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The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update

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Abstract

Apoptosis is a critically important biological process that plays an essential role in cell fate and homeostasis. An important component of the apoptotic pathway is the family of proteins commonly known as the B cell lymphoma-2 (Bcl-2). The primary role of Bcl-2 family members is the regulation of apoptosis. Although the structure of Bcl-2 family of proteins was reported nearly 10 years ago, however, it still surprises us with its structural and functional complexity and diversity. A number of studies have demonstrated that Bcl-2 family influences many other cellular processes beyond apoptosis which are generally independent of the regulation of apoptosis, suggesting additional roles for Bcl-2. The disruption of the regulation of apoptosis is a causative event in many diseases. Since the Bcl-2 family of proteins is the key regulator of apoptosis, the abnormalities in its function have been implicated in many diseases including cancer, neurodegenerative disorders, ischemia and autoimmune diseases. In the past few years, our understanding of the mechanism of action of Bcl-2 family of proteins and its implications in various pathological conditions has enhanced significantly. The focus of this review is to summarize the current knowledge on the structure and function of Bcl-2 family of proteins in apoptotic cellular processes. A number of drugs have been developed in the past few years that target different Bcl-2 members. The role of Bcl-2 proteins in the pathogenesis of various diseases and their pharmacological significance as effective molecular therapeutic targets is also discussed.

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Abbreviations

TNF-α:

Tumor necrosis factor alpha

TNFR1:

Tumor necrosis factor receptor 1

FasL:

Fatty acid synthetase ligand, Fas ligand

FasR:

Fatty acid synthetase receptor, Fas receptor

Apo3L:

Apo3 ligand

DR3:

Death receptor 3

TRAIL:

TNF-related apoptosis-inducing ligand

DR4:

Death receptor 4

DR5:

Death receptor 5

FADD:

Fas-associated death domain

TRADD:

TNF receptor-associated death domain

RIP:

Receptor-interacting protein

DED:

Death effector domain

Caspase:

Cysteinyl aspartic acid protease

FLICE:

FADD-like ICE

c-FLIP:

FLICE-inhibitory protein

Smac/DIABLO:

Second mitochondrial activator of caspases/direct IAP-binding protein with low PI

IAP:

Inhibitor of apoptosis proteins

Apaf-1:

Apoptotic protease-activating factor

AIF:

Apoptosis-inducing factor

CAD:

Caspase-activated DNase

Bcl-2:

B cell lymphoma protein 2

Bcl-x:

Bcl-2-like 1

Bcl-XL:

Bcl-2-related protein long form of Bcl-x

Bcl-XS:

Bcl-2-related protein short isoform

Bcl-w:

Bcl-2-like 2 protein

BAG:

Bcl-2-associated athanogene

Bcl-10:

B cell lymphoma protein 10

Bax:

Bcl-2-associated X protein

Bak:

Bcl-2 antagonist killer 1

Bid:

BH3-interacting domain

Bad:

Bcl-2 antagonist of cell death Bcl-2-binding protein

Bim:

Bcl-2-interacting protein

Bik:

Bcl-2-interacting killer

Blk:

Bik-like killer protein

Puma:

Bcl-2-binding component 3

Noxa:

Phorbol-12-myristate-13-acetate-induced protein 1

14-3-3:

Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein

Aven:

Cell death regulator Aven none

Myc:

Oncogene myc

PARP:

Poly(ADP-ribose) polymerase ADP ribosyltransferase

NuMA:

Nuclear mitotic apparatus protein

CAD:

Caspase-activated DNase

ICAD:

Inhibitor of CAD

References

  • Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science (New York, NY) 281(5381):1322–1326

    CAS  Google Scholar 

  • Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26(9):1324–1337

    PubMed Central  CAS  PubMed  Google Scholar 

  • Aguilar A, Zhou H, Chen J et al (2013) A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J Med Chem 56(7):3048–3067

    PubMed Central  CAS  PubMed  Google Scholar 

  • Alavian KN, Li H, Collis L et al (2011) Bcl-x L regulates metabolic efficiency of neurons through interaction with the mitochondrial F1 FO ATP synthase. Nat Cell Biol 13(10):1224–1233

    PubMed Central  CAS  PubMed  Google Scholar 

  • Allen JC, Talab F, Zuzel M, Lin K, Slupsky JR (2011) c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells. Blood 117(8):2414–2422

    CAS  PubMed  Google Scholar 

  • Almeida S, Sarmento-Ribeiro AB, Januário C, Rego AC, Oliveira CR (2008) Evidence of apoptosis and mitochondrial abnormalities in peripheral blood cells of Huntington’s disease patients. Biochem Biophys Res Commun 374(4):599–603

    CAS  PubMed  Google Scholar 

  • Alves NL, Derks IAM, Berk E, Spijker R, van Lier RAW, Eldering E (2006) The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity 24(6):703–716

    CAS  PubMed  Google Scholar 

  • Annis MG, Soucie EL, Dlugosz PJ et al (2005) Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J 24(12):2096–2103

    PubMed Central  CAS  PubMed  Google Scholar 

  • Antonsson B, Conti F, Ciavatta A et al (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science (New York, NY) 277(5324):370–372

    CAS  Google Scholar 

  • Aouacheria A, Brunet F, Gouy M (2005) Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-only, and BNip families of apoptotic regulators. Mol Biol Evol 22(12):2395–2416

    CAS  PubMed  Google Scholar 

  • Aranovich A, Liu Q, Collins T et al (2012) Differences in the mechanisms of proapoptotic BH3 proteins binding to Bcl-XL and Bcl-2 quantified in live MCF-7 cells. Mol Cell 45(6):754–763

