME, Licklider LJ, Lowell BB, Gygi SP, Korsmeyer SJ (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424:952–956PubMedGoogle Scholar
  45. Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ, Datta SR, Pitter KL, Bird GH, Wikstrom JD, Deeney JT, Robertson K, Morash J, Kulkarni A, Neschen S, Kim S, Greenberg ME, Corkey BE, Shirihai OS, Shulman GI, Lowell BB, Korsmeyer SJ (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144–153PubMedGoogle Scholar
  46. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedGoogle Scholar
  47. Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME (2000) 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 6:41–51PubMedGoogle Scholar
  48. Day CL, Puthalakath H, Skea G, Strasser A, Barsukov I, Lian LY, Huang DC, Hinds MG (2004) Localization of dynein light chains 1 and 2 and their pro-apoptotic ligands. Biochem J 377:597–605PubMedGoogle Scholar
  49. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A (2007) Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117:112–121Google Scholar
  50. Del Gaizo Moore V, Letai A (2013) BH3 profiling—measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. Cancer Lett 332:202–205Google Scholar
  51. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204PubMedGoogle Scholar
  52. Ding WX, Ni HM, Chen X, Yu J, Zhang L, Yin XM (2007) A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol Cancer Ther 6:1062–1069PubMedGoogle Scholar
  53. Dlugosz PJ, Billen LP, Annis MG, Zhu W, Zhang Z, Lin J, Leber B, Andrews DW (2006) Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J 25:2287–2296PubMedGoogle Scholar
  54. Droga-Mazovec G, Bojic L, Petelin A, Ivanova S, Romih R, Repnik U, Salvesen GS, Stoka V, Turk V, Turk B (2008) Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J Biol Chem 283:19140–19150PubMedGoogle Scholar
  55. Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk JE, Kuwana T (2011) BH3 domains other than Bim and Bid can directly activate Bax/Bak. J Biol Chem 286:491–501PubMedGoogle Scholar
  56. Dudgeon C, Wang P, Sun X, Peng R, Sun Q, Yu J, Zhang L (2010) PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01. Mol Cancer Ther 9:2893–2902PubMedGoogle Scholar
  57. Dudgeon C, Peng R, Wang P, Sebastiani A, Yu J, Zhang L (2012) Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3beta and NF-kappaB to suppress tumor cell growth. Oncogene 31:4848–4858Google Scholar
  58. Egle A, Harris AW, Bouillet P, Cory S (2004) Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101:6164–6169PubMedGoogle Scholar
  59. Ekert PG, Jabbour AM, Manoharan A, Heraud JE, Yu J, Pakusch M, Michalak EM, Kelly PN, Callus B, Kiefer T, Verhagen A, Silke J, Strasser A, Borner C, Vaux DL (2006) Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma. Blood 108:1461–1468PubMedGoogle Scholar
  60. Ekoff M, Kaufmann T, Engstrom M, Motoyama N, Villunger A, Jonsson JI, Strasser A, Nilsson G (2007) The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells. Blood 110:3209–3217PubMedGoogle Scholar
  61. Elangovan B, Chinnadurai G (1997) Functional dissection of the pro-apoptotic protein Bik. Heterodimerization with anti-apoptosis proteins is insufficient for induction of cell death. J Biol Chem 272:24494–24498PubMedGoogle Scholar
  62. 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 autoreactive B cells. J Exp Med 198:1119–1126PubMedGoogle Scholar
  63. Engelmann D, Knoll S, Ewerth D, Steder M, Stoll A, Putzer BM (2010) Functional interplay between E2F1 and chemotherapeutic drugs defines immediate E2F1 target genes crucial for cancer cell death. Cell Mol Life Sci 67:931–948PubMedGoogle Scholar
  64. Erlacher M, Michalak EM, Kelly PN, Labi V, Niederegger H, Coultas L, Adams JM, Strasser A, Villunger A (2005) BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106:4131–4138PubMedGoogle Scholar
  65. 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 203:2939–2951PubMedGoogle Scholar
  66. Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20:929–935PubMedGoogle Scholar
  67. Fennell DA, Chacko A, Mutti L (2008) BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 27:1189–1197PubMedGoogle Scholar
  68. Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (2003) Genomic targets of the human c-Myc protein. Genes Dev 17:1115–1129PubMedGoogle Scholar
  69. Fernandez Y, Verhaegen M, Miller TP, Rush JL, Steiner P, Opipari AW Jr, Lowe SW, Soengas MS (2005) Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res 65:6294–6304PubMedGoogle Scholar
  70. Flinterman M, Guelen L, Ezzati-Nik S, Killick R, Melino G, Tominaga K, Mymryk JS, Gaken J, Tavassoli M (2005) E1A activates transcription of p73 and Noxa to induce apoptosis. J Biol Chem 280:5945–5959PubMedGoogle Scholar
  71. Frenzel A, Labi V, Chmelewskij W, Ploner C, Geley S, Fiegl H, Tzankov A, Villunger A (2010) Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad. Blood 115:995–1005PubMedGoogle Scholar
  72. Futami T, Miyagishi M, Taira K (2005) Identification of a network involved in thapsigargin-induced apoptosis using a library of small interfering RNA expression vectors. J Biol Chem 280:826–831PubMedGoogle Scholar
  73. 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 185:279–290PubMedGoogle Scholar
