BH3-Only Proteins and Their Effects on Cancer

  • Thanh-Trang Vo
  • Anthony Letai
Part of the Advances in Experimental Medicine and Biology book series (volume 687)


Apoptosis, a form of cellular suicide is a key mechanism involved in the clearance of cells that are dysfunctional, superfluous or infected. For this reason, the cell needs mechanisms to sense death cues and relay death signals to the apoptotic machinery involved in cellular execution. In the intrinsic apoptotic pathway, a subclass of BCL-2 family proteins called the BH3-only proteins are responsible for triggering apoptosis in response to varied cellular stress cues. The mechanisms by which they are regulated are tied to the type of cellular stress they sense. Once triggered, they interact with other BCL-2 family proteins to cause mitochondrial outer membrane permeabilization which in turn results in the activation of serine proteases necessary for cell killing. Failure to properly sense death cues and relay the death signal can have a major impact on cancer. This chapter will discuss our current models of how BH3-only proteins function as well as their impact on carcinogenesis and cancer treatment.


Death Signal Antiapoptotic Protein Proapoptotic Protein Mitochondrial Outer Membrane Permeabilization Cell Death Differ 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Enari M, Sakahira H, Yokoyama H et al. A caspase-activated DNase that degrades DNA during apoptosis and its inhibitor ICAD. Nature 1998; 391(6662):43–50.PubMedGoogle Scholar
  2. 2.
    Khosravi-Far R, Esposti MD. Death receptor signals to mitochondria. Cancer Biol Ther 2004; 3(11):1051–1057.PubMedGoogle Scholar
  3. 3.
    Du C, Fang M, Li Y et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102(1):33–42.PubMedGoogle Scholar
  4. 4.
    Liu X, Kim CN, Yang J et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 1996; 86(1):147–157.PubMedGoogle Scholar
  5. 5.
    Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001; 15(22):2922–2933.PubMedGoogle Scholar
  6. 6.
    Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 2000; 275(40):31199–31203.PubMedGoogle Scholar
  7. 7.
    Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev 1999; 13(24):3179–3184.PubMedGoogle Scholar
  8. 8.
    Zou H, Li Y, Liu X et al. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999; 274(17):11549–11556.PubMedGoogle Scholar
  9. 9.
    Garcia-Saez AJ, Mingarro I, Perez-Paya E et al. Membrane-insertion fragments of Bcl-xL, Bax and Bid. Biochemistry 2004; 43(34):10930–10943.PubMedGoogle Scholar
  10. 10.
    Schlesinger PH, Saito M. The Bax pore in liposomes, Biophysics. Cell Death Differ 2006; 13(8):1403–1408.PubMedGoogle Scholar
  11. 11.
    Wei MC, Zong WX, Cheng EH et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292(5517):727–730.PubMedGoogle Scholar
  12. 12.
    Wei MC, Lindsten T, Mootha VK et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14(16):2060–2071.PubMedGoogle Scholar
  13. 13.
    Petros AM, Olejniczak ET, Fesik SW. Structural biology of the BCL-2 family of proteins. Biochim Biophys Acta 2004; 1644(2–3):83–94.PubMedGoogle Scholar
  14. 14.
    Hsu YT, Youle RJ. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J Biol Chem 1998; 273(17):10777–10783.PubMedGoogle Scholar
  15. 15.
    Petros AM, Nettesheim DG, Wang Y et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis and biophysical studies. Protein Sci 2000; 9(12):2528–2534.PubMedGoogle Scholar
  16. 16.
    Cheng EH, Levine B, Boise LH et al. Bax-independent inhibition of apoptosis by BCL-XL. Nature 1996; 379(6565):554–556.PubMedGoogle Scholar
  17. 17.
    Certo M, Del Gaizo Moore V, Nishino M et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006; 9(5):351–365.PubMedGoogle Scholar
  18. 18.
    O’Connor L, Strasser A, O’Reilly LA et al. Bim: a novel member of the BCL-2 family that promotes apoptosis. EMBO J 1998; 17(2):384–395.PubMedGoogle Scholar
  19. 19.
    Wang K, Yin XM, Chao DT et al. BID: a novel BH3 domain-only death agonist. Genes Dev 1996; 10(22):2859–2869.PubMedGoogle Scholar
  20. 20.
    Yang E, Zha J, Jockel J et al. Bad, a heterodimeric partner for BCL-XL and BCL-2, displaces Bax and promotes cell death. Cell 1995; 80(2):285–291.PubMedGoogle Scholar
  21. 21.
