BH3‐only Proteins

Lina Happo, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Clare L Scott, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

Published online: September 2009

DOI: 10.1002/9780470015902.a0021569

The deregulation of programmed cell death, apoptosis, is a major contributor to the development of cancer and can impair the response of tumour cells to anticancer therapy. The Bcl-2 family of proteins are critical regulators of apoptosis. BH3 (Bcl-2 homologous 3)-only proteins are pro-apoptotic members that share with each other and the wider Bcl-2 family only the BH3 domain that is critical for their killing capacity. These BH3-only proteins promote cell death by directly or indirectly activating Bax and Bak, in a cell-type and death stimulus-specific manner. Studies of gene-targeted mice that lack two or more BH3-only proteins are beginning to unravel the overlapping functions of these apoptosis initiators. The activation or mimicking of these proteins is expected to improve the treatment of patients suffering from cancer or autoimmune diseases.

Key concepts

  • The ‘Bcl-2-regulated’ (also called ‘intrinsic’ or ‘mitochondrial’) apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation, -irradiation) and is regulated by the interplay of the pro- and antiapoptotic members of the Bcl-2 family of proteins.
  • The survival versus death fate of a cell is decided by the relative levels of pro- and antiapoptotic Bcl-2 family members. During tumourigenesis defects in apoptosis signalling allow abnormal survival of cells undergoing neoplastic transformation and thereby facilitating sustained cell growth and accumulation of further oncogenic mutations.
  • The Bcl-2 family consists of three subgroups of proteins that can be differentiated on the basis of amino acid sequence, 3D structure and function. The pro-survival members, Bcl-2, Bcl-xL, Bcl-w (Bcl-B), Mcl-1 and A1, are essential for cell survival, with cell-type specific expression. Two subfamilies encompass the apoptosis-promoting Bcl-2 family members: the multi-BH domain pro-apoptotic subfamily members Bax, Bak and Bok, and the BH3-only subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa, Bmf and Puma/Bbc3. Bax, Bak (and Bok), are the critical activators of the effector phase of the intrinsic death pathway.
  • Both Puma and Noxa, apoptosis initiators that are transcriptionally activated by p53 in response to DNA damage or oncogenic stress, can function as tumour suppressors in their own right, particularly in the context of an oncogenic lesion that subverts cell cycle control. It is important to bear in mind that apoptosis initiation constitutes only one of several critical mechanisms by which p53 suppresses tumour development.
  • Bid functions as the link between the ‘death receptor’ and the ‘Bcl-2-regulated’ apoptotic pathways by causing an amplification of the caspase cascade that leads to cell destruction. Remarkably, Bid is critical for Fas ‘death receptor’-induced apoptosis in certain cell types, such as hepatocytes, but dispensable in others, including lymphoid cells.
  • Bim is critical for many physiologic and pathologic cell death processes and is a principal regulator of homeostasis in the lymphoid and myeloid compartment. Bim is crucial for the negative selection of autoreactive immature T- and B-lymphoid cells, for growth factor deprivation-induced apoptosis of many cell types and loss of BIM in certain human cancers substantiates its role as a tumour suppressor.
  • BH3-only proteins have a crucial function in chemotherapeutic drug-induced killing of tumour cells and their loss is frequently associated with resistance to anticancer therapy. Mimicking BH3-only proteins represents a promising strategy for enhancing the effects of conventional anticancer therapy and for treating autoimmune diseases whereas the blockade of these proteins may be beneficial in the management of certain degenerative diseases that are characterized by abnormal killing of cells that should be kept alive.