  74. Gandhi L, Camidge DR, de Ribeiro Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (2011) Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29:909–916PubMedGoogle Scholar
  75. Garrison SP, Jeffers JR, Yang C, Nilsson JA, Hall MA, Rehg JE, Yue W, Yu J, Zhang L, Onciu M, Sample JT, Cleveland JL, Zambetti GP (2008) Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol 28:5391–5402PubMedGoogle Scholar
  76. 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 455:1076–1081PubMedGoogle Scholar
  77. Germain M, Mathai JP, Shore GC (2002) BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J Biol Chem 277:18053–18060PubMedGoogle Scholar
  78. Ghiotto F, Fais F, Tenca C, Tomati V, Morabito F, Casciaro S, Mumot A, Zoppoli G, Ciccone E, Parodi S, Bruno S (2009) Apoptosis of B-cell chronic lymphocytic leukemia cells induced by a novel BH3 peptidomimetic. Cancer Biol Ther 8::263–271Google Scholar
  79. Gillespie S, Borrow J, Zhang XD, Hersey P (2006) Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 11:2251–2265PubMedGoogle Scholar
  80. Gilmore AP, Valentijn AJ, Wang P, Ranger AM, Bundred N, O’Hare MJ, Wakeling A, Korsmeyer SJ, Streuli CH (2002) Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 277:27643–27650PubMedGoogle Scholar
  81. Gonzalvez F, Pariselli F, Jalmar O, Dupaigne P, Sureau F, Dellinger M, Hendrickson EA, Bernard S, Petit PX (2010) Mechanistic issues of the interaction of the hairpin-forming domain of tBid with mitochondrial cardiolipin. PLoS One 5:e9342PubMedGoogle Scholar
  82. Gurzov EN, Ortis F, Cunha DA, Gosset G, Li M, Cardozo AK, Eizirik DL (2009) Signaling by IL-1beta + IFN-gamma and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic beta-cell apoptosis. Cell Death Differ 16:1539–1550PubMedGoogle Scholar
  83. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L, Chittenden T (2001) Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA 98:11318–11323PubMedGoogle Scholar
  84. Hao H, Chen C, Rao XM, Gomez-Gutierrez JG, Zhou HS, McMasters KM (2012) E2F-1- and E2Ftr-mediated apoptosis: the role of DREAM and HRK. J Cell Mol Med 16:605–615PubMedGoogle Scholar
  85. Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD, Korsmeyer SJ (1999) Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 3:413–422PubMedGoogle Scholar
  86. Hardwick JM, Youle RJ (2009) SnapShot: BCL-2 proteins. Cell 138:404–404.e1Google Scholar
  87. Hayakawa J, Mittal S, Wang Y, Korkmaz KS, Adamson E, English C, Ohmichi M, McClelland M, Mercola D (2004) Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress. Mol Cell 16:521–535PubMedGoogle Scholar
  88. Heibein JA, Goping IS, Barry M, Pinkoski MJ, Shore GC, Green DR, Bleackley RC (2000) Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax. J Exp Med 192:1391–1402PubMedGoogle Scholar
  89. Heist RS, Fain J, Chinnasami B, Khan W, Molina JR, Sequist LV, Temel JS, Fidias P, Brainerd V, Leopold L, Lynch TJ (2010) Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol 5:1637–1643PubMedGoogle Scholar
  90. Hekman M, Albert S, Galmiche A, Rennefahrt UE, Fueller J, Fischer A, Puehringer D, Wiese S, Rapp UR (2006) Reversible membrane interaction of BAD requires two C-terminal lipid binding domains in conjunction with 14-3-3 protein binding. J Biol Chem 281:17321–17336PubMedGoogle Scholar
  91. Hemann MT, Zilfou JT, Zhao Z, Burgess DJ, Hannon GJ, Lowe SW (2004) Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci USA 101:9333–9338PubMedGoogle Scholar
  92. Hershko T, Ginsberg D (2004) Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 279:8627–8634PubMedGoogle Scholar
  93. Higuchi T, Nakamura M, Shimada K, Ishida E, Hirao K, Konishi N (2008) HRK inactivation associated with promoter methylation and LOH in prostate cancer. Prostate 68:105–113PubMedGoogle Scholar
  94. Hinds MG, Smits C, Fredericks-Short R, Risk JM, Bailey M, Huang DC, Day CL (2007) 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 14:128–136PubMedGoogle Scholar
  95. Hoque MO, Begum S, Sommer M, Lee T, Trink B, Ratovitski E, Sidransky D (2003) PUMA in head and neck cancer. Cancer Lett 199:75–81PubMedGoogle Scholar
  96. Hsu YT, Wolter KG, Youle RJ (1997) Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci USA 94:3668–3672PubMedGoogle Scholar
  97. Hsu SY, Lin P, Hsueh AJ (1998) BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Mol Endocrinol 12:1432–1440PubMedGoogle Scholar
  98. 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 30:98–105PubMedGoogle Scholar
  99. Iglesias-Serret D, de Frias M, Santidrian AF, Coll-Mulet L, Cosialls AM, Barragan M, Domingo A, Gil J, Pons G (2007) Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. Leukemia 21:281–287PubMedGoogle Scholar
  100. 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 272:18842–18848PubMedGoogle Scholar
  101. 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 24:3721–3725PubMedGoogle Scholar
  102. Inohara N, Ding L, Chen S, Nunez G (1997) Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16:1686–1694PubMedGoogle Scholar
  103. Ishihara T, Hoshino T, Namba T, Tanaka K, Mizushima T (2007) Involvement of up-regulation of PUMA in non-steroidal anti-inflammatory drug-induced apoptosis. Biochem Biophys Res Commun 356:711–717PubMedGoogle Scholar
  104. Itahana K, Zhang Y (2008) Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell 13:542–553PubMedGoogle Scholar
