BH3‐Only Proteins

Abstract

The deregulation of programmed cell death, apoptosis, is a major contributor to the development of diseases, including cancer or autoimmunity, and can impair the response of transformed cells to therapy. The Bcl‐2 family of proteins includes critical regulators of the intrinsic apoptosis pathway. BH3 (Bcl‐2 homologous 3)‐only proteins are proapoptotic members that share with each other and the wider Bcl‐2 family only the ‘BH3 domain’. This short stretch of about 16 amino acids is necessary for protein–protein interaction that is critical for their apoptosis‐inducing capacity. BH3‐only proteins promote cell death by regulating activation of Bax and Bak, in a cell‐type and stimulus‐specific manner. Studies of gene‐targeted mice that lack two or more BH3‐only proteins have helped to unravel the overlapping functions of these apoptosis initiators. With the dawn of CRISPR/Cas9 gene‐editing technologies, this strategy was taken even further, opening up allegedly answered questions again, at least at the cellular level. BH3 mimetics were recently approved for the treatment of patients suffering from cancer and it can be anticipated that these drugs make second use to treat autoimmunity and ageing‐related disorders in the future.

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 and γ‐irradiation) and is regulated by the interplay of the pro‐ and antiapoptotic members of the Bcl‐2 family of proteins controlling integrity of the outer mitochondrial membrane (OMM).
  • The survival versus death fate of a cell is decided not only by the relative levels of pro‐ and antiapoptotic Bcl‐2 family members, but also depends on their ‘activation status’, frequently imposed by different posttranslational modifications on these proteins.
  • Abnormal cell survival during establishment and maintenance of immune‐(self)‐tolerance as well as defects in apoptosis signalling at the end of an immune response may lead to neoplastic transformation and tumourigenesis.
  • The Bcl‐2 family consists of three subgroups of proteins that can be differentiated based on amino acid sequence, 3D structure and function. Bcl‐2, Bcl‐xL, Bcl‐w, Bcl‐B, Mcl‐1 and A1 are essential for cell survival, with cell‐type‐specific expression, while Bcl‐B is found active only in humans. The two other, proapoptotic, subfamilies encompass the multi‐BH domain Bcl‐2 family members Bax, Bak and Bok as well as the BH3‐only protein subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa/Pmaip, Bmf and Puma/Bbc3. The BH3‐only proteins are critical activators of the effector phase of the intrinsic death pathway, while Bax and Bak act as executers of apoptosis by initiating mitochondrial outer membrane permeabilisation (MOMP). The role of Bok in this group remains to be clarified in full.
  • Both Puma and Noxa, apoptosis initiators that can be transcriptionally activated by p53 in response to DNA damage or oncogenic stress, can act as tumour suppressors in their own right, particularly in the context of an oncogenic lesion that subverts cell cycle control. Yet, in most circumstances tested, Puma appears more effective, suggesting roles for Noxa outside the p53 response.
  • 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. Additional roles of Bid, downstream of other proteases, have been suggested.
  • Bim, the most studied BH3‐only protein, 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 and for growth factor deprivation‐induced apoptosis of many cell types. Loss of BIM in certain human cancers substantiates its role as a tumour suppressor and ample data supports a key role in anticancer therapy.
  • Additional BH3‐only proteins such as Bmf, Bad, Hrk and Bik are less well studied and poorly understood. Available data suggests that they support the key effectors Bim, Puma or Bid in potentiating cell killing in a cell‐type and stimulus‐dependent manner. Functions outside canonical apoptosis signalling remain plausible.
  • 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. Some proteins are equally important in killing autoreactive immune cells or can become aberrantly activated in chronic inflammatory or degenerative disorders, contributing to diverse pathologies.
  • 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 characterised by abnormal killing of cells that should be kept alive.

Keywords: BH3‐only; apoptosis; Bcl‐2; mitochondria; BH3‐mimetics

Figure 1. Two distinct mammalian apoptotic pathways exist – ‘death receptor’ (‘extrinsic’) and ‘Bcl‐2‐regulated’ (‘mitochondrial’ or ‘intrinsic’) apoptosis signalling. Each activates different initiator caspases, but converges 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 and γ‐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 prosurvival 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 proapoptotic 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 prosurvival 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 prosurvival Bcl‐2 family members. Apoptotic stimuli induce the so‐called indirect activator BH3‐only proteins (e.g. Bad, Bik and Bmf), which by binding to the prosurvival 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 prosurvival Bcl‐2 family members. Apoptotic stimuli activate BH3‐only proteins (in a cell death stimulus‐ and cell‐type‐specific manner). By binding to the prosurvival 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 prosurvival Bcl‐2 family members present must be neutralised 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 prosurvival 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.
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References

Anderson MA, Huang D and Roberts A (2014) Targeting BCL2 for the treatment of lymphoid malignancies. Seminars in Hematology 51: 219–227.

