The BCL-2 protein family: opposing activities that mediate cell death (original) (raw)

• Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).
  Article CAS PubMed Google Scholar
• Bakhshi, A. et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899–906 (1985).
  Article CAS PubMed Google Scholar
• Cleary, M. L., Smith, S. D. & Sklar, J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47, 19–28 (1986). References 1–3 describe the discovery of the human BCL-2 gene.
  Article CAS PubMed Google Scholar
• Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988). Demonstrates that BCL-2 inhibits apoptotic cell death, thereby identifying the first cell death regulator, and shows that defects in apoptosis can promote tumorigenesis.
  Article CAS PubMed Google Scholar
• Adams, J. M. & Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324–1337 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Evan, G. I. et al. Oncogene-dependent tumor suppression: using the dark side of the force for cancer therapy. Cold Spring Harb. Symp. Quant. Biol. 70, 263–273 (2005).
  Article CAS PubMed Google Scholar
• Strasser, A., Harris, A. W., Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).
  Article CAS PubMed Google Scholar
• Zha, H., Aime-Sempe, C., Sato, T. & Reed, J. C. Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J. Biol. Chem. 271, 7440–7444 (1996).
  Article CAS PubMed Google Scholar
• Aouacheria, A., Brunet, F. & Gouy, M. Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-only, and BNip families of apoptotic regulators. Mol. Biol. Evol. 22, 2395–2416 (2005).
  Article CAS PubMed Google Scholar
• Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nature Rev. Cancer 5, 876–885 (2005).
  Article CAS Google Scholar
• Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998). Demonstrated that caspase-9 is crucial for apoptosis that is induced by intrinsic apoptotic stimuli (such as growth-factor deprivation or DNA damage) but is dispensable for death-receptor-induced apoptosis.
  Article CAS PubMed Google Scholar
• Marsden, V. S. et al. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 419, 634–637 (2002).
  Article CAS PubMed Google Scholar
• Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apotosis. Nature 400, 886–891 (1999).
  Article CAS PubMed Google Scholar
• Kaufmann, T. et al. The BH3-only protein Bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 129, 423–433 (2007).
  Article CAS PubMed Google Scholar
• Willis, S. N. et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315, 856–859 (2007).
  Article CAS PubMed Google Scholar
• Youle, R. J. Cell biology. Cellular demolition and the rules of engagement. Science 315, 776–777 (2007).
  Article CAS PubMed Google Scholar
• Newmeyer, D. D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481–490 (2003).
  Article CAS PubMed Google Scholar
• Chipuk, J. E., Bouchier-Hayes, L. & Green, D. R. Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ. 13, 1396–1402 (2006).
  Article CAS PubMed Google Scholar
• Martinou, J. C. & Youle, R. J. Which came first, the cytochrome c release or the mitochondrial fission? Cell Death Differ. 13, 1291–1295 (2006).
  Article CAS PubMed Google Scholar
• Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922–2933 (2001).
  CAS PubMed Google Scholar
• Shi, Y. Mechanical aspects of apoptosome assembly. Curr. Opin. Cell Biol. 18, 677–684 (2006).
  Article CAS PubMed Google Scholar
• Hao, Z. et al. Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell 121, 579–591 (2005).
  Article CAS PubMed Google Scholar
• Okada, H. et al. Generation and characterization of Smac/DIABLO-deficient mice. Mol. Cell. Biol. 22, 3509–3517 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Harlin, H., Reffey, S. B., Duckett, C. S., Lindsten, T. & Thompson, C. B. Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21, 3604–3608 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Franchi, L., McDonald, C., Kanneganti, T. D., Amer, A. & Nunez, G. Nucleotide-binding oligomerization domain-like receptors: intracellular pattern recognition molecules for pathogen detection and host defense. J. Immunol. 177, 3507–3513 (2006).
  Article CAS PubMed Google Scholar
• Bruey, J. M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007).
  Article CAS PubMed Google Scholar
• Ekert, P. G. et al. Apaf-1 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die. J. Cell Biol. 165, 835–842 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Marsden, V. S., Kaufmann, T., O' Reilly L, A., Adams, J. M. & Strasser, A. Apaf-1 and caspase-9 are required for cytokine withdrawal-induced apoptosis of mast cells but dispensable for their functional and clonogenic death. Blood 107, 1872–1877 (2006).