  105. Janssen K, Pohlmann S, Janicke RU, Schulze-Osthoff K, Fischer U (2007) Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. Blood 110:3662–3672PubMedGoogle Scholar
  106. 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 4:321–328PubMedGoogle Scholar
  107. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A, Kaufmann T (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039PubMedGoogle Scholar
  108. Kalinec GM, Fernandez-Zapico ME, Urrutia R, Esteban-Cruciani N, Chen S, Kalinec F (2005) Pivotal role of Harakiri in the induction and prevention of gentamicin-induced hearing loss. Proc Natl Acad Sci USA 102:16019–16024PubMedGoogle Scholar
  109. Kamer I, Sarig R, Zaltsman Y, Niv H, Oberkovitz G, Regev L, Haimovich G, Lerenthal Y, Marcellus RC, Gross A (2005) Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122:593–603PubMedGoogle Scholar
  110. Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned TM, Lock RB, Reynolds CP (2007) Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood 110:2057–2066PubMedGoogle Scholar
  111. Kang MH, Wan Z, Kang YH, Sposto R, Reynolds CP (2008) Mechanism of synergy of N-(4-hydroxyphenyl)retinamide and ABT-737 in acute lymphoblastic leukemia cell lines: Mcl-1 inactivation. J Natl Cancer Inst 100:580–595PubMedGoogle Scholar
  112. Karst AM, Dai DL, Martinka M, Li G (2005) PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene 24:1111–1116PubMedGoogle Scholar
  113. Kaufmann T, Tai L, Ekert PG, Huang DC, Norris F, Lindemann RK, Johnstone RW, Dixit VM, Strasser A (2007) The BH3-only protein bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 129:423–433PubMedGoogle Scholar
  114. Kelly PN, White MJ, Goschnick MW, Fairfax KA, Tarlinton DM, Kinkel SA, Bouillet P, Adams JM, Kile BT, Strasser A (2010) Individual and overlapping roles of BH3-only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development. Cell Death Differ 17:1655–1664PubMedGoogle Scholar
  115. Kemp CJ, Wheldon T, Balmain A (1994) p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat Genet 8:66–69PubMedGoogle Scholar
  116. Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH (2004a) BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med 199:113–124PubMedGoogle Scholar
  117. Kim TH, Zhao Y, Ding WX, Shin JN, He X, Seo YW, Chen J, Rabinowich H, Amoscato AA, Yin XM (2004b) Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release. Mol Biol Cell 15:3061–3072PubMedGoogle Scholar
  118. 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 8:1348–1358PubMedGoogle Scholar
  119. 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 36:487–499PubMedGoogle Scholar
  120. Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M (2003) Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 46:4259–4264PubMedGoogle Scholar
  121. Kohler B, Anguissola S, Concannon CG, Rehm M, Kogel D, Prehn JH (2008) Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands’ apoptotic and synergistic effects. PLoS One 3:e2844PubMedGoogle Scholar
  122. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M (2006) Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375–388PubMedGoogle Scholar
  123. Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, Bornmann W, Kantarjian H, Viallet J, Samudio I, Andreeff M (2008) Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 68:3413–3420PubMedGoogle Scholar
  124. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173PubMedGoogle Scholar
  125. Koutsodontis G, Vasilaki E, Chou WC, Papakosta P, Kardassis D (2005) Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. Biochem J 389:443–455PubMedGoogle Scholar
  126. Krajewska M, Zapata JM, Meinhold-Heerlein I, Hedayat H, Monks A, Bettendorf H, Shabaik A, Bubendorf L, Kallioniemi OP, Kim H, Reifenberger G, Reed JC, Krajewski S (2002) Expression of Bcl-2 family member Bid in normal and malignant tissues. Neoplasia 4:129–140PubMedGoogle Scholar
  127. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC, Kimura S, Ottmann OG, Druker BJ, Villunger A, Roberts AW, Strasser A (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 103:14907–14912PubMedGoogle Scholar
  128. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525–535PubMedGoogle Scholar
  129. Labi V, Erlacher M, Kiessling S, Villunger A (2006) BH3-only proteins in cell death initiation, malignant disease and anticancer therapy. Cell Death Differ 13:1325–1338PubMedGoogle Scholar
  130. Labi V, Erlacher M, Kiessling S, Manzl C, Frenzel A, O’Reilly L, Strasser A, Villunger A (2008) Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates gamma irradiation-induced thymic lymphoma development. J Exp Med 205:641–655PubMedGoogle Scholar
  131. Labi V, Erlacher M, Krumschnabel G, Manzl C, Tzankov A, Pinon J, Egle A, Villunger A (2010) Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev 24:1602–1607PubMedGoogle Scholar
  132. Leber B, Lin J, Andrews DW (2007) Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 12:897–911PubMedGoogle Scholar
  133. Leber B, Lin J, Andrews DW (2010) Still embedded together binding to membranes regulates Bcl-2 protein interactions. Oncogene 29:5221–5230PubMedGoogle Scholar
  134. Lee SH, Soung YH, Lee JW, Kim HS, Lee JH, Park JY, Cho YG, Kim CJ, Kim SY, Park WS, Kim SH, Lee JY, Yoo NJ (2003) Mutational analysis of Noxa gene in human cancers. APMIS 111:599–604PubMedGoogle Scholar