    CAS  PubMed  Google Scholar 

  • Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012) Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem 287(27):23152–23161

    PubMed Central  CAS  PubMed  Google Scholar 

  • Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905

    PubMed Central  CAS  PubMed  Google Scholar 

  • Billen LP, Shamas-Din A, Andrews DW (2008) Bid: ABax-like BH3 protein. Oncogene 27(Suppl 1):S93–S104

    CAS  PubMed  Google Scholar 

  • Bird GH, Bernal F, Pitter K, Walensky LD (2008) Chapter 22. Synthesis and biophysical characterization of stabilized α-helices of BCL-2 domains. Methods Enzymol 446:369–386

    CAS  PubMed  Google Scholar 

  • Blackshaw S, Sawa A, Sharp AH, Ross CA, Snyder SH, Khan AA (2000) Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J 14(10):1375–1379

    CAS  PubMed  Google Scholar 

  • Blume Jensen P, Janknecht R, Hunter T (1998) The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr Biol 8(13):779–782

    CAS  PubMed  Google Scholar 

  • Boersma MD, Haase HS, Peterson-Kaufman KJ et al (2012) Evaluation of diverse α/β-backbone patterns for functional α-helix mimicry: analogues of the Bim BH3 domain. J Am Chem Soc 134(1):315–323

    PubMed Central  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Boyd JM, Gallo GJ, Elangovan B 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(9):1921–1928

    CAS  PubMed  Google Scholar 

  • Bratton SB, Salvesen GS (2010) Regulation of the Apaf-1-caspase-9 apoptosome. J Cell Sci 123(19):3209–3214

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bratton DL, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM (1997) Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J Biol Chem 272(42):26159–26165

    CAS  PubMed  Google Scholar 

  • Breitschopf K, Haendeler J, Malchow P, Zeiher AM, Dimmeler S (2000) Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol Cell Biol 20(5):1886–1896

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brenner C, Grimm S (2006) The permeability transition pore complex in cancer cell death. Oncogene 25(34):4744–4756

    CAS  PubMed  Google Scholar 

  • Brenner D, Mak TW (2009) Mitochondrial cell death effectors. Curr Opin Cell Biol 21(6):871–877

    CAS  PubMed  Google Scholar 

  • Brock SE, Li C, Wattenberg BW (2010) The Bax carboxy-terminal hydrophobic helix does not determine organelle-specific targeting but is essential for maintaining Bax in an inactive state and for stable mitochondrial membrane insertion. Apoptosis 1:14–27

    Google Scholar 

  • Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci 122(Pt 4):437–441

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96(6):857–868

    CAS  PubMed  Google Scholar 

  • Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science (New York, NY) 282(5392):1318–1321

    CAS  Google Scholar 

  • Carrington EM, Vikstrom IB, Light A et al (2010) BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc Natl Acad Sci USA 107(24):10967–10971

    PubMed Central  CAS  PubMed  Google Scholar 

  • Certo M, Moore VDG, Nishino M et al (2006) Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9(5):351–365

    CAS  PubMed  Google Scholar 

  • Chao JR, Wang JM, Lee SF et al (1998) Mcl-1 is an immediate-early gene activated by the granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol 18(8):4883–4898

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen ZX, Pervaiz S (2010) Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Diff 17(3):408–420

    CAS  Google Scholar 

  • Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA (2001) Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 276(33):30724–30728

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Chen J, Zhou H, Aguilar A et al (2012) Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J Med Chem 55(19):8502–8514

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng WC, Leach KM, Hardwick JM (2008) Mitochondrial death pathways in yeast and mammalian cells. Biochim Biophys Acta 1783(7):1272–1279

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chiappori AA, Schreeder MT, Moezi MM et al (2012) A phase 1 trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer. Brit J Cancer 106(5):839–845

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chinnadurai G, Vijayalingam S, Gibson SB (2008) BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 27(Suppl 1):S114–S127

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chinnaiyan AM, Chaudhary D, O’Rourke K, Koonin EV, Dixit VM (1997) Role of CED-4 in the activation of CED-3. Nature 388(6644):728–729

    CAS  PubMed  Google Scholar 

  • Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trend Cell Biol 18(4):157–164

    CAS  Google Scholar 

  • Chipuk JE, Kuwana T, Bouchier-Hayes L et al (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science (New York, NY) 303(5660):1010–1014

    CAS  Google Scholar 

  • Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102(39):13944–13949

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656

    CAS  PubMed  Google Scholar 

  • Czabotar PE, Lessene G (2010) Bcl-2 family proteins as therapeutic targets. Curr Pharm Des 16:3132–3148

    CAS  PubMed  Google Scholar 

  • Czabotar PE, Lee EF, Van Delft MF et al (2007) Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA 104(15):6217–6222

    PubMed Central  CAS  PubMed  Google Scholar 

  • Czabotar PE, Lee EF, Thompson GV, Wardak AZ, Fairlie WD, Colman PM (2011) Mutation to bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis. J Biol Chem 286(9):7123–7131

    PubMed Central  CAS  PubMed  Google Scholar 

  • Czabotar PE, Westphal D, Dewson G et al (2013) Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell 152(3):519–531

    CAS  PubMed  Google Scholar 

  • Danial NN, Gramm CF, Scorrano L et al (2003) BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424(6951):952–956

    CAS  PubMed  Google Scholar 

  • Danial NN, Walensky LD, Zhang CY et al (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14(2):144–153

    PubMed Central  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Day CL, Smits C, Fan FC, Lee EF, Fairlie WD, Hinds MG (2008) Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. J Mol Biol 380(5):958–971