  Article CAS PubMed Google Scholar
• Muchmore, S. W. et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381, 335 (1996). Revealed the first 3D structure of a BCL-2 family member.
  Article CAS PubMed Google Scholar
• Petros, A. M. et al. Solution structure of the antiapoptotic protein bcl-2. Proc. Natl Acad. Sci. USA 98, 3012–3017 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Denisov, A. Y. et al. Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix. J. Biol. Chem. 278, 21124–21128 (2003).
  Article CAS PubMed Google Scholar
• Hinds, M. G. et al. The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity. EMBO J. 22, 1497–1507 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Day, C. L. et al. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands. J. Biol. Chem. 280, 4738–4744 (2005).
  Article CAS PubMed Google Scholar
• Suzuki, M., Youle, R. J. & Tjandra, N. Structure of Bax: co-regulation of dimer formation and intracellular localization. Cell 103, 645–654 (2000). This paper presents the 3D structure of BAX, revealing that it is remarkably similar to that of BCL-XL, although BAX promotes apoptosis whereas BCL-XL promotes cell survival.
  Article CAS PubMed Google Scholar
• Moldoveanu, T. et al. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol. Cell 24, 677–688 (2006).
  Article CAS PubMed Google Scholar
• McDonnell, J. M., Fushman, D., Milliman, C. L., Korsmeyer, S. J. & Cowburn, D. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 96, 625–634 (1999).
  Article CAS PubMed Google Scholar
• Chou, J. J., Li, H., Salvesen, G. S., Yuan, J. & Wagner, G. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96, 615–624 (1999).
  Article CAS PubMed Google Scholar
• Huang, Q., Petros, A. M., Virgin, H. W., Fesik, S. W. & Olejniczak, E. T. Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus. Proc. Natl Acad. Sci. USA 99, 3428–3433 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Kvansakul, M. et al. A structural viral mimic of prosurvival bcl-2: a pivotal role for sequestering proapoptotic Bax and Bak. Mol. Cell 25, 933–942 (2007).
  Article CAS PubMed Google Scholar
• Douglas, A. E., Corbett, K. D., Berger, J. M., McFadden, G. & Handel, T. M. Structure of M11L: a myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2. Protein Sci. 16, 695–703 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Aoyagi, M. et al. Vaccinia virus N1L protein resembles a B cell lymphoma-2 (Bcl-2) family protein. Protein Sci. 16, 118–124 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Zha, J., Weiler, S., Oh, K. J., Wei, M. C. & Korsmeyer, S. J. Posttranslational _N_-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290, 1761–1765 (2000).
  Article CAS PubMed Google Scholar
• Sattler, M. et al. Structure of Bcl-xL–Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983–986 (1997).
  Article CAS PubMed Google Scholar
• Petros, A. M. et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9, 2528–2534 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, X., Dai, S., Zhu, Y., Marrack, P. & Kappler, J. W. The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity 19, 341–352 (2003).
  Article CAS PubMed Google Scholar
• Zhong, Q., Gao, W., Du, F. & Wang, X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005).
  Article CAS PubMed Google Scholar
• Warr, M. R. et al. BH3-ligand regulates access of MCL-1 to its E3 ligase. FEBS Lett. 579, 5603–5608 (2005).
  Article CAS PubMed Google Scholar
• Oberstein, A., Jeffrey, P. & Shi, Y. Crystal structure of the BCL-XL–beclin 1 peptide complex: beclin 1 is a novel BH3-only protein. J. Biol. Chem. 282, 13123–13132 (2007).
  Article CAS PubMed Google Scholar
• Hinds, M. G. et al. Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ. 14, 128–136 (2007).
  Article CAS PubMed Google Scholar
• Grinberg, M. et al. tBID homooligomerizes in the mitochondrial membrane to induce apoptosis. J. Biol. Chem. 277, 12237–12245 (2002).
  Article CAS PubMed Google Scholar
• Schendel, S. L. et al. Ion channel activity of the BH3 only Bcl-2 family member, BID. J. Biol. Chem. 274, 21932–21936 (1999).