  135. Lee JH, Soung YH, Lee JW, Park WS, Kim SY, Cho YG, Kim CJ, Seo SH, Kim HS, Nam SW, Yoo NJ, Lee SH, Lee JY (2004) Inactivating mutation of the pro-apoptotic gene BID in gastric cancer. J Pathol 202:439–445PubMedGoogle Scholar
  136. 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 180:341–355PubMedGoogle Scholar
  137. Lei K, Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 100:2432–2437PubMedGoogle Scholar
  138. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183–192PubMedGoogle Scholar
  139. Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMedGoogle Scholar
  140. Li J, Lee B, Lee AS (2006) Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281:7260–7270PubMedGoogle Scholar
  141. Li YZ, Lu DY, Tan WQ, Wang JX, Li PF (2008) p53 initiates apoptosis by transcriptionally targeting the antiapoptotic protein ARC. Mol Cell Biol 28:564–574PubMedGoogle Scholar
  142. Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY (2010) Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci Signal 3:ra13Google Scholar
  143. Liu X, Dai S, Zhu Y, Marrack P, Kappler JW (2003) The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity 19:341–352PubMedGoogle Scholar
  144. Liu Z, Lu H, Shi H, Du Y, Yu J, Gu S, Chen X, Liu KJ, Hu CA (2005) PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. Cancer Res 65:1647–1654 PubMedGoogle Scholar
  145. Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B (2009) An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15:3172–3176PubMedGoogle Scholar
  146. Liu Q, Moldoveanu T, Sprules T, Matta-Camacho E, Mansur-Azzam N, Gehring K (2010) Apoptotic regulation by MCL-1 through heterodimerization. J Biol Chem 285:19615–19624PubMedGoogle Scholar
  147. Liu Y, Bertram CC, Shi Q, Zinkel SS (2011) Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ 18:841–852PubMedGoogle Scholar
  148. Liu Y, Aiello A, Zinkel SS (2012) Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. Cell Death DifferGoogle Scholar
  149. 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 44:517–531PubMedGoogle Scholar
  150. Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B, Andrews DW (2008) Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135:1074–1084PubMedGoogle Scholar
  151. Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMedGoogle Scholar
  152. Lutter M, Fang M, Luo X, Nishijima M, Xie X, Wang X (2000) Cardiolipin provides specificity for targeting of tBid to mitochondria. Nat Cell Biol 2:754–761PubMedGoogle Scholar
  153. Ma C, Ying C, Yuan Z, Song B, Li D, Liu Y, Lai B, Li W, Chen R, Ching YP, Li M (2007) dp5/HRK is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons. J Biol Chem 282:30901–30909PubMedGoogle Scholar
  154. Macip S, Igarashi M, Berggren P, Yu J, Lee SW, Aaronson SA (2003) Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol 23:8576–8585PubMedGoogle Scholar
  155. Mandic A, Viktorsson K, Strandberg L, Heiden T, Hansson J, Linder S, Shoshan MC (2002) Calpain-mediated Bid cleavage and calpain-independent Bak modulation: two separate pathways in cisplatin-induced apoptosis. Mol Cell Biol 22:3003–3013PubMedGoogle Scholar
  156. Maryanovich M, Oberkovitz G, Niv H, Vorobiyov L, Zaltsman Y, Brenner O, Lapidot T, Jung S, Gross A (2012) The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 14:535–541PubMedGoogle Scholar
  157. Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281:2027–2031PubMedGoogle Scholar
  158. Mathai JP, Germain M, Marcellus RC, Shore GC (2002) Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 21:2534–2544PubMedGoogle Scholar
  159. Mathai JP, Germain M, Shore GC (2005) BH3-only BIK regulates BAX, BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. J Biol Chem 280:23829–23836PubMedGoogle Scholar
  160. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, Korsmeyer SJ (1989) bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88PubMedGoogle Scholar
  161. McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D (1999) Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 96:625–634PubMedGoogle Scholar
  162. Melino G, Bernassola F, Ranalli M, Yee K, Zong WX, Corazzari M, Knight RA, Green DR, Thompson C, Vousden KH (2004) p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J Biol Chem 279:8076–8083PubMedGoogle Scholar
  163. Meng Y, Tang W, Dai Y, Wu X, Liu M, Ji Q, Ji M, Pienta K, Lawrence T, Xu L (2008) Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 7:2192–2202PubMedGoogle Scholar
  164. Mérino D, Giam M, Hughes PD, Siggs OM, Heger K, O’Reilly LA, Adams JM, Strasser A, Lee EF, Fairlie WD, Bouillet P (2009) The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J Cell Biol 186:355–362PubMedGoogle Scholar
  165. Mérino D, Strasser A, Bouillet P (2012) Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression. Oncogene 31:3392–3396Google Scholar
  166. Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V, Beltran E, Agirre X, Marugan I, Marin M, Rosenwald A, Sugimoto KJ, Wheat LM, Karran EL, Garcia JF, Sanchez L, Prosper F, Staudt LM, Pinkel D, Dyer MJ, Martinez-Climent JA (2007) Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109:271–280PubMedGoogle Scholar
  167. Michalak EM, Villunger A, Adams JM, Strasser A (2008) In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 15:1019–1029PubMedGoogle Scholar