Keywords: BH3-only; apoptosis; Bcl-2

Figure 1. Two distinct mammalian apoptotic pathways exist – ‘death receptor’ (‘extrinsic’) and ‘Bcl-2-regulated’ (‘mitochondrial’ or ‘intrinsic’) apoptosis signalling. Each activate different initiator caspases but converge at the level of effector caspases. The ‘Bcl-2-regulated’ apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation, -irradiation) and is regulated by the interplay of the pro- and antiapoptotic members of the Bcl-2 family of proteins.
Figure 2. The Bcl-2 protein family consists of three subgroups that can be differentiated on the basis of amino acid sequence, 3D structure and function. The pro-survival members, Bcl-2, Bcl-xL, Bcl-w (Bcl-B), Mcl-1 and A1, share four conserved Bcl-2 homologous (BH) domains and are essential for cell survival, with cell-type-specific expression. Two subfamilies encompass the apoptosis-promoting Bcl-2 family members: the multi-BH domain pro-apoptotic subfamily members Bax, Bak and Bok, which are critical for the execution phase of apoptosis, and the BH3-only subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa, Bmf and Puma/Bbc3, which are essential for initiation of apoptosis.
Figure 3. Different apoptotic stimuli activate different BH3-only proteins via distinct signalling pathways. (a) Some death stimuli activate predominantly one BH3-only protein. (b) Other death stimuli appear to elicit cell-type-specific induction of an array of BH3-only proteins. This may reflect the wiring of the particular cell type, the availability of particular BH3-only proteins or may reflect the requirement for combinatorial signalling through multiple BH3-only proteins to allow blockade of all pro-survival Bcl-2 family members present in a particular cell type.
Figure 4. Two competing models have been proposed to explain how BH3-only proteins activate Bax/Bak to unleash the downstream effector phases of apoptosis. According to the ‘direct model’, in healthy cells certain so-called direct activator BH3-only proteins (particularly Bid, Bim and possibly Puma) are kept in check by binding to the pro-survival Bcl-2 family members. Apoptotic stimuli induce so-called indirect activator BH3-only proteins (e.g. Bad, Bik and Bmf), which by binding to the pro-survival Bcl-2 family members unleash Bid, Bim and Puma, thereby allowing them to bind and directly activate (orange) Bax and Bak from an inactive state (brown). According to the ‘indirect model’, in healthy cells Bax and Bak are kept in an inactive state (brown) by binding to the pro-survival Bcl-2 family members. Apoptotic stimuli activate BH3-only proteins (in a cell death stimulus- and cell-type-specific manner). By binding to the pro-survival Bcl-2 family members, the BH3-only proteins cause release and activation of Bax and Bak (orange) indirectly. According to this model, for a cell to be committed to undergo apoptosis all pro-survival Bcl-2 family members present must be neutralized by BH3-only proteins. It is important to note that BH3-only proteins differ in their potency to trigger apoptosis and this is due to their differences in binding affinities for the different pro-survival Bcl-2 family members. Bim, Puma and Bid bind all (or most) these proteins with high affinity. In contrast, Bad only binds to Bcl-2, Bcl-xL and Bcl-w, whereas Noxa only binds to Mcl-1 and A1.
close
 References
    Adams JM and Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26: 1324–1337.
    Bouillet P, Cory S, Zhang L-C, Strasser A and Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency are prevented by loss of its BH3-only antagonist Bim. Developmental Cell 1: 645–653.
    Bouillet P, Metcalf D, Huang DCS et al. (1999) Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735–1738.
    Bouillet P, Purton JF, Godfrey DI et al. (2002) BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922–926.
    Chen L, Willis SN, Wei A et al. (2005) Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular Cell 17: 393–403.
    Chipuk JE and Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends in Cell Biology 18: 157–164.
    Choy EY, Siu KL, Kok KH et al. (2008) An Epstein–Barr virus-encoded microRNA targets PUMA to promote host cell survival. Journal of Experimental Medicine 205: 2551–2560.
    Coultas L, Bouillet P, Loveland KL et al. (2005) Concomitant loss of proapoptotic BH3-only Bcl-2 antagonists Bik and Bim arrests spermatogenesis. EMBO Journal 24: 3963–3973.
    Coultas L, Bouillet P, Stanley EG et al. (2004) Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Molecular and Cellular Biology 24: 1570–1581.
    Coultas L, Terzano S, Thomas T et al. (2007) Hrk/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis. Journal of Cell Science 120: 2044–2052.
    Cragg MS, Harris C, Strasser A and Scott CL (2009) Synergy between ABT-737 and targeted therapies. Nature Reviews Cancer 9: 321–326.
    Cragg MS, Jansen ES, Cook M et al. (2008) Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. Journal of Clinical Investigation 118: 3651–3659.
    Daniel PT, Pun KT, Ritschel S et al. (1999) Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice. Blood 94: 1100–1107.