    Boyd JM, Gallo GJ, Elangovan B et al. 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 1995; 11(9):1921–1928.PubMedGoogle Scholar
  22. 22.
    Oda E, Ohki R, Murasawa H et al. Noxa, a BH3-only member of the BCL-2 family and candidate mediator of p53-induced apoptosis. Science 2000; 288(5468):1053–1058.PubMedGoogle Scholar
  23. 23.
    Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001; 7(3):683–694.PubMedGoogle Scholar
  24. 24.
    Inohara N, Ding L, Chen S et al. 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 1997; 16(7):1686–1694.PubMedGoogle Scholar
  25. 25.
    Puthalakath H, Villunger A, O’Reilly LA et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 2001; 293(5536):1829–1832.PubMedGoogle Scholar
  26. 26.
    Zhong Q, Gao W, Du F et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 2005; 121(7):1085–1095.PubMedGoogle Scholar
  27. 27.
    Guo B, Godzik A, Reed JC. Bcl-G, a novel pro-apoptotic member of the BCL-2 family. J Biol Chem 2001; 276(4):2780–2785.PubMedGoogle Scholar
  28. 28.
    Yasuda M, Theodorakis P, Subramanian T et al. Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence. J Biol Chem 1998; 273(20):12415–12421.PubMedGoogle Scholar
  29. 29.
    Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the BCL-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 2007; 282(17):13123–13132.PubMedGoogle Scholar
  30. 30.
    Liu Z, Lu H, Jiang Z et al. Apolipoprotein l6, a novel proapoptotic BCL-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells. Mol Cancer Res 2005; 3(1):21–31.PubMedGoogle Scholar
  31. 31.
    Broustas CG, Gokhale PC, Rahman A et al. BRCC2, a novel BH3-like domain-containing protein, induces apoptosis in a caspase-dependent manner. J Biol Chem 2004; 279(25):26780–26788.PubMedGoogle Scholar
  32. 32.
    Mund T, Gewies A, Schoenfeld N et al. Spike, a novel BH3-only protein, regulates apoptosis at the endoplasmic reticulum. FASEB J 2003; 17(6):696–698.PubMedGoogle Scholar
  33. 33.
    Tan KO, Tan KM, Chan SL et al. MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its BCL-2 homology domains. J Biol Chem 2001; 276(4):2802–2807.PubMedGoogle Scholar
  34. 34.
    Letai A, Bassik MC, Walensky LD et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2(3):183–192.PubMedGoogle Scholar
  35. 35.
    Zong WX, Lindsten T, Ross AJ et al. BH3-only proteins that bind pro-survival BCL-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15(12):1481–1486.PubMedGoogle Scholar
  36. 36.
    Kuwana T, Mackey MR, Perkins G et al. Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 2002; 111(3):331–342.PubMedGoogle Scholar
  37. 37.
    Lovell JF, Billen LP, Bindner S et al. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 2008; 135(6):1074–1084.PubMedGoogle Scholar
  38. 38.
    Gavathiotis E, Suzuki M, Davis ML et al. BAX activation is initiated at a novel interaction site. Nature 2008; 455(7216):1076–1081.PubMedGoogle Scholar
  39. 39.
    Willis SN, Fletcher JI, Kaufmann T et al. Apoptosis initiated when BH3 ligands engage multiple BCL-2 homologs, not Bax or Bak. Science 2007; 315(5813):856–859.PubMedGoogle Scholar
  40. 40.
    Chipuk JE, Kuwana T, Bouchier-Hayes L et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303(5660):1010–1014.PubMedGoogle Scholar
  41. 41.
    Kim H, Rafiuddin-Shah M, Tu HC et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 2006; 8(12):1348–1358.PubMedGoogle Scholar
  42. 42.
    Pagliari LJ, Kuwana T, Bonzon C et al. The multidomain proapoptotic molecules Bax and Bak are directly activated by heat. Proc Natl Acad Sci USA 2005; 102(50):17975–17980.PubMedGoogle Scholar
  43. 43.
    Cheng EH, Wei MC, Weiler S et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX-and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8(3):705–711.PubMedGoogle Scholar
  44. 44.
    Chen L, Willis SN, Wei A et al. Differential targeting of prosurvival BCL-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 2005; 17(3):393–403.PubMedGoogle Scholar
  45. 45.
    O’Reilly LA, Cullen L, Visvader J et al. The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal and germ cells. Am J Pathol 2000; 157(2):449–461.PubMedGoogle Scholar
  46. 46.