  168. Michalak EM, Vandenberg CJ, Delbridge AR, Wu L, Scott CL, Adams JM, Strasser A (2010) Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Genes Dev 24:1608–1613PubMedGoogle Scholar
  169. Ming L, Sakaida T, Yue W, Jha A, Zhang L, Yu J (2008) Sp1 and p73 activate PUMA following serum starvation. Carcinogenesis 29:1878–1884PubMedGoogle Scholar
  170. Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K (2006) The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell 24:677–688PubMedGoogle Scholar
  171. Mora J, Cheung NK, Chen L, Qin J, Gerald W (2001) Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin Cancer Res 7:1358–1361PubMedGoogle Scholar
  172. Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N (2005) Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas. Acta Neuropathol 110:402–410PubMedGoogle Scholar
  173. Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N (2006) Defective expression of HRK is associated with promoter methylation in primary central nervous system lymphomas. Oncology 70:212–221PubMedGoogle Scholar
  174. Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7:683–694PubMedGoogle Scholar
  175. Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC (2007) Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 104:19512–19517PubMedGoogle Scholar
  176. Obata T, Toyota M, Satoh A, Sasaki Y, Ogi K, Akino K, Suzuki H, Murai M, Kikuchi T, Mita H, Itoh F, Issa JP, Tokino T, Imai K (2003) Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9:6410–6418PubMedGoogle Scholar
  177. O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17:384–395PubMedGoogle Scholar
  178. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058PubMedGoogle Scholar
  179. Oki Y, Copeland A, Hagemeister F, Fayad LE, Fanale M, Romaguera J, Younes A (2012) Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma. Blood 119:2171–2172PubMedGoogle Scholar
  180. Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ (2007) NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci USA 104:8953–8958PubMedGoogle Scholar
  181. 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 435:677–681PubMedGoogle Scholar
  182. O’Reilly LA, Cullen L, Visvader J, Lindeman GJ, Print C, Bath ML, Huang DC, Strasser A (2000) The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells. Am J Pathol 157:449–461PubMedGoogle Scholar
  183. Osundiji MA, Godes ML, Evans ML, Danial NN (2011) BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding. PLoS One 6:e28016PubMedGoogle Scholar
  184. Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, Travis W, James L, Ginsberg MS, Juergens R, Markus S, Tyson L, Subzwari S, Kris MG, Krug LM (2011) A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer 74:481–485PubMedGoogle Scholar
  185. Paquet C, Schmitt E, Beauchemin M, Bertrand R (2004) Activation of multidomain and BH3-only pro-apoptotic Bcl-2 family members in p53-defective cells. Apoptosis 9:815–831PubMedGoogle Scholar
  186. Pastorino JG, Tafani M, Rothman RJ, Marcinkeviciute A, Hoek JB, Farber JL (1999) Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 274:31734–31739PubMedGoogle Scholar
  187. Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J, Swift K, Matayoshi ED, Zhang H, Thompson CB, Fesik SW (2000) Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 9:2528–2534PubMedGoogle Scholar
  188. Pinon JD, Labi V, Egle A, Villunger A (2008) Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 27(Suppl 1):S41–S52PubMedGoogle Scholar
  189. Pitter K, Bernal F, Labelle J, Walensky LD (2008) Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol 446:387–408PubMedGoogle Scholar
  190. Ploner C, Rainer J, Niederegger H, Eduardoff M, Villunger A, Geley S, Kofler R (2008) The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22:370–377PubMedGoogle Scholar
  191. Ploner C, Rainer J, Lobenwein S, Geley S, Kofler R (2009) Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells. Apoptosis 14:821–828PubMedGoogle Scholar
  192. Polzien L, Baljuls A, Rennefahrt UE, Fischer A, Schmitz W, Zahedi RP, Sickmann A, Metz R, Albert S, Benz R, Hekman M, Rapp UR (2009) Identification of novel in vivo phosphorylation sites of the human proapoptotic protein BAD: pore-forming activity of BAD is regulated by phosphorylation. J Biol Chem 284:28004–28020PubMedGoogle Scholar
  193. Polzien L, Baljuls A, Roth HM, Kuper J, Benz R, Schweimer K, Hekman M, Rapp UR (2011) Pore-forming activity of BAD is regulated by specific phosphorylation and structural transitions of the C-terminal part. Biochim Biophys Acta 1810:162–169PubMedGoogle Scholar
  194. Pompeia C, Hodge DR, Plass C, Wu YZ, Marquez VE, Kelley JA, Farrar WL (2004) Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res 64:3465–3473PubMedGoogle Scholar
  195. Ponassi R, Biasotti B, Tomati V, Bruno S, Poggi A, Malacarne D, Cimoli G, Salis A, Pozzi S, Miglino M, Damonte G, Cozzini P, Spyraki F, Campanini B, Bagnasco L, Castagnino N, Tortolina L, Mumot A, Frassoni F, Daga A, Cilli M, Piccardi F, Monfardini I, Perugini M, Zoppoli G, D’Arrigo C, Pesenti R, Parodi S (2008) A novel Bim-BH3-derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex vivo anti-leukemic activity. Cell Cycle 7:3211–3224PubMedGoogle Scholar