  Article CAS PubMed Google Scholar
• Wiens, M., Krasko, A., Muller, C. I. & Muller, W. E. Molecular evolution of apoptotic pathways: cloning of key domains from sponges (Bcl-2 homology domains and death domains) and their phylogenetic relationships. J. Mol. Evol. 50, 520–531 (2000).
  Article CAS PubMed Google Scholar
• Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000).
  Article CAS PubMed Google Scholar
• Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).
  Article CAS PubMed Google Scholar
• Yu, J., Zhang, L., Hwang, P. M., Kinzler, K. W. & Vogelstein, B. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell 7, 673–682 (2001).
  Article CAS PubMed Google Scholar
• Dijkers, P. F., Medema, R. H., Lammers, J. W., Koenderman, L. & Coffer, P. J. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10, 1201–1204 (2000).
  Article CAS PubMed Google Scholar
• Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim via de-phosphorylation and transcription induction. Cell 129, 1337–1349 (2007).
  Article CAS PubMed Google Scholar
• Zha, J., Harada, H., Yang, E., Jockel, J. & Korsmeyer, S. J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87, 619–628 (1996).
  Article CAS PubMed Google Scholar
• Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998).
  Article CAS PubMed Google Scholar
• Luo, X., Budihardjo, I., Zou, H., Slaughter, C. & Wang, X. Bid, a Bcl2 interacting protein mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481–490 (1998).
  Article CAS PubMed Google Scholar
• Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 (1999).
  Article CAS PubMed Google Scholar
• Akiyama, T. et al. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J. 22, 6653–6664 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ley, R., Ewings, K. E., Hadfield, K. & Cook, S. J. Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ. 12, 1008–1014 (2005).
  Article CAS PubMed Google Scholar
• Puthalakath, H. et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293, 1829–1832 (2001).
  Article CAS PubMed Google Scholar
• Shimazu, T. et al. NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes Dev. 21, 929–941 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Grad, J. M., Zeng, X. R. & Boise, L. H. Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr. Opin. Oncol. 12, 543–549 (2000).
  Article CAS PubMed Google Scholar
• Cuconati, A., Mukherjee, C., Perez, D. & White, E. DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev. 17, 2922–2932 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Letai, A. et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183–192 (2002).
  Article CAS PubMed Google Scholar
• Chen, L. et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393–403 (2005).
  Article CAS PubMed Google Scholar
• Kuwana, T. et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell 17, 525–535 (2005).
  Article CAS PubMed Google Scholar
• Kim, H. et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nature Cell Biol. 8, 1348–1358 (2006).
  Article CAS PubMed Google Scholar
• Certo, M. et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9, 351–365 (2006).
  Article CAS PubMed Google Scholar
• Willis, S. N. et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 19, 1294–1305 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Walensky, L. D. et al. A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 24, 199–210 (2006).
  Article CAS PubMed Google Scholar
• Nguyen, M., Millar, D. G., Yong, V. W., Korsmeyer, S. J. & Shore, G. C. Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence. J. Biol. Chem. 268, 25265–25268 (1993).
  CAS PubMed Google Scholar
• Lithgow, T., van Driel, R., Bertram, J. F. & Strasser, A. The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Differ. 5, 411–417 (1994).
  CAS PubMed Google Scholar
• Heath-Engel, H. M. & Shore, G. C. Regulated targeting of Bax and Bak to intracellular membranes during apoptosis. Cell Death Differ. 13, 1277–1280 (2006).
  Article CAS PubMed Google Scholar
• Pinton, P. & Rizzuto, R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 13, 1409–1418 (2006).
  Article CAS PubMed Google Scholar
• Hsu, Y.-T., Wolter, K. & Youle, R. J. Cytosol to membrane redistribution of members of the Bcl-2 family during apoptosis. Proc. Natl Acad. Sci. USA 94, 3668–3672 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Hsu, Y. T. & Youle, R. J. Bax in murine thymus is a soluble monomeric protein that displays differential detergent-induced conformations. J. Biol. Chem. 273, 10777–10783 (1998).
  Article CAS PubMed Google Scholar
• Goping, I. S. et al. Regulated targeting of BAX to mitochondria. J. Cell Biol. 143, 207–215 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Wolter, K. G. et al. Movement of Bax from the cytosol to mitochondria. J. Cell Biol. 139, 1281–1292 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Cartron, P. F. et al. Involvement of the N-terminus of Bax in its intracellular localization and function. FEBS Lett. 512, 95–100 (2002).
