B-cell lymphoma-2 (BCL-2) family proteins regulate programmed cell death. Some members of the family (such as BCL-2 and BCL-XL) inhibit apoptosis, whereas others (such as BAX and BAK) promote cell death.
BH3-only proteins are a distinct and structurally diverse class of proteins that share one motif, the BH3 domain, with BCL-2 family proteins. BH3-only proteins serve as death sentinels and transmit a signal to promote apoptosis to the core BCL-2 family proteins.
Various BH3-only proteins interact with specific subsets of anti-apoptotic BCL-2 family members, yielding combinatorial signalling pathways towards apoptosis.
Different tissues die prematurely in mice that lack different anti-apoptotic BCL-2 family members. Knockout of certain BH3-only proteins can compensate for the specific tissue defects that are found in mice deficient in BCL-2 family members.
At the onset of apoptosis, BAX and BAK undergo conformational changes, cause the outer membrane of the mitochondria to become permeable to various proteins and induce mitochondria to fragment into smaller units.
The changes in mitochondria during apoptosis, especially the release of cytochrome c, result in the activation of caspase proteases that orchestrate the efficient dismantling of dying cells.
BCL-2 family proteins, which have either pro- or anti-apoptotic activities, have been studied intensively for the past decade owing to their importance in the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. They control the point of no return for clonogenic cell survival and thereby affect tumorigenesis and host–pathogen interactions and regulate animal development. Recent structural, phylogenetic and biological analyses, however, suggest the need for some reconsideration of the accepted organizational principles of the family and how the family members interact with one another during programmed cell death. Although these insights into interactions among BCL-2 family proteins reveal how these proteins are regulated, a unifying hypothesis for the mechanisms they use to activate caspases remains elusive.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).
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).
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.
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.
Adams, J. M. & Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324–1337 (2007).
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).
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).
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).
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).
Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nature Rev. Cancer 5, 876–885 (2005).
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.
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).
Yin, X. M. et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apotosis. Nature 400, 886–891 (1999).
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).
Willis, S. N. et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315, 856–859 (2007).
Youle, R. J. Cell biology. Cellular demolition and the rules of engagement. Science 315, 776–777 (2007).
Newmeyer, D. D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481–490 (2003).
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).
Martinou, J. C. & Youle, R. J. Which came first, the cytochrome c release or the mitochondrial fission? Cell Death Differ. 13, 1291–1295 (2006).
Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922–2933 (2001).
Shi, Y. Mechanical aspects of apoptosome assembly. Curr. Opin. Cell Biol. 18, 677–684 (2006).
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).
Okada, H. et al. Generation and characterization of Smac/DIABLO-deficient mice. Mol. Cell. Biol. 22, 3509–3517 (2002).
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).
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).
Bruey, J. M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007).
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).
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).
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.
Petros, A. M. et al. Solution structure of the antiapoptotic protein bcl-2. Proc. Natl Acad. Sci. USA 98, 3012–3017 (2001).
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).
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).
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).
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.
Moldoveanu, T. et al. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol. Cell 24, 677–688 (2006).
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).
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).
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).
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).
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).
Aoyagi, M. et al. Vaccinia virus N1L protein resembles a B cell lymphoma-2 (Bcl-2) family protein. Protein Sci. 16, 118–124 (2007).
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).
Sattler, M. et al. Structure of Bcl-xL–Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983–986 (1997).
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).
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).
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).
Warr, M. R. et al. BH3-ligand regulates access of MCL-1 to its E3 ligase. FEBS Lett. 579, 5603–5608 (2005).
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).
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).
Grinberg, M. et al. tBID homooligomerizes in the mitochondrial membrane to induce apoptosis. J. Biol. Chem. 277, 12237–12245 (2002).
Schendel, S. L. et al. Ion channel activity of the BH3 only Bcl-2 family member, BID. J. Biol. Chem. 274, 21932–21936 (1999).
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).
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).
Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Letai, A. et al. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2, 183–192 (2002).
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).
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).
Kim, H. et al. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nature Cell Biol. 8, 1348–1358 (2006).
Certo, M. et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9, 351–365 (2006).
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).
Walensky, L. D. et al. A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 24, 199–210 (2006).
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).
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).
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).
Pinton, P. & Rizzuto, R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 13, 1409–1418 (2006).
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).
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).
Goping, I. S. et al. Regulated targeting of BAX to mitochondria. J. Cell Biol. 143, 207–215 (1998).
Wolter, K. G. et al. Movement of Bax from the cytosol to mitochondria. J. Cell Biol. 139, 1281–1292 (1997).
Cartron, P. F. et al. Involvement of the N-terminus of Bax in its intracellular localization and function. FEBS Lett. 512, 95–100 (2002).
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).
Hsu, Y.-T. & Youle, R. J. Nonionic detergent induced dimerization of members of the Bcl-2 family. J. Biol. Chem. 272, 13829–13834 (1997).
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).
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).
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).
Jeong, S. Y. et al. Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. EMBO J. 23, 2146–2155 (2004).