    CAS  PubMed  Google Scholar 

  • De Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456(7222):605–610

    PubMed  Google Scholar 

  • De Jong D, Prins FA, Mason DY, Reed JC, Van Ommen GB, Kluin PM (1994) Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells. Can Res 54(1):256–260

    Google Scholar 

  • Dejean LM, Martinez-Caballero S, Guo L et al (2005) Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol Biol Cell 16(5):2424–2432

    PubMed Central  CAS  PubMed  Google Scholar 

  • Deng X, Ruvolo P, Carr B, May WS Jr (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci USA 97(4):1578–1583

    PubMed Central  CAS  PubMed  Google Scholar 

  • Denisov AY, Madiraju MSR, Chen G et al (2003) Solution structure of human BCL-w. Modulation of ligand binding by the C-terminal helix. J Biol Chem 278(23):21124–21128

    CAS  PubMed  Google Scholar 

  • Denton D, Nicolson S, Kumar S (2012) Cell death by autophagy: facts and apparent artefacts. Cell Death Diff 19(1):87–95

    CAS  Google Scholar 

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

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dewson G, Ma S, Frederick P et al (2012) Bax dimerizes via a symmetric BH3:groove interface during apoptosis. Cell Death Diff 19(4):661–670

    CAS  Google Scholar 

  • Distelhorst CW, Bootman MD (2011) Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: role in Ca2+ signaling and disease. Cell Calcium 50(3):234–241

    PubMed Central  CAS  PubMed  Google Scholar 

  • Douglas AE, Corbett KD, Berger JM, McFadden G, Handel TM (2007) Structure of M11L: a myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2. Protein Sci 16(4):695–703

    PubMed Central  CAS  PubMed  Google Scholar 

  • Duprez L, Wirawan E, Vanden Berghe T, Vandenabeele P (2009) Major cell death pathways at a glance. Microbes Infect (Institut Pasteur) 11(13):1050–1062

    CAS  Google Scholar 

  • Echeverry N, Bachmann D, Ke F, Strasser A, Simon HU, Kaufmann T (2013) Intracellular localization of the BCL-2 family member BOK and functional implications. Cell Death Diff 20(6):785–799

    CAS  Google Scholar 

  • Edlich F, Banerjee S, Suzuki M et al (2011) Bcl-xL retrotranslocates Bax from the mitochondria into the cytosol. Cell 145(1):104–116

    PubMed Central  CAS  PubMed  Google Scholar 

  • Eischen CM, Woo D, Roussel MF, Cleveland JL (2001) Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis. Mol Cell Biol 21(15):5063–5070

    PubMed Central  CAS  PubMed  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ethell DW, Buhler LA (2003) Fas ligand-mediated apoptosis in degenerative disorders of the brain. J Clin Immunol 23(6):439–446

    CAS  PubMed  Google Scholar 

  • Fadok VA, Chimini G (2001) The phagocytosis of apoptotic cells. Sem Immunol 13(6):365–372

    CAS  Google Scholar 

  • Faustin B, Chen Y, Zhai D et al (2009) Mechanism of Bcl-2 and Bcl-XL inhibition of NLRP1 inflammasome: loop domain-dependent suppression of ATP binding and oligomerization. Proc Natl Acad Sci USA 106(10):3935–3940

    PubMed Central  CAS  PubMed  Google Scholar 

  • Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1999) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274(4):2225–2233

    CAS  PubMed  Google Scholar 

  • Fulda S, Gorman AM, Hori O, Samali A (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010:214074

    PubMed Central  PubMed  Google Scholar 

  • Galluzzi L, Joza N, Tasdemir E et al (2008) No death without life: vital functions of apoptotic effectors. Cell Death Diff 15(7):1113–1123

    CAS  Google Scholar 

  • Galluzzi L, Morselli E, Kepp O, Kroemer G (2009) Targeting post-mitochondrial effectors of apoptosis for neuroprotection. Biochim Biophys Acta Bioenerg 1787(5):402–413

    CAS  Google Scholar 

  • Galluzzi L, Morselli E, Kepp O et al (2010) Mitochondrial gateways to cancer. Mol Asp Med 31(1):1–20

    CAS  Google Scholar 

  • Galluzzi L, Kepp O, Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 13(12):780–788

    CAS  PubMed  Google Scholar 

  • Gavathiotis E, Suzuki M, Davis ML et al (2008) BAX activation is initiated at a novel interaction site. Nature 455(7216):1076–1081

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gavathiotis E, Reyna DE, Davis ML, Bird GH, Walensky LD (2010) BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell 40(3):481–492

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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(20):18053–18060

    CAS  PubMed  Google Scholar 

  • Gil Parrado S, Fernández-Montalván A, Assfalg-Machleidt I et al (2002) Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members. J Biol Chem 277(30):27217–27226

    CAS  PubMed  Google Scholar 

  • Giorgi C, De Stefani D, Bononi A, Rizzuto R, Pinton P (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol 41(10):1817–1827

    PubMed Central  CAS  PubMed  Google Scholar 

  • Görlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Red Signal 8(9–10):1391–1418

    Google Scholar 

  • Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science (New York, NY) 305(5684):626–629

    CAS  Google Scholar 

  • Green DR, Reed JC (1998) Mitochondria and apoptosis. Science (New York, NY) 281(5381):1309–1312

    CAS  Google Scholar 

  • Griffiths GJ, Dubrez L, Morgan CP et al (1999) Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J Cell Biol 144(5):903–914

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gross A, Jockel J, Wei MC, Korsmeyer SJ (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J 17(14):3878–3885

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gross A, Yin XM, Wang K et al (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-X(L) prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274(2):1156–1163