  Article CAS PubMed Google Scholar
• Gao, S., Fu, W., Durrenberger, M., De Geyter, C. & Zhang, H. Membrane translocation and oligomerization of hBok are triggered in response to apoptotic stimuli and Bnip3. Cell. Mol. Life Sci. 62, 1015–1024 (2005).
  Article CAS PubMed Google Scholar
• Hsu, Y.-T. & Youle, R. J. Nonionic detergent induced dimerization of members of the Bcl-2 family. J. Biol. Chem. 272, 13829–13834 (1997).
  Article CAS PubMed Google Scholar
• Cheng, E. H., Sheiko, T. V., Fisher, J. K., Craigen, W. J. & Korsmeyer, S. J. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301, 513–517 (2003).
  Article CAS PubMed Google Scholar
• Setoguchi, K., Otera, H. & Mihara, K. Cytosolic factor- and TOM-independent import of C-tail-anchored mitochondrial outer membrane proteins. EMBO J. 25, 5635–5647 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J. & Molkentin, J. D. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nature Cell Biol. 9, 550–555 (2007).
  Article CAS PubMed Google Scholar
• Jeong, S. Y. et al. Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. EMBO J. 23, 2146–2155 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Nijhawan, D. et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 17, 1475–1486 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Hausmann, G. et al. Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L). J. Cell Biol. 149, 623–634 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Wilson-Annan, J. et al. Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity. J. Cell Biol. 162, 877–887 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, P. K., Annis, M. G., Dlugosz, P. J., Leber, B. & Andrews, D. W. During apoptosis Bcl-2 changes membrane topology at both the endoplasmic reticulum and mitochondria. Mol. Cell 14, 523–529 (2004).
  Article CAS PubMed Google Scholar
• Strasser, A., O'Connor, L. & Dixit, V. M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).
  Article CAS PubMed Google Scholar
• Nechushtan, A., Smith, C. L., Hsu, Y.-T. & Youle, R. J. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J. 18, 2330–2341 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Desagher, S. et al. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J. Cell Biol. 144, 891–901 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Tan, Y. J., Beerheide, W. & Ting, A. E. Biophysical characterization of the oligomeric state of Bax and its complex formation with Bcl-XL. Biochem. Biophys. Res. Commun. 255, 334–339 (1999).
  Article CAS PubMed Google Scholar
• Antonsson, B., Montessuit, S., Lauper, S., Eskes, R. & Martinou, J. C. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem. J. 345, 271–278 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Mikhailov, V. et al. Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for Bak reorganization and cytochrome c release. J. Biol. Chem. 278, 5367–5376 (2003).
  Article CAS PubMed Google Scholar
• Valentijn, A. J., Metcalfe, A. D., Kott, J., Streuli, C. H. & Gilmore, A. P. Spatial and temporal changes in Bax subcellular localization during anoikis. J. Cell Biol. 162, 599–612 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Peyerl, F. W. et al. Elucidation of some Bax conformational changes through crystallization of an antibody-peptide complex. Cell Death Differ. 14, 447–452 (2006).
  Article CAS PubMed Google Scholar
• Griffiths, G. J. et al. Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J. Cell Biol. 144, 903–914 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Dlugosz, P. J. et al. Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J. 25, 2287–2296 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Annis, M. G. et al. Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J. 24, 2096–2103 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Ruffolo, S. C. & Shore, G. C. BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. J. Biol. Chem. 278, 25039–25045 (2003).
  Article CAS PubMed Google Scholar
• Ekert, P. G. & Vaux, D. L. The mitochondrial death squad: hardened killers or innocent bystanders? Curr. Opin. Cell Biol. 17, 626–630 (2005).
  Article CAS PubMed Google Scholar
• Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004).
  Article CAS PubMed Google Scholar
• Arnoult, D., Grodet, A., Lee, Y. J., Estaquier, J. & Blackstone, C. Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation. J. Biol. Chem. 280, 35742–35750 (2005).
  Article CAS PubMed Google Scholar
• Antonsson, B. et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 277, 370–372 (1997).
  Article CAS PubMed Google Scholar
• Minn, A. J. et al. Bcl-xL forms an ion channel in synthetic lipid membranes. Nature 385, 353–357 (1997).