Bakhshi A, Jensen JP, Goldman P, et al. (1985) 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.

Baumgartner F and Villunger A (2011) Apoptosis: a barrier against cancer no more? Hepatology 54: 1121–1124.

Baumgartner F, Woess C, Pedit V, et al. (2013) Minor cell‐death defects but reduced tumor latency in mice lacking the BH3‐only proteins Bad and Bmf. Oncogene 32: 621–630.

Bock FJ and Villunger A (2011) GSK3 TIPping off p53 to unleash PUMA. Molecular Cell 42: 555–556.

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, 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.

Carrington EM, Vikstrom IB, Light A, et al. (2010) BH3 mimetics antagonizing restricted prosurvival Bcl‐2 proteins represent another class of selective immune modulatory drugs. Proceedings of the National Academy of Sciences of the United States of America 107: 10967–10971.

Carter MJ, Cox KL, Blakemore SJ, et al. (2016) BCR‐signaling‐induced cell death demonstrates dependency on multiple BH3‐only proteins in a murine model of B‐cell lymphoma. Cell Death and Differentiation 23: 303–312.

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

Chang J, Wang Y, Shao L, et al. (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine 22: 78–83.

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

Chen L, Monti S, Juszczynski P, et al. (2013) SYK inhibition modulates distinct PI3K/AKT‐ dependent survival pathways and cholesterol biosynthesis in diffuse large B cell lymphomas. Cancer Cell 23: 826–838.

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, Bouillet P, Loveland KL, et al. (2005) Concomitant loss of proapoptotic BH3‐only Bcl‐2 antagonists Bik and Bim arrests spermatogenesis. EMBO Journal 24 (22): 3963–3973.

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, 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.

Czabotar PE, Lessene G, Strasser A and Adams JM (2014) Control of apoptosis by the BCL‐2 protein family: implications for physiology and therapy. Nature Reviews. Molecular Cell Biology 15: 49–63.

Danial NN (2008) BAD: undertaker by night, candyman by day. Oncogene 27 (Suppl 1): S53–S70.

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.

Dehan E, Bassermann F, Guardavaccaro D, et al. (2009) betaTrCP‐ and Rsk1/2‐mediated degradation of BimEL inhibits apoptosis. Molecular Cell 33: 109–116.

Delbridge AR, Grabow S, Strasser A and Vaux DL (2016) Thirty years of BCL‐2: translating cell death discoveries into novel cancer therapies. Nature Reviews. Cancer 16: 99–109.

Dijkers PF, Medema RH, Lammers JW, 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: CB 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 United States of America 101: 6164–6169.

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.

Erlacher M, Labi 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.

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.

Frenzel A, Grespi F, Chmelewskij W and Villunger A (2009) Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis: An International Journal on Programmed Cell Death 14 (4): 584–596.

Frenzel A, Labi V, Chmelewskij W, et al. (2010) Suppression of B‐cell lymphomagenesis by the BH3‐only proteins Bmf and Bad. Blood 115: 995–1005.

Garcia Saez AJ and Villunger A (2016) MOMP in the absence of BH3‐only proteins. Genes & Development 30: 878–880.

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.

Grespi F, Soratroi C, Krumschnabel G, et al. (2010) BH3‐only protein Bmf mediates apoptosis upon inhibition of CAP‐dependent protein synthesis. Cell Death and Differentiation 17: 1672–1683.

Gross A, Zaltsman Y and Maryanovich M (2016) The ATM‐BID pathway plays a critical role in the DNA damage response by regulating mitochondria metabolism. Cell Death and Differentiation 23: 182.

Haschka MD, Soratroi C, Kirschnek S, et al. (2015) The NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest. Nature Communications 6: 6891.

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.

Hubner A, Barrett T, Flavell RA and Davis RJ (2008) Multisite phosphorylation regulates Bim stability and apoptotic activity. Molecular Cell 30: 415–425.

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, 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.

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.

Inoue S, Riley J, Gant TW, Dyer MJ and Cohen GM (2007) Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 21: 1773–1782.

Karlberg M, Ekoff M, Labi V, et al. (2010) Pro‐apoptotic Bax is the major and Bak an auxiliary effector in cytokine deprivation‐induced mast cell apoptosis. Cell Death & Disease 1: e43. DOI: 10.1038/cddis.2010.20.