    CAS  PubMed  Google Scholar 

  • Grumont RJ, Rourke IJ, Gerondakis S (1999) Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Gene Dev 13(4):400–411

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gu J, Kawai H, Wiederschain D, Yuan ZM (2001) Mechanism of functional inactivation of a Li–Fraumeni syndrome p53 that has a mutation outside of the DNA-binding domain. Cancer Res 61(4):1741–1746

    CAS  PubMed  Google Scholar 

  • Gupta S, Kass GE, Szegezdi E, Joseph B (2009) The mitochondrial death pathway: a promising therapeutic target in diseases. J Cell Mol Med 13(6):1004–1033

    CAS  PubMed  Google Scholar 

  • Gustafsson AB, Gottlieb RA (2008) Heart mitochondria: gates of life and death. Cardiovasc Res 77(2):334–343

    CAS  PubMed  Google Scholar 

  • Hajnóczky G, Csordás G, Das S et al (2006) Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 40(5–6):553–560

    PubMed Central  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    CAS  PubMed  Google Scholar 

  • Harada H, Becknell B, Wilm M et al (1999) Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 3(4):413–422

    CAS  PubMed  Google Scholar 

  • Hayden MS, West AP, Ghosh S (2006) NF-κB and the immune response. Oncogene 25(51):6758–6780

    CAS  PubMed  Google Scholar 

  • Heist SR, Fain J, Chinnasami B et al (2010) Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. J Thorac Oncol 5(10):1637–1643

    PubMed  Google Scholar 

  • Hekman M, Albert S, Galmiche A et al (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(25):17321–17336

    CAS  PubMed  Google Scholar 

  • Hinds MG, Day CL (2005) Regulation of apoptosis: uncovering the binding determinants. Curr Opin Struct Biol 15(6):690–699

    CAS  PubMed  Google Scholar 

  • Hinds MG, Lackmann M, Skea GL, Harrison PJ, Huang DCS, Day CL (2003) The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. EMBO J 22(7):1497–1507

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hinds MG, Smits C, Fredericks-Short R et al (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 Diff 14(1):128–136

    CAS  Google Scholar 

  • Høyer-Hansen M, Jäättelä M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Diff 14(9):1576–1582

    Google Scholar 

  • 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(8):3668–3672

    PubMed Central  CAS  PubMed  Google Scholar 

  • Huang DCS, Strasser A (2000) BH3-only proteins—essential initiators of apoptotic cell death. Cell 103(6):839–842

    CAS  PubMed  Google Scholar 

  • Huang DCS, Adams JM, Cory S (1998) The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. EMBO J 17(4):1029–1039

    PubMed Central  CAS  PubMed  Google Scholar 

  • Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2(4):277–288

    CAS  PubMed  Google Scholar 

  • Inohara N, Ding L, Chen S, Núñez 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(7):1686–1694

    PubMed Central  CAS  PubMed  Google Scholar 

  • Inohara N, Gourley TS, Carrio R et al (1998) Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. J Biol Chem 273(49):32479–32486

    CAS  PubMed  Google Scholar 

  • Johnson CH, Bonzo JA, Cheng J et al (2013) Cytochrome P450 regulation by alpha-tocopherol in Pxr-null and PXR-humanized mice. Drug Metab Disp 2:406–413

    Google Scholar 

  • 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(44):16019–16024

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kane DJ, Sarafian TA, Anton R et al (1993) Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science (New York, NY) 262(5137):1274–1277

    CAS  Google Scholar 

  • Kang R, Zeh HJ, Lotze MT, Tang D (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Diff 18(4):571–580

    CAS  Google Scholar 

  • Kawamoto SA, Coleska A, Ran X, Yi H, Yang CY, Wang S (2012) Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction. J Med Chem 55(3):1137–1146

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim H, Rafiuddin-Shah M, Tu HC et al (2006) Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8(12):1348–1358

    CAS  PubMed  Google Scholar 

  • King KL, Cidlowski JA (1998) Cell cycle regulation and apoptosis. Ann Rev Physiol 60:601–617

    CAS  Google Scholar 

  • Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8(11):931–937

    CAS  PubMed  Google Scholar 

  • Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW (1993) MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA 90(8):3516–3520

    PubMed Central  CAS  PubMed  Google Scholar 

  • Krebs JF, Armstrong RC, Srinivasan A et al (1999) Activation of membrane-associated procaspase-3 is regulated by Bcl-2. J Cell Biol 144(5):915–926

    PubMed Central  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Kroemer G, Galluzzi L, Vandenabeele P et al (2009) Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Diff 16(1):3–11

    CAS  Google Scholar 

  • Kucharczak J, Simmons MJ, Fan Y, Gélinas C (2003) To be, or not to be: NF-κB is the answer—role of Rel/NF-κB in the regulation of apoptosis. Oncogene 22(56 REV. ISS. 8):8961–8982

    CAS  PubMed  Google Scholar 

  • Kutuk O, Letai A (2008) Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol Med 8(2):102–118

    CAS  PubMed  Google Scholar 

  • Kuwana T, Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 15(6):691–699

    CAS  PubMed  Google Scholar 

  • Kuwana T, Mackey MR, Perkins G et al (2002) Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111(3):331–342

    CAS  PubMed  Google Scholar 

  • Kvansakul M, Yang H, Fairlie WD et al (2008) Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. Cell Death Diff 15(10):1564–1571

    CAS  Google Scholar 

  • Labbe K, Saleh M (2008) Cell death in the host response to infection. Cell Death Diff 15(9):1339–1349

    CAS  Google Scholar 

  • LaBelle JL, Katz SG, Bird GH et al (2012) A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest 122(6):2018–2031