    van Delft MF, Wei AH, Mason KD et al. (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptois via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10: 389–399.
    Dijkers PF, Medema RH, Lammers JJ, Koenderman L and Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Current Biology 10: 1201–1204.
    Egle A, Harris AW, Bouillet P and Cory S (2004) Bim is a suppressor of Myc-induced mouse B cell leukemia. Proceedings of the National Academy of Sciences of the USA 101: 6164–6169.
    Ekoff M, Kaufmann T, Engstrom M et al. (2007) The BH3-only protein Puma plays an essential role in cytokine deprivation-induced apoptosis of mast cells. Blood 110: 3209–3217.
    Enders A, Bouillet P, Puthalakath H et al. (2003) Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreative B cells. Journal of Experimental Medicine 198: 1119–1126.
    Erlacher M, Laabi V, Manzl C et al. (2006) Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. Journal of Experimental Medicine 203: 2939–2951.
    Erlacher M, Michalak EM, Kelly PN et al. (2005) BH3-only proteins Puma and Bim are rate-limiting for {gamma}-radiation and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106: 4131–4138.
    Ewings KE, Hadfield-Moorhouse K, Wiggins CM et al. (2007) ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO Journal 26: 2856–2867.
    Garrison SP, Jeffers JR, Yang C et al. (2008) Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Molecular and Cellular Biology 28: 5391–5402.
    Germain M, Mathai JP and Shore GC (2002) BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. Journal of Biological Chemistry 277: 18053–18060.
    Hemann MT, Bric A, Teruya-Feldstein J et al. (2005) Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436: 807–811.
    Hemann MT, Zilfou JT, Zhao Z et al. (2004) Suppression of tumorigenesis by the p53 target PUMA. Proceedings of the National Academy of Sciences of the USA 101: 9333–9338.
    Huntington ND, Puthalakath H, Gunn P et al. (2007) Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nature Immunology 8: 856–863.
    Imaizumi K, Benito A, Kiryu-Seo S et al. (2004) Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death. Journal of Neuroscience 24: 3721–3725.
    Imaizumi K, Tsuda M, Imai Y et al. (1997) Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. Journal of Biological Chemistry 272: 18842–18848.
    Inohara N, Ding L, Chen S and 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-XL. EMBO Journal 16: 1686–1694.
    Jiang A and Clark EA (2001) Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. Journal of Immunology 166: 6025–6033.
    Kaufmann T, Tai L, Ekert PG et al. (2007) The BH3-only protein Bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell 129: 423–433.
    Kim JY, Ahn HJ, Ryu JH, Suk K and Park JH (2004) BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. Journal of Experimental Medicine 199: 113–124.
    Kuroda J, Kimura S, Strasser A et al. (2007) Apoptosis-based dual molecular targeting by INNO-406, a second generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of anti-apoptotic Bcl-2 proteins against Bcr-Abl-positive leukemia. Cell Death and Differentiation 14: 1667–1677.
    Kuroda J, Puthalakath H, Cragg MS et al. (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proceedings of the National Academy of Sciences 103: 14907–14912.
    Kuroda J and Taniwaki M (2008) Involvement of BH3-only proteins in hematologic malignancies. Critical Reviews in Oncology/Hematology, doi: 10.1016/j.critrevonc.2008.10.004.
    Labi V, Erlacher M, Kiessling S et al. (2008) Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates gamma irradiation-induced thymic lymphoma development. Journal of Experimental Medicine 205: 641–655.
    Labi V, Erlacher M, Kiessling S and Villunger A (2006) BH3-only proteins in cell death initiation, malignant disease and anticancer therapy. Cell Death and Differentiation 13: 1325–1328.
    Lessene G, Czabotar PE and Colman PM (2008) BCL-2 family antagonists for cancer therapy. Nature Reviews Drug Discovery 7: 989–1000.
    Letai AG (2008) Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Reviews of Cancer 8: 121–132.
    Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323–331.
    Marshansky V, Wang X, Bertrand R et al. (2001) Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. Journal of Immunology 166: 3130–3142.
    Mathai JP, Germain M, Marcellus RC and Shore GC (2002) Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 21: 2534–2544.
    Mathai JP, Germain M and Shore GC (2005) BH3-only BIK regulates BAX,BAK-dependent release of Ca2+ from endoplasmic reticulum stores and mitochondrial apoptosis during stress-induced cell death. Journal of Biological Chemistry 280: 23829–23836.
    McKenzie MD, Carrington EM, Kaufmann T et al. (2008) Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells. Diabetes 57: 1284–1292.
    Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA et al. (2007) Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109: 271–280.
    Michalak EM, Jansen ES, Happo L et al. (2009) Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death and Differentiation 16: 684–696.