  196. Pradhan S, Kim HK, Thrash CJ, Cox MA, Mantena SK, Wu JH, Athar M, Katiyar SK, Elmets CA, Timares L (2008) A critical role for the proapoptotic protein bid in ultraviolet-induced immune suppression and cutaneous apoptosis. J Immunol 181:3077–3088PubMedGoogle Scholar
  197. Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, Johnson EM (2001) Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 29:615–628PubMedGoogle Scholar
  198. Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A (1999) The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296PubMedGoogle Scholar
  199. Puthalakath H, Villunger A, O’Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A (2001) Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293:1829–1832PubMedGoogle Scholar
  200. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349PubMedGoogle Scholar
  201. Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, Grant S, Hylemon PB, Dent P (2003) Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol 23:3052–3066PubMedGoogle Scholar
  202. Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V, Bennett F, Pollock PM, Trent JM, Hendrix MJ, Rizzo P, Miele L, Nickoloff BJ (2005) Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 65:6282–6293PubMedGoogle Scholar
  203. Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti GP, Zhang L, Yu J (2008) PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell 2:576–583PubMedGoogle Scholar
  204. 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 USA 100:9324–9329PubMedGoogle Scholar
  205. Ready N, Karaseva NA, Orlov SV, Luft AV, Popovych O, Holmlund JT, Wood BA, Leopold L (2011) Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer. J Thorac Oncol 6:781–785PubMedGoogle Scholar
  206. Real PJ, Sanz C, Gutierrez O, Pipaon C, Zubiaga AM, Fernandez-Luna JL (2006) Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells. FEBS Lett 580:5905–5909PubMedGoogle Scholar
  207. Reed JC (2006) Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 13:1378–1386PubMedGoogle Scholar
  208. Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J, Muthuswamy SK, Brugge JS (2003) Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5:733–740PubMedGoogle Scholar
  209. Reimertz C, Kogel D, Rami A, Chittenden T, Prehn JH (2003) Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. J Cell Biol 162:587–597PubMedGoogle Scholar
  210. 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 330:1390–1393PubMedGoogle Scholar
  211. Rizvi F, Heimann T, Herrnreiter A, O’Brien WJ (2011) Mitochondrial dysfunction links ceramide activated HRK expression and cell death. PLoS One 6:e18137PubMedGoogle Scholar
  212. 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 30:488–496PubMedGoogle Scholar
  213. Ruffolo SC, Breckenridge DG, Nguyen M, Goping IS, Gross A, Korsmeyer SJ, Li H, Yuan J, Shore GC (2000) BID-dependent and BID-independent pathways for BAX insertion into mitochondria. Cell Death Differ 7:1101–1108PubMedGoogle Scholar
  214. Saito M, Korsmeyer SJ, Schlesinger PH (2000) BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2:553–555PubMedGoogle Scholar
  215. Sanz C, Benito A, Inohara N, Ekhterae D, Nunez G, Fernandez-Luna JL (2000) Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells. Blood 95:2742–2747PubMedGoogle Scholar
  216. Sanz C, Mellstrom B, Link WA, Naranjo JR, Fernandez-Luna JL (2001) Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic Hrk gene in hematopoietic progenitor cells. EMBO J 20:2286–2292PubMedGoogle Scholar
  217. Sanz C, Horita M, Fernandez-Luna JL (2002) Fas signaling and blockade of Bcr-Abl kinase induce apoptotic Hrk protein via DREAM inhibition in human leukemia cells. Haematologica 87:903–907PubMedGoogle Scholar
  218. 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 275:983–986PubMedGoogle Scholar
  219. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS (2002) BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 4:842–849PubMedGoogle Scholar
  220. Sborgi L, Barrera-Vilarmau S, Obregon P, de Alba E (2010) Characterization of a novel interaction between Bcl-2 members Diva and Harakiri. PLoS One 5:e15575PubMedGoogle Scholar
  221. Schafer B, Quispe J, Choudhary V, Chipuk JE, Ajero TG, Du H, Schneiter R, Kuwana T (2009) Mitochondrial outer membrane proteins assist Bid in Bax-mediated lipidic pore formation. Mol Biol Cell 20:2276–2285PubMedGoogle Scholar
  222. Schimmer AD, O’Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, Yee K, Ravandi F, Giles F, Schuh A, Gupta V, Andreeff M, Koller C, Chang H, Kamel-Reid S, Berger M, Viallet J, Borthakur G (2008) A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 14:8295–8301PubMedGoogle Scholar
  223. Schmelzle T, Mailleux AA, Overholtzer M, Carroll JS, Solimini NL, Lightcap ES, Veiby OP, Brugge JS (2007) Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci USA 104:3787–3792PubMedGoogle Scholar
  224. Schmutte C, Tombline G, Rhiem K, Sadoff MM, Schmutzler R, von Deimling A, Fishel R (1999) Characterization of the human Rad51 genomic locus and examination of tumors with 15q14-15 loss of heterozygosity (LOH). Cancer Res 59:4564–4569PubMedGoogle Scholar
  225. Schoenwaelder SM, Jarman KE, Gardiner E, Hua M, Qiao J, White MJ, Josefsson EC, Alwis I, Ono A, Willcox A, Andrews RK, Mason KD, Salem HH, Huang DC, Kile BT, Roberts AW, Jackson SP (2011) Bcl-xL inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 118:1663–1674Google Scholar