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lamkanfi M, Festjens N, Declercq W, Berghe TV, Vandenabeele P (2007) Caspases in cell survival, proliferation and differentiation. Cell Death Diff 14(1):44–55

    CAS  Google Scholar 

  • Le GT, Abbenante G (2005) Inhibitors of TACE and caspase-1 as anti-inflammatory drugs. Curr Med Chem 12:2963–2977

    CAS  PubMed  Google Scholar 

  • Leber B, Lin J, Andrews DW (2010) Still embedded together binding to membranes regulates Bcl-2 protein interactions. Oncogene 29(38):5221–5230

    CAS  PubMed  Google Scholar 

  • Leshchiner ES, Braun CR, Bird GH, Walensky LD (2013) Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci USA 110(11):E986–E995

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lessene G, Czabotar PE, Sleebs BE et al (2013) Structure-guided design of a selective BCL-XL inhibitor. Nat Chem Biol 9(6):390–397

    CAS  PubMed  Google Scholar 

  • 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(3):183–192

    CAS  PubMed  Google Scholar 

  • Leu JIJ, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6(5):443–450

    CAS  PubMed  Google Scholar 

  • Ley R, Ewings KE, Hadfield K, Howes E, Balmanno K, Cook SJ (2004) Extracellular signal-regulated kinases 1/2 are serum-stimulated “BimEL kinases” that bind to the BH3-only protein Bim EL causing its phosphorylation and turnover. J Biol Chem 279(10):8837–8847

    CAS  PubMed  Google Scholar 

  • Li CJ, Friedman DJ, Wang C, Metelev V, Pardee AB (1995) Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science (New York, NY) 268(5209):429–431

    CAS  Google Scholar 

  • Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489

    CAS  PubMed  Google Scholar 

  • Liang XH, Jackson S, Seaman M et al (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672–676

    CAS  PubMed  Google Scholar 

  • Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH (2011) MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer 47(2):163–174

    CAS  PubMed  Google Scholar 

  • Liu L, Chen J, Zhang J et al (2007) Overexpression of BimSs3, the novel isoform of Bim, can trigger cell apoptosis by inducing cytochrome c release from mitochondria. Acta Biochim Pol 54(3):603–610

    CAS  PubMed  Google Scholar 

  • Lizcano JM, Morrice N, Cohen P (2000) Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. Biochem J 349(2):547–557

    PubMed Central  CAS  PubMed  Google Scholar 

  • Llambi F, Moldoveanu T, Tait S et al (2011) A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 44(4):517–531

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lovell JF, Billen LP, Bindner S et al (2008) Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135(6):1074–1084

    CAS  PubMed  Google Scholar 

  • Lucken-Ardjomande S, Montessuit S, Martinou JC (2008) Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane. Cell Death Diff 15(5):929–937

    CAS  Google Scholar 

  • 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(4):481–490

    CAS  PubMed  Google Scholar 

  • Maiuri MC, Le Toumelin G, Criollo A et al (2007) Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J 26(10):2527–2539

    PubMed Central  CAS  PubMed  Google Scholar 

  • Martinvalet D, Zhu P, Lieberman J (2005) Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 22(3):355–370

    CAS  PubMed  Google Scholar 

  • Mason KD, Lin A, Robb L et al (2013) Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease. Proc Natl Acad Sci USA 110(7):2599–2604

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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(16):2534–2544

    CAS  PubMed  Google Scholar 

  • 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(5):625–634

    CAS  PubMed  Google Scholar 

  • Mihara M, Erster S, Zaika A et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590

    CAS  PubMed  Google Scholar 

  • Mille F, Thibert C, Fombonne J et al (2009) The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat Cell Biol 11(6):739–746

    PubMed Central  CAS  PubMed  Google Scholar 

  • Milot E, Filep JG (2011) Regulation of neutrophil survival/apoptosis by Mcl-1. Sci World J 11:1948–1962

    CAS  Google Scholar 

  • Mitchell KO, Ricci MS, Miyashita T et al (2000) Bax is a transcriptional target and mediator of c-myc-induced apoptosis. Cancer Res 60(22):6318–6325

    CAS  PubMed  Google Scholar 

  • Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80(2):293–299

    CAS  PubMed  Google Scholar 

  • Miyashita T, Krajewski S, Krajewska M et al (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9(6):1799–1805

    CAS  PubMed  Google Scholar 

  • Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741

    CAS  PubMed  Google Scholar 

  • Mocanu MM, Baxter GF, Yellon DM (2000) Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury. Brit J Pharmacol 130:197–200

    CAS  Google Scholar 

  • 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(5):677–688

    CAS  PubMed  Google Scholar 

  • Moldoveanu T, Grace CR, Llambi F et al (2013) BID-induced structural changes in BAK promote apoptosis. Nat Struct Mol Biol 20(5):589–597

    PubMed Central  CAS  PubMed  Google Scholar 

  • Muchmore SW, Sattler M, Liang H et al (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381(6580):335–341

    CAS  PubMed  Google Scholar 

  • Nagley P, Higgins GC, Atkin JD, Beart PM (2010) Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta 1802(1):167–185

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Zhu H, Morishima N et al (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403(6765):98–103

    CAS  PubMed  Google Scholar 

  • Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7(3):683–694

    CAS  PubMed  Google Scholar 

  • Ng FWH, Nguyen M, Kwan T et al (1997) p28 Bap31, a Bcl-2/Bcl-X(L)- and procaspase-8-associated protein in the endoplasmic reticulum. J Cell Biol 139(2):327–338

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nicholson DW (2000) From bench to clinic with apoptosis-based therapeutic agents. Nature 407(6805):810–816