    Marani M, Tenev T, Hancock D et al. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002; 22(11):3577–3589.PubMedGoogle Scholar
  47. 47.
    Adachi M, Zhao X, Imai K. Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms. Cell Death Differ 2005; 12(2):192–193.PubMedGoogle Scholar
  48. 48.
    Puthalakath H, Huang DC, O’Reilly LA et al. The proapoptotic activity of the BCL-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3(3):287–296.PubMedGoogle Scholar
  49. 49.
    Dijkers PF, Medema RH, Lammers JW et al. Expression of the pro-apoptotic BCL-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10(19):1201–1204.PubMedGoogle Scholar
  50. 50.
    Reginato MJ, Mills KR, Paulus JK et al. Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 2003; 5(8):733–740.PubMedGoogle Scholar
  51. 51.
    Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA 2003; 100(5):2432–2437.PubMedGoogle Scholar
  52. 52.
    Akiyama T, Bouillet P, Miyazaki T et al. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only BCL-2 family member Bim. EMBO J 2003; 22(24):6653–6664.PubMedGoogle Scholar
  53. 53.
    Barry M, Heibein JA, Pinkoski MJ et al. Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol 2000; 20(11):3781–3794.PubMedGoogle Scholar
  54. 54.
    Sutton VR, Davis JE, Cancilla M et al. Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J Exp Med 2000; 192(10):1403–1414.PubMedGoogle Scholar
  55. 55.
    Droga-Mazovec G, Bojic L, Petelin A et al. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic BCL-2 homologues. J Biol Chem 2008; 283(27):19140–19150.PubMedGoogle Scholar
  56. 56.
    Zha J, Weiler S, Oh KJ et al. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 2000; 290(5497):1761–1765.PubMedGoogle Scholar
  57. 57.
    Sax JK, Fei P, Murphy ME et al. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 2002; 4(11):842–849.PubMedGoogle Scholar
  58. 58.
    Kamer I, Sarig R, Zaltsman Y et al. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 2005; 122(4):593–603.PubMedGoogle Scholar
  59. 59.
    Ranger AM, Zha J, Harada H et al. Bad-deficient mice develop diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 2003; 100(16):9324–9329.PubMedGoogle Scholar
  60. 60.
    Datta SR, Dudek H, Tao X et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91(2):231–241.PubMedGoogle Scholar
  61. 61.
    del Peso L, Gonzalez-Garcia M, Page C et al. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278(5338):687–689.PubMedGoogle Scholar
  62. 62.
    Wang HG, Rapp UR, Reed JC. BCL-2 targets the protein kinase Raf-1 to mitochondria. Cell 1996; 87(4):629–638.PubMedGoogle Scholar
  63. 63.
    Harada H, Becknell B, Wilm M et al. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 1999; 3(4):413–422.PubMedGoogle Scholar
  64. 64.
    Zha J, Harada H, Yang E et al. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 1996; 87(4):619–628.PubMedGoogle Scholar
  65. 65.
    Wang HG, Pathan N, Ethell IM et al. Ca2?-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999; 284(5412):339–343.PubMedGoogle Scholar
  66. 66.
    Ayllon V, Martinez AC, Garcia A et al. Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J 2000; 19(10):2237–2246.PubMedGoogle Scholar
  67. 67.
    Chiang CW, Harris G, Ellig C et al. Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin-3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 2001; 97(5):1289–1297.PubMedGoogle Scholar
  68. 68.
    Mathai JP, Germain M, Marcellus RC et al. Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 2002; 21(16):2534–2544.PubMedGoogle Scholar
  69. 69.
    Verma S, Zhao LJ, Chinnadurai G. Phosphorylation of the pro-apoptotic protein BIK: mapping of phosphorylation sites and effect on apoptosis. J Biol Chem 2001; 276(7):4671–4676.PubMedGoogle Scholar
  70. 70.
    Real PJ, Sanz C, Gutierrez O et al. Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells. FEBS Lett 2006; 580(25):5905–5909.PubMedGoogle Scholar
  71. 71.
    Han J, Flemington C, Houghton AB et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA 2001; 98(20):11318–11323.PubMedGoogle Scholar
  72. 72.
    Jeffers JR, Parganas E, Lee Y et al. Puma is an essential mediator of p53-dependent and-independent apoptotic pathways. Cancer Cell 2003; 4(4):321–328.PubMedGoogle Scholar
  73. 73.
    Villunger A, Michalak EM, Coultas L et al. p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302(5647):1036–1038.PubMedGoogle Scholar
  74. 74.