  226. Seo YW, Shin JN, Ko KH, Cha JH, Park JY, Lee BR, Yun CW, Kim YM, Seol DW, Kim DW, Yin XM, Kim TH (2003) The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death. J Biol Chem 278:48292–48299PubMedGoogle Scholar
  227. Shao Y, Aplin AE (2010) Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res 70:6670–6681PubMedGoogle Scholar
  228. Shao Y, Aplin AE (2012) ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death Dis 3:e253PubMedGoogle Scholar
  229. Shelton SN, Shawgo ME, Robertson JD (2009) Cleavage of Bid by executioner caspases mediates feed forward amplification of mitochondrial outer membrane permeabilization during genotoxic stress-induced apoptosis in Jurkat cells. J Biol Chem 284:11247–11255PubMedGoogle Scholar
  230. Shen H, Yu H, Liang PH, Xufeng R, Song Y, Hu X, Chen X, Yin XM, Cheng T (2011) Bid is a positive regulator for donor-derived lymphoid cell regeneration in gamma-irradiated recipients. Exp Hematol 39(947–957):e941Google Scholar
  231. Shi Y (2006) Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18:677–684PubMedGoogle Scholar
  232. Shibue T, Takeda K, Oda E, Tanaka H, Murasawa H, Takaoka A, Morishita Y, Akira S, Taniguchi T, Tanaka N (2003) Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 17:2233–2238PubMedGoogle Scholar
  233. Sinicrope FA, Rego RL, Foster NR, Thibodeau SN, Alberts SR, Windschitl HE, Sargent DJ (2008a) Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers. Clin Cancer Res 14:4128–4133PubMedGoogle Scholar
  234. Sinicrope FA, Rego RL, Okumura K, Foster NR, O’Connell MJ, Sargent DJ, Windschitl HE (2008b) Prognostic impact of bim, puma, and noxa expression in human colon carcinomas. Clin Cancer Res 14:5810–5818PubMedGoogle Scholar
  235. Smits C, Czabotar PE, Hinds MG, Day CL (2008) Structural plasticity underpins promiscuous binding of the prosurvival protein A1. Structure 16:818–829PubMedGoogle Scholar
  236. Song G, Chen GG, Chau DK, Miao J, Lai PB (2008) Bid exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. Apoptosis 13:693–701PubMedGoogle Scholar
  237. Steckley D, Karajgikar M, Dale LB, Fuerth B, Swan P, Drummond-Main C, Poulter MO, Ferguson SS, Strasser A, Cregan SP (2007) Puma is a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis. J Neurosci 27:12989–12999PubMedGoogle Scholar
  238. Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S, Jung K, Loening S, Dorken B, Daniel PT (2006) Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ 13:619–627PubMedGoogle Scholar
  239. Sun Q, Ming L, Thomas SM, Wang Y, Chen ZG, Ferris RL, Grandis JR, Zhang L, Yu J (2009) PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells. Oncogene 28:2348–2357PubMedGoogle Scholar
  240. Sunayama J, Ando Y, Itoh N, Tomiyama A, Sakurada K, Sugiyama A, Kang D, Tashiro F, Gotoh Y, Kuchino Y, Kitanaka C (2004) Physical and functional interaction between BH3-only protein Hrk and mitochondrial pore-forming protein p32. Cell Death Differ 11:771–781PubMedGoogle Scholar
  241. Sutton VR, Davis JE, Cancilla M, Johnstone RW, Ruefli AA, Sedelies K, Browne KA, Trapani JA (2000) Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J Exp Med 192:1403–1414PubMedGoogle Scholar
  242. Suzuki M, Youle RJ, Tjandra N (2000) Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 103:645–654PubMedGoogle Scholar
  243. Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, Morishima Y, Nakamura S, Seto M (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24:1348–1358PubMedGoogle Scholar
  244. Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P, Villunger A, Adams JM, White E (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238PubMedGoogle Scholar
  245. Terasawa K, Ichimura A, Sato F, Shimizu K, Tsujimoto G (2009) Sustained activation of ERK1/2 by NGF induces microRNA-221 and 222 in PC12 cells. FEBS J 276:3269–3276PubMedGoogle Scholar
  246. 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 68:3421–3428PubMedGoogle Scholar
  247. Tsujimoto Y, Cossman J, Jaffe E, Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science 228:1440–1443PubMedGoogle Scholar
  248. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399PubMedGoogle Scholar
  249. VanBrocklin MW, Verhaegen M, Soengas MS, Holmen SL (2009) Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 69:1985–1994PubMedGoogle Scholar
  250. Verma S, Zhao LJ, Chinnadurai G (2001) Phosphorylation of the pro-apoptotic protein BIK: mapping of phosphorylation sites and effect on apoptosis. J Biol Chem 276:4671–4676PubMedGoogle Scholar
  251. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A (2003a) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302:1036–1038PubMedGoogle Scholar
  252. Villunger A, Scott C, Bouillet P, Strasser A (2003b) Essential role for the BH3-only protein Bim but redundant roles for Bax, Bcl-2, and Bcl-w in the control of granulocyte survival. Blood 101:2393–2400PubMedGoogle Scholar
  253. Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799PubMedGoogle Scholar
  254. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283PubMedGoogle Scholar
  255. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466–1470PubMedGoogle Scholar
  256. 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 24:199–210PubMedGoogle Scholar