    CAS  PubMed  Google Scholar 

  • O’Connor L, Strasser A, O’Reilly LA et al (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17(2):384–395

    PubMed Central  PubMed  Google Scholar 

  • Oda E, Ohki R, Murasawa H et al (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science (New York, NY) 288(5468):1053–1058

    CAS  Google Scholar 

  • Ofengeim D, Chen YB, Miyawaki T et al (2012) N-terminally cleaved Bcl-x L mediates ischemia-induced neuronal death. Nat Neurosci 15(4):574–580

    CAS  PubMed  Google Scholar 

  • Ola MS, Nawaz M, Ahsan H (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem 351(1–2):41–58

    CAS  PubMed  Google Scholar 

  • Oltersdorf T, Elmore SW, Shoemaker AR et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435(7042):677–681

    CAS  PubMed  Google Scholar 

  • O’Reilly LA, Kruse EA, Puthalakath H et al (2009) MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation. J Immunol 183(1):261–269

    PubMed Central  PubMed  Google Scholar 

  • Otake Y, Soundararajan S, Sengupta TK et al (2007) Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA. Blood 109(7):3069–3075

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ottilie S, Diaz JL, Horne W et al (1997) Dimerization properties of human BAD: Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-X(L) proteins. J Biol Chem 272(49):30866–30872

    CAS  PubMed  Google Scholar 

  • Pan G, O’Rourke K, Dixit VM (1998) Caspase-9, Bcl-X(L), and Apaf-1 form a ternary complex. J Biol Chem 273(10):5841–5845

    CAS  PubMed  Google Scholar 

  • Pavlov EV, Priault M, Pietkiewicz D et al (2001) A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J Cell Biol 155(5):725–731

    PubMed Central  CAS  PubMed  Google Scholar 

  • Perciavalle RM, Stewart DP, Koss B et al (2012) Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 14(6):575–583

    PubMed Central  CAS  PubMed  Google Scholar 

  • Petros AM, Nettesheim DG, Wang Y et al (2000) Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 9(12):2528–2534

    PubMed Central  CAS  PubMed  Google Scholar 

  • Petros AM, Medek A, Nettesheim DG et al (2001) Solution structure of the antiapoptotic protein bcl-2. Proc Natl Acad Sci USA 98(6):3012–3017

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pietenpol JA, Stewart ZA (2002) Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 181–182:475–481

    PubMed  Google Scholar 

  • Poommipanit PB, Chen B, Oltvai ZN (1999) Interleukin-3 induces the phosphorylation of a distinct fraction of Bcl-2. J Biol Chem 274(2):1033–1039

    CAS  PubMed  Google Scholar 

  • Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT (2011) Anti-apoptosis and cell survival: a review. Biochim Biophys Acta 1813(1):238–259

    CAS  PubMed  Google Scholar 

  • Puthalakath H, Huang DCS, 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(3):287–296

    CAS  PubMed  Google Scholar 

  • Qian S, Wang C, Yang L, Huang HW (2008) Structure of transmembrane pore induced by Bax-derived peptide: evidence for lipidic pores. Proc Natl Acad Sci USA 105(45):17379–17383

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rao RV, Castro-Obregon S, Frankowski H et al (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 277(24):21836–21842

    CAS  PubMed  Google Scholar 

  • Rautureau GJ, Yabal M, Yang H, Huang DC, Kvansakul M, Hinds MG (2012) The restricted binding repertoire of Bcl-B leaves Bim as the universal BH3-only prosurvival Bcl-2 protein antagonist. Cell Death Dis 3(12):e443

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science (New York, NY) 262(5134):744–747

    CAS  Google Scholar 

  • Roberts AW, Seymour JF, Brown JR et al (2012) Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30(5):488–496

    CAS  PubMed  Google Scholar 

  • Rodriguez D, Rojas-Rivera D, Hetz C (2011) Integrating stress signals at the endoplasmic reticulum: the BCL-2 protein family rheostat. Biochim Biophys Acta Mol Cell Res 1813(4):564–574

    CAS  Google Scholar 

  • Rong Y, Distelhorst CW (2008) Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Ann Rev Physiol 70:73–91

    CAS  Google Scholar 

  • Rudin CM, Hann CL, Garon EB et al (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18(11):3163–3169

    PubMed Central  CAS  PubMed  Google Scholar 

  • Saito M, Korsmeyer SJ, Schlesinger PH (2000) BAX-dependent transport of cytochrome C reconstituted in pure liposomes. Nat Cell Biol 2(8):553–555

    CAS  PubMed  Google Scholar 

  • Sato T, Irie S, Krajewski S, Reed JC (1994) Cloning and sequencing of a cDNA encoding the rat Bc1-2 protein. Gene 140(2):291–292

    CAS  PubMed  Google Scholar 

  • Sattler M, Liang H, Nettesheim D et al (1997) Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science (New York, NY) 275(5302):983–986

    CAS  Google Scholar 

  • 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(11):842–849

    CAS  PubMed  Google Scholar 

  • Scatena CD, Stewart ZA, Mays D et al (1998) Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and taxol-induced growth arrest. J Biol Chem 273(46):30777–30784

    CAS  PubMed  Google Scholar 

  • Schafer B, Quispe J, Choudhary V et al (2009) Mitochondrial outer membrane proteins assist bid in bax-mediated lipidic pore formation. Mol Biol Cell 20(8):2276–2285

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schellenberg B, Wang P, Keeble JA et al (2013) Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell 49(5):959–971

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schwarz M, Andrade-Navarro MA, Gross A (2007) Mitochondrial carriers and pores: key regulators of the mitochondrial apoptotic program? Apoptosis 12(5):869–876