    Schmelzle T, Mailleux AA, Overholtzer M et al. Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci USA 2007; 104(10):3787–3792.PubMedGoogle Scholar
  75. 75.
    Imaizumi K, Tsuda M, Imai Y et al. Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 1997; 272(30):18842–18848.PubMedGoogle Scholar
  76. 76.
    Sanz C, Benito A, Inohara N et al. Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells. Blood 2000; 95(9):2742–2747.PubMedGoogle Scholar
  77. 77.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1):57–70.PubMedGoogle Scholar
  78. 78.
    Bouillet P, Metcalf D, Huang DC et al. Proapoptotic BCL-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis and to preclude autoimmunity. Science 1999; 286(5445):1735–1738.PubMedGoogle Scholar
  79. 79.
    Egle A, Harris AW, Bouillet P et al. Bim is a suppressor of Myc-induced mouse B-cell leukemia. Proc Natl Acad Sci USA 2004; 101(16):6164–6169.PubMedGoogle Scholar
  80. 80.
    Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 2007; 109(1):271–280.PubMedGoogle Scholar
  81. 81.
    Zinkel SS, Ong CC, Ferguson DO et al. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev 2003; 17(2):229–239.PubMedGoogle Scholar
  82. 82.
    Krajewska M, Zapata JM, Meinhold-Heerlein I et al. Expression of BCL-2 family member Bid in normal and malignant tissues. Neoplasia 2002; 4(2):129–140.PubMedGoogle Scholar
  83. 83.
    Pompeia C, Hodge DR, Plass C et al. Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res 2004; 64(10):3465–3473.PubMedGoogle Scholar
  84. 84.
    Sturm I, Stephan C, Gillissen B et al. Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ 2006; 13(4):619–627.PubMedGoogle Scholar
  85. 85.
    Hemann MT, Zilfou JT, Zhao Z et al. Suppression of tumorigenesis by the p53 target PUMA. Proc Natl Acad Sci USA 2004; 101(25):9333–9338.PubMedGoogle Scholar
  86. 86.
    Hoque MO, Begum S, Sommer M et al. PUMA in head and neck cancer. Cancer Lett 2003; 199(1):75–81.PubMedGoogle Scholar
  87. 87.
    Karst AM, Dai DL, Martinka M et al. PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene 2005; 24(6):1111–1116.PubMedGoogle Scholar
  88. 88.
    Chin L, Merlino G, DePinho RA. Malignant melanoma: modern black plague and genetic black box. Genes Dev 1998; 12(22):3467–3481.PubMedGoogle Scholar
  89. 89.
    Lee SH, Soung YH, Lee JW et al. Mutational analysis of Noxa gene in human cancers. APMIS 2003; 111(6):599–604.PubMedGoogle Scholar
  90. 90.
    Schmutte C, Tombline G, Rhiem K et al. Characterization of the human Rad51 genomic locus and examination of tumors with 15q14–15 loss of heterozygosity (LOH). Cancer Res 1999; 59(18):4564–4569.PubMedGoogle Scholar
  91. 91.
    Wick W, Petersen I, Schmutzler RK et al. Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. Oncogene 1996; 12(5):973–978.PubMedGoogle Scholar
  92. 92.
    Obata T, Toyota M, Satoh A et al. Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 2003; 9(17):6410–6418.PubMedGoogle Scholar
  93. 93.
    Nieborowska-Skorska M, Hoser G, Kossev P et al. Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. Blood 2002; 99(12):4531–4539.PubMedGoogle Scholar
  94. 94.
    Packham G, White EL, Eischen CM et al. Selective regulation of BCL-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Genes Dev 1998; 12(16):2475–2487.PubMedGoogle Scholar
  95. 95.
    Zhou P, Levy NB, Xie H et al. MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood 2001; 97(12):3902–3909.PubMedGoogle Scholar
  96. 96.
    Sinicrope FA, Rego RL, Okumura K et al. Prognostic impact of bim, puma and noxa expression in human colon carcinomas. Clin Cancer Res 2008; 14(18):5810–5818.PubMedGoogle Scholar
  97. 97.
    Sinicrope FA, Rego RL, Foster NR et al. Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers. Clin Cancer Res 2008; 14(13):4128–4133.PubMedGoogle Scholar
  98. 98.
    Lee JH, Soung YH, Lee JW et al. Inactivating mutation of the pro-apoptotic gene BID in gastric cancer. J Pathol 2004; 202(4):439–445.PubMedGoogle Scholar
  99. 99.