Nijhawan, D. et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 17, 1475–1486 (2003).
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).
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).
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).
Strasser, A., O'Connor, L. & Dixit, V. M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
Dlugosz, P. J. et al. Bcl-2 changes conformation to inhibit Bax oligomerization. EMBO J. 25, 2287–2296 (2006).
Annis, M. G. et al. Bax forms multispanning monomers that oligomerize to permeabilize membranes during apoptosis. EMBO J. 24, 2096–2103 (2005).
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).
Ekert, P. G. & Vaux, D. L. The mitochondrial death squad: hardened killers or innocent bystanders? Curr. Opin. Cell Biol. 17, 626–630 (2005).
Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004).
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).
Antonsson, B. et al. Inhibition of Bax channel-forming activity by Bcl-2. Science 277, 370–372 (1997).
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).
Kuwana, T. et al. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondral membreane. Cell 111, 331–342 (2002).
Basanez, G. et al. Full length Bax disrupts planar phospholipid membranes. Proc. Natl Acad. Sci. USA 96, 5492–5497 (1999).
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).
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).
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).
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).
Youle, R. J. & Karbowski, M. Mitochondrial fission in apoptosis. Nature Rev. Mol. Cell Biol. 6, 657–663 (2005).
Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001).
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).
Abdelwahid, E. et al. Mitochondrial disruption in Drosophila apoptosis. Dev. Cell 12, 793–806 (2007).
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).
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).
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).
Cipolat, S. et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126, 163–175 (2006).
Parone, P. A. et al. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol. Cell. Biol. 26, 7397–7408 (2006).
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).
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.
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.
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.
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).
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).
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).
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).
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).
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).
Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).
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.
Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).
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).
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.
Strasser, A. The role of BH3-only proteins in the immune system. Nature Rev. Immunol. 5, 189–200 (2005).
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.
Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).
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).
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).
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).
Putcha, G. V. et al. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38, 899–914 (2003).
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).
Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302, 1036–1038 (2003).
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.
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).
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).
Ranger, A. M. et al. Bad-deficient mice develop diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 100, 9324–9329 (2003).
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).
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).
Deckwerth, T. L. et al. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411 (1996).
Coultas, L. et al. Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. EMBO J. 24, 3963–3973 (2005).
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).
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.
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).
Kratz, E. et al. Functional characterization of the Bcl-2 gene family in the zebrafish. Cell Death Differ. 13, 1631–1640 (2006).
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.
Cheng, E. H. et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278, 1966–1968 (1997).
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).
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).
GFP-BAX imaged in two HeLa cells over a 5-hour time course during staurosporine-induced apoptosis1. BAX changes distribution from the cytosol to mitochondria upstream of caspase activation. (MOV 3994 kb)
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).
- BH3 motif
The amino-acid sequence LXXXGD, in which X represents any amino acid. This motif is conserved between most core BCL-2 family members and among BH3-only proteins.
- TNF receptor family
Cell-surface receptors in the tumour necrosis factor (TNF) family.
- Death domain
A protein-interaction module that consists of six α-helices and that is involved in apoptosis and other signalling pathways.
- Mitochondrial outer membrane permeabilization
The process by which the outer membrane of mitochondria leaks certain soluble intermembrane space proteins, such as cytochrome c, into the cytoplasm.
The caspase-9 activation complex that is composed of APAF1 heptamers and that is assembled on binding of APAF1 monomers to cytochrome c.
- Inhibitor of apoptosis protein
(IAP). One of a family of proteins that inhibits apoptosis by binding or degrading caspases.
- NOD-like receptor
A cytosolic receptor that is homologous to NOD1 and is involved in innate immunity pathways.
- E3 ligase
One of a family of proteins that facilitate the transfer of ubiquitin from a donor protein to a specific substrate protein that may signal the target for proteosomal degradation.
- ER stress
The accumulation of unfolded or incompletely glycosylated proteins in the endoplasmic reticulum (ER) results in stress that may lead to apoptosis.
- Dynein motor complex
A molecular machine that transports cargo along microtubules.
- JAK–STAT pathway
The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway is a signalling pathway that is activated by growth factors and cytokines.
The production of red blood cells.
- SLE-like autoimmune disease
A rodent pathology that resembles human systemic lupus erythematosus, which is commonly known as lupus.
About this article
Cite this article
Youle, R., Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9, 47–59 (2008). https://doi.org/10.1038/nrm2308
Anti-tumor activity of resveratrol against gastric cancer: a review of recent advances with an emphasis on molecular pathways
Cancer Cell International (2021)
Metformin induces apoptosis via uterus mitochondrial permeability transition pore opening and protects against estradiol benzoate-induced uterine defect and associated pathophysiological disorder in female Wistar rats
Bulletin of the National Research Centre (2021)
BMC Bioinformatics (2021)
BMC Complementary Medicine and Therapies (2021)
Pyrroloquinoline quinone regulates the redox status in vitro and in vivo of weaned pigs via the Nrf2/HO-1 pathway
Journal of Animal Science and Biotechnology (2021)