    CAS  PubMed  Google Scholar 

  • Setoguchi K, Otera H, Mihara K (2006) Cytosolic factor- and TOM-independent import of C-tail-anchored mitochondrial outer membrane proteins. EMBO J 25(24):5635–5647

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shamas Din A, Kale J, Leber B, Andrews DW (2013) Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol 5(4):a008714

    PubMed  Google Scholar 

  • Shimizu S, Eguchi Y, Kamiike W et al (1998) Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Nal Acad Sci USA 95(4):1455–1459

    CAS  Google Scholar 

  • Shoshan Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Asp Med 31(3):227–285

    CAS  Google Scholar 

  • Siebenlist U, Brown K, Claudio E (2005) Control of lymphocyte development by nuclear factor-kB. Nat Rev Immunol 5(6):435–445

    CAS  PubMed  Google Scholar 

  • Silke J, Hawkins CJ, Ekert PG et al (2002) The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase-3- and caspase-9-interacting sites. J Cell Biol 157:115–124

    PubMed Central  CAS  PubMed  Google Scholar 

  • Simmen T, Aslan JE, Blagoveshchenskaya AD et al (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24(4):717–729

    PubMed Central  CAS  PubMed  Google Scholar 

  • Simmons MJ, Fan G, Zong WX, Degenhardt K, White E, Gélinas C (2008) Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist. Oncogene 27(10):1421–1428

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sinha S, Levine B (2008) The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene 27(Suppl 1):S137–S148

    PubMed Central  CAS  PubMed  Google Scholar 

  • Slee EA, Adrain C, Martin SJ (2001) Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 276(10):7320–7326

    CAS  PubMed  Google Scholar 

  • Sleebs BE, Czabotar PE, Fairbrother WJ et al (2011) Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity. J Med Chem 54(6):1914–1926

    CAS  PubMed  Google Scholar 

  • Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD (2013) Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins. ChemBioChem 14(13):1564–1572

    PubMed Central  CAS  PubMed  Google Scholar 

  • Souers AJ, Leverson JD, Boghaert ER et al (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19(2):202–208

    CAS  PubMed  Google Scholar 

  • Stewart ML, Fire E, Keating AE, Walensky LD (2010) The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol 6(8):595–601

    PubMed Central  CAS  PubMed  Google Scholar 

  • Susin SA, Lorenzo HK, Zamzami N et al (1999) Molecular characterization of mitochodrial apoptosis-inducing factor. Nature 397(6718):441–446

    CAS  PubMed  Google Scholar 

  • Suzuki M, Youle RJ, Tjandra N (2000) Structure of bax: coregulation of dimer formation and intracellular localization. Cell 103(4):645–654

    CAS  PubMed  Google Scholar 

  • Szabadkai G, Bianchi K, Várnai P et al (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175(6):901–911

    PubMed Central  CAS  PubMed  Google Scholar 

  • Szegezdi E, MacDonald DC, Chonghaile TN, Gupta S, Samali A (2009) Bcl-2 family on guard at the ER. Am J Physiol Cell Physiol 296(5):C941–C953

    CAS  PubMed  Google Scholar 

  • Tait SWG, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621–632

    CAS  PubMed  Google Scholar 

  • Tan Y, Demeter MR, Ruan H, Comb MJ (2000) BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem 275(33):25865–25869

    CAS  PubMed  Google Scholar 

  • Tasdemir E, Maiuri MC, Galluzzi L et al (2008) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10(6):676–687

    PubMed Central  CAS  PubMed  Google Scholar 

  • Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9(3):231–241

    CAS  PubMed  Google Scholar 

  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science (New York, NY) 281(5381):1312–1316

    CAS  Google Scholar 

  • Todt F, Cakir Z, Reichenbach F, Youle RJ, Edlich F (2013) The C-terminal helix of Bcl-x L mediates Bax retrotranslocation from the mitochondria. Cell Death Diff 20(2):333–342

    CAS  Google Scholar 

  • Touré BB, Miller-Moslin K, Yusuff N et al (2013) The role of the acidity of N-heteroaryl sulfonamides as inhibitors of Bcl-2 family protein-protein interactions. ACS Med Chem Lett 4(2):186–190

    PubMed Central  PubMed  Google Scholar 

  • Tse C, Shoemaker AR, Adickes J et al (2008) ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68(9):3421–3428

    CAS  PubMed  Google Scholar 

  • Tsujimoto Y (1998) Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 3(11):697–707

    CAS  PubMed  Google Scholar 

  • Tsujimoto Y, Croce CM (1986) Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci USA 83(14):5214–5218

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vaillant F, Merino D, Lee L et al (2013) Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24(1):120–129

    CAS  PubMed  Google Scholar 

  • Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265(13):7248–7256

    CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-x(L) regulates the membrane potential and volume homeostasis of mitochondria. Cell 91(5):627–637

    CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB (1999) Bcl-x(L) prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell 3(2):159–167

    CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M (2001) Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 276(22):19414–19419

    Google Scholar 

  • Vaughn AE, Deshmukh M (2008) Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 10(12):1477–1483

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vaux DL, Korsmeyer SJ (1999) Cell death in development. Cell 96(2):245–254

    CAS  PubMed  Google Scholar 

  • Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335(6189):440–442

    CAS  PubMed  Google Scholar 

  • Vella AT, Dow S, Potter TA, Kappler J, Marrack P (1998) Cytokine-induced survival of activated T cells in vitro and in vivo. Proc Natl Acad Sci USA 95(7):3810–3815

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ventura A, Young AG, Winslow MM et al (2008) Targeted deletion reveals essential and overlapping functions of the miR-17–92 family of miRNA clusters. Cell 132(5):875–886