    Zantl N, Weirich G, Zall H et al. Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance. Oncogene 2007; 26(49):7038–7048.PubMedGoogle Scholar
  100. 100.
    Kohler B, Anguissola S, Concannon CG et al. Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands’ apoptotic and synergistic effects. PLoS ONE 2008; 3(7):e2844.Google Scholar
  101. 101.
    Fennell DA, Chacko A, Mutti L. BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 2008; 27(9):1189–1197.PubMedGoogle Scholar
  102. 102.
    Shelton SN, Shawgo ME, Robertson JD. 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 2009.Google Scholar
  103. 103.
    Song G, Chen GG, Chau DK et al. Bid exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. Apoptosis 2008; 13(5):693–701.PubMedGoogle Scholar
  104. 104.
    Cragg MS, Kuroda J, Puthalakath H et al. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med 2007; 4(10):1681–1689; discussion 1690.PubMedGoogle Scholar
  105. 105.
    Gilmore AP, Valentijn AJ, Wang P et al. Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 2002; 277(31):27643–27650.PubMedGoogle Scholar
  106. 106.
    Abrams MT, Robertson NM, Yoon K et al. Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. J Biol Chem 2004; 279(53):55809–55817.PubMedGoogle Scholar
  107. 107.
    Erlacher M, Michalak EM, Kelly PN et al. BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation-and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 2005; 106(13):4131–4138.PubMedGoogle Scholar
  108. 108.
    Zhang L, Insel PA. The pro-apoptotic protein Bim is a convergence point for cAMP/protein kinase A-and glucocorticoid-promoted apoptosis of lymphoid cells. J Biol Chem 2004; 279(20):20858–20865.PubMedGoogle Scholar
  109. 109.
    Gillespie S, Borrow J, Zhang XD et al. Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 2006; 11(12):2251–2265.PubMedGoogle Scholar
  110. 110.
    Zhang Y, Adachi M, Kawamura R et al. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ 2006; 13(1):129–140.PubMedGoogle Scholar
  111. 111.
    Kuroda J, Puthalakath H, Cragg MS et al. 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 2006; 103(40):14907–14912.PubMedGoogle Scholar
  112. 112.
    Pradhan S, Kim HK, Thrash CJ et al. A critical role for the proapoptotic protein bid in ultraviolet-induced immune suppression and cutaneous apoptosis. J Immunol 2008; 181(5):3077–3088.PubMedGoogle Scholar
  113. 113.
    VanBrocklin MW, Verhaegen M, Soengas MS et al. Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 2009; 69(5):1985–1994.PubMedGoogle Scholar
  114. 114.
    Tan TT, Degenhardt K, Nelson DA et al. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 2005; 7(3):227–238.PubMedGoogle Scholar
  115. 115.
    Li R, Moudgil T, Ross HJ et al. Apoptosis of nonsmall-cell lung cancer cell lines after paclitaxel treatment involves the BH3-only proapoptotic protein Bim. Cell Death Differ 2005; 12(3):292–303.PubMedGoogle Scholar
  116. 116.
    Janssen K, Pohlmann S, Janicke RU et al. Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. Blood 2007; 110(10):3662–3672.PubMedGoogle Scholar
  117. 117.
    Kuribara R, Honda H, Matsui H et al. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. Mol Cell Biol 2004; 24(14):6172–6183.PubMedGoogle Scholar
  118. 118.
    Oltersdorf T, Elmore SW, Shoemaker AR et al. An inhibitor of BCL-2 family proteins induces regression of solid tumours. Nature 2005; 435(7042):677–681.PubMedGoogle Scholar
  119. 119.
    Del Gaizo Moore V, Brown JR, Certo M et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007; 117(1):112–121.PubMedGoogle Scholar
  120. 120.
    Labi V, Grespi F, Baumgartner F et al. Targeting the BCL-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death Differ 2008; 15(6):977–987.PubMedGoogle Scholar
  121. 121.
    Kang MH, Kang YH, Szymanska B et al. 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 2007; 110(6):2057–2066.PubMedGoogle Scholar
  122. 122.
    Deng J, Carlson N, Takeyama K et al. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007; 12(2):171–185.PubMedGoogle Scholar
  123. 123.
    van Delft MF, Wei AH, Mason KD et al. The BH3 mimetic ABT-737 targets selective BCL-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10(5):389–399.PubMedGoogle Scholar
  124. 124.
    Konopleva M, Contractor R, Tsao T et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10(5):375–388.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA

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