  257. Wang HG, Rapp UR, Reed JC (1996a) Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87:629–638PubMedGoogle Scholar
  258. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999) Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339–343PubMedGoogle Scholar
  259. Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ (1996b) BID: a novel BH3 domain-only death agonist. Genes Dev 10:2859–2869PubMedGoogle Scholar
  260. Wang P, Yu J, Zhang L (2007) The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damage. Proc Natl Acad Sci USA 104:4054–4059PubMedGoogle Scholar
  261. Wang P, Qiu W, Dudgeon C, Liu H, Huang C, Zambetti GP, Yu J, Zhang L (2009) PUMA is directly activated by NF-kappaB and contributes to TNF-alpha-induced apoptosis. Cell Death Differ 16:1192–1202PubMedGoogle Scholar
  262. Wang X, Wang R, Hao MW, Dong K, Wei SH, Lin F, Ren JH, Zhang HZ (2008) The BH3-only protein PUMA is involved in green tea polyphenol-induced apoptosis in colorectal cancer cell lines. Cancer Biol Ther 7:902–908PubMedGoogle Scholar
  263. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071PubMedGoogle Scholar
  264. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730PubMedGoogle Scholar
  265. Wilfling F, Weber A, Potthoff S, Vogtle FN, Meisinger C, Paschen SA, Hacker G (2012) BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax. Cell Death DifferGoogle Scholar
  266. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC (2005) Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19:1294–1305PubMedGoogle Scholar
  267. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315:856–859PubMedGoogle Scholar
  268. 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 11:1149–1159PubMedGoogle Scholar
  269. Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, Look AT (2005) Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123:641–653PubMedGoogle Scholar
  270. Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R, Hosokawa H, Hasegawa A, Motohashi S, Iwama A, Nakayama T (2008) Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. J Exp Med 205:1109–1120PubMedGoogle Scholar
  271. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291PubMedGoogle Scholar
  272. Yong WH, Ueki K, Chou D, Reeves SA, von Deimling A, Gusella JF, Mohrenweiser HW, Buckler AJ, Louis DN (1995) Cloning of a highly conserved human protein serine-threonine phosphatase gene from the glioma candidate region on chromosome 19q13.3. Genomics 29:533–536PubMedGoogle Scholar
  273. Yoo NJ, Lee JW, Jeong EG, Lee SH (2007) Immunohistochemical analysis of pro-apoptotic PUMA protein and mutational analysis of PUMA gene in gastric carcinomas. Dig Liver Dis 39:222–227PubMedGoogle Scholar
  274. Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7:673–682PubMedGoogle Scholar
  275. Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L (2003) PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100:1931–1936PubMedGoogle Scholar
  276. Yu J, Zhang L (2005) The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 331:851–858PubMedGoogle Scholar
  277. Yu J, Yue W, Wu B, Zhang L (2006) PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation. Clin Cancer Res 12:2928–2936PubMedGoogle Scholar
  278. Yu J, Zhang L (2008) PUMA, a potent killer with or without p53. Oncogene 27(Suppl 1):S71–S83PubMedGoogle Scholar
  279. Zaltsman Y, Shachnai L, Yivgi-Ohana N, Schwarz M, Maryanovich M, Houtkooper RH, Vaz FM, De Leonardis F, Fiermonte G, Palmieri F, Gillissen B, Daniel PT, Jimenez E, Walsh S, Koehler CM, Roy SS, Walter L, Hajnoczky G, Gross A (2010) MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol 12:553–562PubMedGoogle Scholar
  280. Zantl N, Weirich G, Zall H, Seiffert BM, Fischer SF, Kirschnek S, Hartmann C, Fritsch RM, Gillissen B, Daniel PT, Hacker G (2007) Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance. Oncogene 26:7038–7048PubMedGoogle Scholar
  281. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628PubMedGoogle Scholar
  282. Zhang Z, Lapolla SM, Annis MG, Truscott M, Roberts GJ, Miao Y, Shao Y, Tan C, Peng J, Johnson AE, Zhang XC, Andrews DW, Lin J (2004) Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J Biol Chem 279:43920–43928PubMedGoogle Scholar
  283. Zhang Z, Song T, Zhang T, Gao J, Wu G, An L, Du G (2011) A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1. Int J Cancer 128:1724–1735PubMedGoogle Scholar
  284. Zhang Y, Adachi M, Kawamura R, Imai K (2006) Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ 13:129–140PubMedGoogle Scholar
  285. Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG, McCubrey J, Cortes J, Andreeff M (2008) Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 22:808–818PubMedGoogle Scholar
  286. Zinkel SS, Ong CC, Ferguson DO, Iwasaki H, Akashi K, Bronson RT, Kutok JL, Alt FW, Korsmeyer SJ (2003) Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev 17:229–239PubMedGoogle Scholar
  287. Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ (2005) A role for proapoptotic BID in the DNA-damage response. Cell 122:579–591PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Fabio Ghiotto
    • 1
  • Claudya Tenca
    • 1
  • Franco Fais
    • 1
  • Silvia Bruno
    • 1
    Email author
  1. 1.Human Anatomy Section, Department of Experimental MedicineUniversity of GenoaGenoaItaly

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