    Michalak EM, Villunger A, Adams JM and Strasser A. (2008) In several cell types the tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death and Differentiation 15: 1019–1029.
    Naik E, Michalak EM, Villunger A, Adams JM and Strasser A (2007) UV-radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. Journal of Cell Biology 176: 415–424.
    Nikrad M, Johnson T, Puthalalath H et al. (2005) The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Molecular and Cancer Therapy 4: 443–449.
    O'Connor L, Strasser A, O'Reilly LA et al. (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO Journal 17: 384–395.
    O'Reilly LA, Cullen L, Visvader J et al. (2000) The pro-apoptotic BH3-only protein Bim is expressed in hemopoietic, epithelial, neuronal and germ cells. American Journal of Pathology 157: 449–461.
    Oltersdorf T, Elmore SW, Shoemaker AR et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681.
    Oppermann M, Geilen CC, Fecker LF et al. (2005) Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk/Bik. Oncogene 24: 7369–7380.
    Ploner C, Rainer J, Niederegger H et al. (2008) The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22: 370–377.
    Putcha GV, Le S, Frank S et al. (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38: 899–914.
    Puthalakath H, O'Reilly LA, Gunn P et al. (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337–1349.
    Puthalakath H and Strasser A (2002) Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death and Differentiation 9: 505–512.
    Shimazu T, Degenhardt K, Nur EKA et al. (2007) NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibition. Genes & Development 21: 929–941.
    Strasser A (2005) The role of BH3-only proteins in the immune system. Nature Reviews of Immunology 5: 189–200.
    Strasser A, Harris AW, Bath ML and Cory S (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348: 331–333.
    Strasser A, Harris AW and Cory S (1991) Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67: 889–899.
    Strasser A, Harris AW, Jacks T and Cory S (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79: 329–339.
    Tagawa H, Karnan S, Suzuki R et al. (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene 24: 1348–1358.
    Tan TT, Degenhardt K, Nelson DA et al. (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7: 227–238.
    Tse C, Shoemaker AR, Adickes J et al. (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Research 68: 3421–3428.
    Tsujimoto Y, Cossman J, Jaffe E and Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science 228: 1440–1443.
    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: 875–886.
    Verma S, Zhao L and Chinnadurai G (2001) Phosphorylation of the pro-apoptotic protein bik. Mapping of phosphorylation sites and effect on apoptosis. Journal of Biological Chemistry 276: 4671–4676.
    Villunger A, Michalak EM, Coultas L et al. (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302: 1036–1038.
    Vogelstein B, Lane D and Levine AJ (2000) Surfing the p53 network. Nature 408: 307–310.
    Xiao C, Srinivasan L, Calado DP et al. (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nature Immunology 9: 404–414.
    Yamakuchi M, Ferlito M and Lowenstein CJ (2008) miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences of the USA 105: 13421–13426.
    Youle RJ and Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nature Review. Molecular Cell Biology 9: 47–59.
    Zinkel SS, Ong CC, Ferguson DO et al. (2003) Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes & Development 17: 229–239.
 Further Reading
    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: 1921–1928.
    Han J, Sabbatini P and White E (1996) Induction of apoptosis by human Nbk/Bik, a BH3-containing protein that interacts with E1B 19K. Molecular and Cellular Biology 16: 5857–5864.
    Hsu SY, Lin P and Hsueh AJW (1998) BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Molecular Endocrinology 12: 1432–1440.
    Nakano K and Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Molecular Cell 7: 683–694.
    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 288: 1053–1058.
    Puthalakath H, Villunger A, O'Reilly LA et al. (2001) Bmf: a pro-apoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293: 1829–1832.
    Wang K, Yin X-M, Chao DT, Milliman CL and Korsmeyer SJ (1996) BID: a novel BH3 domain-only death agonist. Genes & Development 10: 2859–2869.
    Yang E, Zha J, Jockel J et al. (1995) Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell 80: 285–291.
    Yu J, Zhang L, Hwang PM, Kinzler KW and Vogelstein B (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Molecular Cell 7: 673–682.

Related Sub-Topics:

Intracellular and Extracellular Signalling | Cell Biology of Cancer | Cell Cycle | Cell Death and Cellular Senescence | Protein Structure | Protein Folding, Evolution and Degradation | Mechanisms of Cell Death, Senescence and Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: BH3‐only Proteins
 
How to Cite close
Happo, Lina, Strasser, Andreas, and Scott, Clare L(Sep 2009) BH3‐only Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021569]