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.

Kaufmann T, Jost PJ, Pellegrini M, et al. (2009) Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase‐8 and involves the BH3‐only proteins Bid and Bim. Immunity 30: 56–66.

Kelly PN, White MJ, Goschnick MW, et al. (2010) Individual and overlapping roles of BH3‐only proteins Bim and Bad in apoptosis of lymphocytes and platelets and in suppression of thymic lymphoma development. Cell Death and Differentiation 17: 1655–1664.

Kerr JB, Hutt KJ, Michalak EM, et al. (2012) DNA damage‐induced primordial follicle oocyte apoptosis and loss of fertility require TAp63‐mediated induction of Puma and Noxa. Molecular Cell 48: 343–352.

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, 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 of the United States of America 103: 14907–14912.

Kuroda J and Taniwaki M (2009) Involvement of BH3‐only proteins in hematologic malignancies. Critical Reviews in Oncology/Hematology 71: 89–101.

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: 1325–1338.

Labi V, Erlacher M, Kiessling S, et al. (2008a) 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, Grespi F, Baumgartner F and Villunger A (2008b) Targeting the Bcl‐2‐regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death and Differentiation 15: 977–987.

Labi V, Erlacher M, Krumschnabel G, et al. (2010) Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes & Development 24: 1602–1607.

Labi V and Villunger A (2010) PUMA‐mediated tumor suppression: a tale of two stories. Cell Cycle 9: 4269–4275.

Labi V, Woess C, Tuzlak S, et al. (2014) Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3‐only proteins Bim and Bmf. Blood 123: 2652–2662.

Lopez J, Hesling C, Prudent J, et al. (2012) Src tyrosine kinase inhibits apoptosis through the Erk1/2‐ dependent degradation of the death accelerator Bik. Cell Death and Differentiation 19: 1459–1469.

Mailleux AA, Overholtzer M, Schmelzle T, et al. (2007) BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Developmental Cell 12: 221–234.

Manzl C, Peintner L, Krumschnabel G, et al. (2012) PIDDosome‐independent tumor suppression by Caspase‐2. Cell Death and Differentiation 19: 1722–1732.

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.

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, Villunger A, Adams JM and Strasser A (2008) In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death and Differentiation 15 (6): 1019–1029.

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.

Murphy JM and Silke J (2014) Ars Moriendi; the art of dying well ‐ new insights into the molecular pathways of necroptotic cell death. EMBO Reports 15: 155–164.

Naik E, Michalak EM, Villunger A, Adams JM and Strasser A (2007) Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3‐only protein Noxa. Journal of Cell Biology 176: 415–424.

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

Ng KP, Hillmer AM, Chuah CT, et al. (2012) A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Medicine 18: 521–528.

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 Cancer Therapeutics 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.

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.

Ottina E, Sochalska M, Sgonc R and Villunger A (2015) The BH3‐only protein Bad is dispensable for TNF‐mediated cell death. Cell Death & Disease 6: e1611.

Pinon JD, Labi V, Egle A and Villunger A (2008) Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 27 (Suppl 1): S41–S52.

Ploner C, Kofler R and Villunger A (2008) Noxa: at the tip of the balance between life and death. Oncogene 27 (Suppl 1): S84–S92.

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.

Puthalakath H, O'Reilly LA, Gunn P, et al. (2007) ER stress triggers apoptosis by activating BH3‐only protein Bim. Cell 129: 1337–1349.

Qiu W, Carson‐Walter EB, Kuan SF, Zhang L and Yu J (2009) PUMA suppresses intestinal tumorigenesis in mice. Cancer Research 69: 4999–5006.

Qiu W, Wang X, Leibowitz B, et al. (2011) PUMA‐mediated apoptosis drives chemical hepatocarcinogenesis in mice. Hepatology 54 (4): 1249–1258.

Ranger AM, Zha J, Harada H, et al. (2003) Bad‐deficient mice develop diffuse large B cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 100: 9324–9329.

Sanz C, Benito A, Inohara N, et al. (2000) Specific and rapid induction of the proapoptotic protein Hrk after growth factor withdrawal in hematopoietic progenitor cells. Blood 95: 2742–2747.

Schmelzle T, Mailleux AA, Overholtzer M, et al. (2007) Functional role and oncogene‐regulated expression of the BH3‐only factor Bmf in mammary epithelial anoikis and morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 104: 3787–3792.

Schuler F, Baumgartner F, Klepsch V, et al. (2016) The BH3‐only protein BIM contributes to late‐stage involution in the mouse mammary gland. Cell Death and Differentiation 23: 41–51.