• Jurgensmeier, J. M. et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 4997–5002 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Kuwana, T. et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondral membreane. Cell 111, 331–342 (2002).
  Article CAS PubMed Google Scholar
• Basanez, G. et al. Full length Bax disrupts planar phospholipid membranes. Proc. Natl Acad. Sci. USA 96, 5492–5497 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Martinou, I. et al. The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible event. J. Cell Biol. 144, 883–889 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Potts, M. B., Vaughn, A. E., McDonough, H., Patterson, C. & Deshmukh, M. Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J. Cell Biol. 171, 925–930 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Nechushtan, A., Smith, C. L., I., L., Yoon, S. H. & Youle, R. J. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J. Cell Biol. 153, 1265–1276 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Karbowski, M. et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J. Cell Biol. 159, 931–938 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Youle, R. J. & Karbowski, M. Mitochondrial fission in apoptosis. Nature Rev. Mol. Cell Biol. 6, 657–663 (2005).
  Article CAS Google Scholar
• Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).
  Article CAS PubMed Google Scholar
• Goyal, G., Fell, B., Sarin, A., Youle, R. J. & Sriram, V. Role of mitochondrial remodeling in programmed cell death in Drosophila melanogaster. Dev. Cell 12, 807–816 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Abdelwahid, E. et al. Mitochondrial disruption in Drosophila apoptosis. Dev. Cell 12, 793–806 (2007).
  Article CAS PubMed Google Scholar
• Jagasia, R., Grote, P., Westermann, B. & Conradt, B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754–760 (2005).
  Article CAS PubMed Google Scholar
• Olichon, A. et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J. Biol. Chem. 278, 7743–7746 (2003).
  Article CAS PubMed Google Scholar
• Karbowski, M., Norris, K. L., Cleland, M. M., Jeong, S. Y. & Youle, R. J. Role of Bax and Bak in mitochondrial morphogenesis. Nature 443, 658–662 (2006).
  Article CAS PubMed Google Scholar
• Cipolat, S. et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126, 163–175 (2006).
  Article CAS PubMed Google Scholar
• Parone, P. A. et al. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol. Cell. Biol. 26, 7397–7408 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Delivani, P., Adrain, C., Taylor, R. C., Duriez, P. J. & Martin, S. J. Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Mol. Cell 21, 761–773 (2006).
  Article CAS PubMed Google Scholar
• Rinkenberger, J. L., Horning, S., Klocke, B., Roth, K. & Korsmeyer, S. J. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev. 14, 23–27 (2000). Shows that the anti-apoptotic BCL-2 family member MCL1 is required for early steps in mouse embryonic development.
  CAS PubMed PubMed Central Google Scholar
• Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510 (1995). Shows that BCL-XL is essential for the survival of immature erythroid progenitors and neuronal cells during mouse embryonic development.
  Article CAS PubMed Google Scholar
• Veis, D. J., Sorenson, C. M., Shutter, J. R. & Korsmeyer, S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240 (1993). Shows that BCL-2 is essential for survival of renal epithelial progenitors, mature lymphocytes and melanocyte progenitors in the mouse.
  Article CAS PubMed Google Scholar
• Bouillet, P., Cory, S., Zhang, L. C., Strasser, A. & Adams, J. M. Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev. Cell 1, 645–653 (2001).
  Article CAS PubMed Google Scholar
• Print, C. G. et al. Apoptosis regulator Bcl-w is essential for spermatogenesis but appears otherwise redundant. Proc. Natl Acad. Sci. USA 95, 12424–12431 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Hamasaki, A. et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the Bcl-2-related A1 gene. J. Exp. Med. 188, 1985–1992 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Xiang, Z. et al. Essential role of the prosurvival Bcl-2 homologue A1 in mast cell survival after allergic activation. J. Exp. Med. 194, 1561–1569 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Knudson, C. M., Tung, K. S., Tourtellotte, W. G., Brown, G. A. & Korsmeyer, S. J. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99 (1995).
  Article CAS PubMed Google Scholar
• Lindsten, T. et al. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389–1399 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).
  Article CAS PubMed Google Scholar
• Rathmell, J. C., Lindsten, T., Zong, W. X., Cinalli, R. M. & Thompson, C. B. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nature Immunol. 3, 932–939 (2002). Along with reference 136, demonstrates that BAX and BAK have largely overlapping functions in developmentally programmed cell death and stress-induced apoptosis.