    PubMed Central  CAS  PubMed  Google Scholar 

  • Virdee K, Parone PA, Tolkovsky AM (2000) Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Curr Biol 10(18):1151–1154

    CAS  PubMed  Google Scholar 

  • Voll RE, Jimi E, Phillips RJ et al (2000) NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13(5):677–689

    CAS  PubMed  Google Scholar 

  • Von Freeden-Jeffry U, Solvason N, Howard M, Murray R (1997) The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7(1):147–154

    Google Scholar 

  • Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431

    CAS  PubMed  Google Scholar 

  • Walensky LD, Kung AL, Escher I et al (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science (New York, NY) 305(5689):1466–1470

    CAS  Google Scholar 

  • Wang C, Youle RJ (2009) The role of mitochondria in apoptosis. Ann Rev Genet 43:95–118

    CAS  PubMed  Google Scholar 

  • Wang K, Gross A, Waksman G, Korsmeyer SJ (1998) Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing. Mol Cell Biol 18(10):6083–6089

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wang XW, Zhong TY, Xiong YH, Lin HB, Liu QY (2012) Lack of association between the CYP1A1 Ile462Val polymorphism and endometrial cancer risk: a meta-analysis. Asian Pac J Cancer Prev 13(8):3717–3721

    PubMed  Google Scholar 

  • Weber A, Paschen SA, Heger K et al (2007) BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins. J Cell Biol 177(4):625–636

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wei J, Stebbins JL, Kitada S et al (2010) BI-97C1, an optically pure apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/Leukemia-2 (Bcl-2) family proteins. J Med Chem 53(10):4166–4176

    PubMed Central  CAS  PubMed  Google Scholar 

  • Westphal D, Dewson G, Czabotar PE, Kluck RM (2011) Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta Mol Cell Res 1813(4):521–531

    CAS  Google Scholar 

  • Whelan RS, Kaplinskiy V, Kitsis RN (2010) Cell death in the pathogenesis of heart disease: mechanisms and significance. Ann Rev Physiol 72:19–44

    CAS  Google Scholar 

  • Wilfling F, Weber A, Potthoff S et al (2012) BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax. Cell Death Diff 19(8):1328–1336

    CAS  Google Scholar 

  • Willis SN, Adams JM (2005) Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17(6):617–625

    PubMed Central  CAS  PubMed  Google Scholar 

  • Willis SN, Chen L, Dewson G et al (2005) Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19(11):1294–1305

    PubMed Central  CAS  PubMed  Google Scholar 

  • Willis SN, Fletcher JI, Kaufmann T et al (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science (New York, NY) 315(5813):856–859

    CAS  Google Scholar 

  • Wilson WH, O’Connor OA, Czuczman MS et al (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11(12):1149–1159

    PubMed Central  CAS  PubMed  Google Scholar 

  • Worth A, Thrasher AJ, Gaspar HB (2006) Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Brit J Haematol 133(2):124–140

    CAS  Google Scholar 

  • Wyllie AH (2010) “Where, O death, is thy sting?” A brief review of apoptosis biology. Mol Neurobiol 42(1):4–9

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yacoubian TA, Standaert DG (2009) Targets for neuroprotection in Parkinson’s disease. Biochim Biophys Acta 1792(7):676–687

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang L, Harroun TA, Weiss TM, Ding L, Huang HW (2001) Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J 81(3):1475–1485

    PubMed Central  PubMed  Google Scholar 

  • Yi CH, Pan H, Seebacher J et al (2011) Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146(4):607–620

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yoneda T, Imaizumi K, Oono K et al (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276(17):13935–13940

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zaltsman Y, Shachnai L, Yivgi-Ohana N et al (2010) MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria. Nat Cell Biol 12(6):553–562

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G (1998) Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16(17):2265–2282

    CAS  PubMed  Google Scholar 

  • Zeng X, Overmeyer JH, Maltese WA (2006) Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J Cell Sci 119(2):259–270

    CAS  PubMed  Google Scholar 

  • 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(4):619–628

    CAS  PubMed  Google Scholar 

  • Zhai D, Jin C, Satterthwait AC, Reed JC (2006) Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Diff 13(8):1419–1421

    CAS  Google Scholar 

  • Zhong F, Davis MC, McColl KS, Distelhorst CW (2006) Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation. J Cell Biol 172(1):127–137

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ziegler DS, Kung AL, Kieran MW (2008) Anti-apoptosis mechanisms in malignant gliomas. J Clin Oncol 26(3):493–500

    CAS  PubMed  Google Scholar 

  • Zitvogel L, Kepp O, Galluzzi L, Kroemer G (2012) Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13(4):343–351

    CAS  PubMed  Google Scholar 

  • Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90(3):405–413

    CAS  PubMed  Google Scholar 

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Acknowledgments

This review article is dedicated to Dr. Nihal Ahmad and Dr. Hasan Mukhtar, Professors at the School of Medicine and Public Health, University of Wisconsin, Madison (USA). The authors sincerely appreciate the valuable and encouraging comments of the editor(s) and reviewer(s).

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The authors declare that there is no conflict of interest.

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    Authors and Affiliations

    1. Department of Biochemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, 110062, India

      Waseem Ahmad Siddiqui & Amjid Ahad

    2. Department of Biochemistry, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, 110025, India

      Haseeb Ahsan

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    1. Waseem Ahmad Siddiqui
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    Correspondence to Haseeb Ahsan.

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    Waseem Ahmad Siddiqui and Amjid Ahad have contributed equally to this work.

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    Siddiqui, W.A., Ahad, A. & Ahsan, H. The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol 89, 289–317 (2015). https://doi.org/10.1007/s00204-014-1448-7

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