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.

Silke J (2011) The regulation of TNF signalling: what a tangled web we weave. Current Opinion in Immunology 23: 620–626.

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

Sutton VR, Davis JE, Cancilla M, et al. (2000) Initiation of apoptosis by granzyme B requires direct cleavage of Bid, but not direct granzyme B‐mediated caspase activation. Journal of Experimental Medicine 192: 1403–1414.

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.

Tischner D, Woess C, Ottina E and Villunger A (2010) Bcl‐2‐regulated cell death signalling in the prevention of autoimmunity. Cell Death & Disease 1: e48.

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.

Vandenberg CJ, Waring P, Strasser A and Cory S (2014) Plasmacytomagenesis in Emu‐v‐abl transgenic mice is accelerated when apoptosis is restrained. Blood 124: 1099–1109.

Ventura A, Young AG, Winslow MM, et al. (2008) Targeted deletion reveals essential and overlapping functions of the miR‐17 through 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.

Villunger A, Labi V, Bouillet P, Adams J and Strasser A (2012) Can the analysis of BH3‐only protein knockout mice clarify the issue of 'direct versus indirect' activation of Bax and Bak? Cell Death and Differentiation 18: 1545–1546.

Vousden KH and Lane DP (2007) p53 in health and disease. Nature Reviews. Molecular Cell Biology 8: 275–283.

Wang K, Yin X‐M, Chao DT, Milliman CL and Korsmeyer SJ (1996) BID: a novel BH3 domain‐only death agonist. Genes and Development 10: 2859–2869.

Wang P, Lindsay J, Owens TW, et al. (2014) Phosphorylation of the proapoptotic BH3‐only protein bid primes mitochondria for apoptosis during mitotic arrest. Cell Reports 7: 661–671.

Weber A, Heinlein M, Dengjel J, et al. (2016) The deubiquitinase Usp27x stabilizes the BH3‐only protein Bim and enhances apoptosis. EMBO Reports 17: 724–738.

Wiegmans AP, Alsop AE, Bots M, et al. (2011) Deciphering the molecular events necessary for synergistic tumor cell apoptosis mediated by the histone deacetylase inhibitor vorinostat and the BH3 mimetic ABT‐737. Cancer Research 71: 3603–3615.

Wree A, Johnson CD, Font‐Burgada J, et al. (2015) Hepatocyte‐specific Bid depletion reduces tumor development by suppressing inflammation‐related compensatory proliferation. Cell Death and Differentiation 22: 1985–1994.

Yamakuchi M, Ferlito M and Lowenstein CJ (2008) miR‐34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences of the United States of America 105: 13421–13426.

Yan J, Xiang J, Lin Y, et al. (2013) Inactivation of BAD by IKK inhibits TNFalpha‐induced apoptosis independently of NF‐kappaB activation. Cell 152: 304–315.

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.

Yin X‐M, Wang K, Gross A, et al. (1999) Bid‐deficient mice are resistant to Fas‐induced hepatocellular apoptosis. Nature 400: 886–891.

Further Reading

Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ and Green DR (2010) The BCL‐2 family reunion. Molecular Cell 37: 299–310.

Doerflinger M, Glab JA and Puthalakath H (2015) BH3‐only proteins: a 20‐year stock‐take. FEBS Journal 282: 1006–1016.

Galluzzi L, Bravo‐San Pedro JM, Vitale I, et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death and Differentiation 22: 58–73.

Green DR (2011) Means to an End, vol. 1. New York: Cold Spring Harbor Laboratory Press.

Kurokawa M and Kornbluth S (2009) Caspases and kinases in a death grip. Cell 138: 838–854.

Shacka JJ and Roth KA (2005) Regulation of neuronal cell death and neurodegeneration by members of the Bcl‐2 family: therapeutic implications. Current Drug Targets. CNS and Neurological Disorders 4: 25–39.

Sochalska M, Tuzlak S, Egle A and Villunger A (2015) Lessons from gain‐ and loss‐of‐function models of pro‐survival Bcl2 family proteins: implications for targeted therapy. FEBS Journal 282: 834–849.

Strasser A (2005) The role of BH3‐only proteins in the immune system. Nature Reviews. Immunology 5: 189–200.

Tait SW and Green DR (2013) Mitochondrial regulation of cell death. Cold Spring Harbor Perspectives in Biology 5 (9pii: a008706).

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Tuzlak, Selma, and Villunger, Andreas(Nov 2016) BH3‐Only Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021569.pub2]