  Article CAS Google Scholar
• Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Zong, W. X., Lindsten, T., Ross, A. J., MacGregor, G. R. & Thompson, C. B. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 15, 1481–1486 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, E. H. et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8, 705–711 (2001). References 140 and 141 demonstrate that BAX and/or BAK are required for apoptosis induced by BH3-only proteins.
  Article CAS PubMed Google Scholar
• Strasser, A. The role of BH3-only proteins in the immune system. Nature Rev. Immunol. 5, 189–200 (2005).
  Article CAS Google Scholar
• Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999). Provides the first evidence that a BH3-only protein, BIM, is essential for developmentally programmed cell death in mammals.
  Article CAS PubMed Google Scholar
• Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).
  Article CAS PubMed Google Scholar
• Enders, A. et al. 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, 1119–1126 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Pellegrini, M., Belz, G., Bouillet, P. & Strasser, A. Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc. Natl Acad. Sci. USA 100, 14175–14180 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Alfredsson, J., Puthalakath, H., Martin, H., Strasser, A. & Nilsson, G. Proapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation. Cell Death Differ. 12, 136–144 (2005).
  Article CAS PubMed Google Scholar
• Putcha, G. V. et al. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38, 899–914 (2003).
  Article CAS PubMed Google Scholar
• Whitfield, J., Neame, S. J., Paquet, L., Bernard, O. & Ham, J. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29, 629–643 (2001).
  Article CAS PubMed Google Scholar
• Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302, 1036–1038 (2003).
  Article CAS PubMed Google Scholar
• Jeffers, J. R. et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4, 321–328 (2003). Together with reference 150, shows that the BH3-only protein PUMA is essential for p53-mediated apoptosis triggered by DNA damage and also for apoptosis that is induced by certain p53-independent stimuli, such as cytokine deprivation or treatment with glucocorticoids.
  Article CAS PubMed Google Scholar
• Erlacher, M. et al. BH3-only proteins Puma and Bim are rate-limiting for γ-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106, 4131–4138 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Naik, E., Michalak, E. M., Villunger, A., Adams, J. M. & Strasser, A. Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J. Cell Biol. 176, 415–424 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ranger, A. M. et al. Bad-deficient mice develop diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 100, 9324–9329 (2003).
  Article PubMed PubMed Central Google Scholar
• Imaizumi, K. et al. 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, 3721–3725 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Coultas, L. et al. Pro-apoptotic BH3-only Bcl-2 family member Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensible for hemopoetic cell apoptosis. J. Cell Sci. 120, 2044–2052 (2007).
  Article CAS PubMed Google Scholar
• Deckwerth, T. L. et al. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411 (1996).
  Article CAS PubMed Google Scholar
• Coultas, L. et al. Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. EMBO J. 24, 3963–3973 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Erlacher, M. et al. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J. Exp. Med. 203, 2939–2951 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Conradt, B. & Horvitz, H. R. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93, 519–529 (1998). Shows that the BH3-only protein EGL-1 is essential for developmentally programmed cell death in C. elegans.
  Article CAS PubMed Google Scholar
• Schumacher, B. et al. C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ. 12, 153–161 (2005).
  Article CAS PubMed Google Scholar
• Kratz, E. et al. Functional characterization of the Bcl-2 gene family in the zebrafish. Cell Death Differ. 13, 1631–1640 (2006).
  Article CAS PubMed Google Scholar
• Hengartner, M. O. & Horvitz, H. R. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318–320 (1994). Shows that CED-9, which is essential for cell survival during development in C. elegans , is a homologue of mammalian BCL-2, indicating that the control of apoptosis is evolutionarily conserved.
  Article CAS PubMed Google Scholar
• Cheng, E. H. et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278, 1966–1968 (1997).
  Article CAS PubMed Google Scholar
• Lin, B. et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116, 527–540 (2004).
  Article CAS PubMed Google Scholar
• Sevrioukov, E. A. et al. Drosophila Bcl-2 proteins participate in stress-induced apoptosis, but are not required for normal development. Genesis 45, 184–193 (2007).
  Article CAS PubMed Google Scholar