Abstract
BH3-only BCL-2 family proteins are effectors of canonical mitochondrial apoptosis. They discharge their pro-apoptotic functions through BH1–3 pro-apoptotic proteins such as BAX and BAK, while their activity is suppressed by BH1–4 anti-apoptotic BCL-2 family members. The precise mechanism by which BH3-only proteins mediate apoptosis remains unresolved. The existing data are consistent with three mutually non-exclusive models (1) displacement of BH1–3 proteins from complexes with BH1–4 proteins; (2) direct interaction with and conformational activation of BH1–3 proteins; and (3) membrane insertion and membrane remodeling. The BH3-only proteins appear to play critical roles in restraining cancer and inflammatory diseases such as rheumatoid arthritis. Molecules that mimic the effect of BH3-only proteins are being used in treatments against these diseases. The cell death activity of a subclass of BH3-only members (BNIP3 and BNIP3L) is linked to cardiomyocyte loss during heart failure. In addition to their established role in apoptosis, several BH3-only members also regulate diverse cellular functions in cell-cycle regulation, DNA repair and metabolism. Several members are implicated in the induction of autophagy and autophagic cell death, possibly through unleashing of the BH3-only autophagic effector Beclin 1 from complexes with BCL-2/BCL-xL. The Chapters included in the current Oncogene Review issues provide in-depth discussions on various aspects of major BH3-only proteins.
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References
Akiyama T, Bouillet P, Miyazaki T, Kadono Y, Chikuda H, Chung UI et al. (2003). Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J 22: 6653–6664.
Arena V, Martini M, Luongo M, Capelli A, Larocca LM . (2003). Mutations of the BIK gene in human peripheral B-cell lymphomas. Genes Chromosomes Cancer 38: 91–96.
Bachmann PS, Gorman R, Mackenzie KL, Lutze-Mann L, Lock RB . (2005). Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor. Blood 105: 2519–2526.
Bae J, Leo CP, Hsu SY, Hsueh AJ . (2000). MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 275: 25255–25261.
Bai L, Ni HM, Chen X, DiFrancesca D, Yin XM . (2005). Deletion of Bid impedes cell proliferation and hepatic carcinogenesis. Am J Pathol 166: 1523–1532.
Baksh S, Tommasi S, Fenton S, Yu VC, Martins LM, Pfeifer GP et al. (2005). The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death. Mol Cell 18: 637–650.
Bessho T, Sancar A . (2000). Human DNA damage checkpoint protein hRAD9 is a 3′–5′ exonuclease. J Biol Chem 275: 7451–7454.
Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK . (2000). Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem 275: 22136–22146.
Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A et al. (2006). PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol Cell 21: 481–493.
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F 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, Strasser A . (2002). BH3-only proteins—evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 115: 1567–1574.
Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ 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.
Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B et al. (1994). Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79: 341–351.
Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD et al. (2005). High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res 65: 4088–4096.
Broustas CG, Gokhale PC, Rahman A, Dritschilo A, Ahmad I, Kasid U . (2004). BRCC2, a novel BH3-like domain-containing protein, induces apoptosis in a caspase-dependent manner. J Biol Chem 279: 26780–26788.
Bruick RK . (2000). Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97: 9082–9087.
Burton TR, Henson ES, Baijal P, Eisenstat DD, Gibson SB . (2006). The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. Int J Cancer 118: 1660–1669.
Cao X, Liu W, Lin F, Li H, Kolluri SK, Lin B et al. (2004). Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Mol Cell Biol 24: 9705–9725.
Cartron PF, Gallenne T, Bougras G, Gautier F, Manero F, Vusio P et al. (2004). The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol Cell 16: 807–818.
Castells A, Ino Y, Louis DN, Ramesh V, Gusella JF, Rustgi AK . (1999). Mapping of a target region of allelic loss to a 0.5-cM interval on chromosome 22q13 in human colorectal cancer. Gastroenterology 117: 831–837.
Chattopadhyay A, Chiang CW, Yang E . (2001). BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene 20: 4507–4518.
Chen GG, Lai PB, Chak EC, Xu H, Lee KM, Lau WY . (2001). Immunohistochemical analysis of pro-apoptotic Bid level in chronic hepatitis, hepatocellular carcinoma and liver metastases. Cancer Lett 172: 75–82.
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG et al. (2005). Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17: 393–403.
Chipuk JE, Green DR . (2008). How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18: 157–164.
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M et al. (2004). Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303: 1010–1014.
Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B et al. (1995). A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 14: 5589–5596.
Chou JJ, Li H, Salvesen GS, Yuan J, Wagner G . (1999). Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96: 615–624.
Claveria C, Torres M . (2003). Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators. Biochem Biophys Res Commun 304: 531–537.
Conradt B, Horvitz HR . (1998). 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.
Cristea IM, Degli Esposti M . (2004). Membrane lipids and cell death: an overview. Chem Phys Lipids 129: 133–160.
Czabotar PE, Lee EF, van Delft MF, Day CL, Smith BJ, Huang DC et al. (2007). Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA 104: 6217–6222.
Dai Z, Liu S, Marcucci G, Sadee W . (2006). 5-Aza-2′-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun 351: 455–461.
Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S . (2004). Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 64: 4286–4293.
Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM et al. (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424: 952–956.
Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ et al. (2008). Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14: 144–153.
Day CL, Smits C, Fan FC, Lee EF, Fairlie WD, Hinds MG . (2008). Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. J Mol Biol 380: 958–971.
Denisov AY, Chen G, Sprules T, Moldoveanu T, Beauparlant P, Gehring K . (2006). Structural model of the BCL-w-BID peptide complex and its interactions with phospholipid micelles. Biochemistry 45: 2250–2256.
Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ . (2000). Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10: 1201–1204.
Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT et al. (2007a). Unrestrained erythroblast development in Nix−/− mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci USA 104: 6794–6799.
Diwan A, Krenz M, Syed FM, Wansapura J, Ren X, Koesters AG et al. (2007b). Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117: 2825–2833.
Dorn II GW, Diwan A . (2008). The rationale for cardiomyocyte resuscitation in myocardial salvage. J Mol Med 86: 1085–1095.
Egle A, Harris AW, Bouillet P, Cory S . (2004). Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 101: 6164–6169.
Elangovan B, Chinnadurai G . (1997). Functional dissection of the pro-apoptotic protein Bik. Heterodimerization with anti-apoptosis proteins is insufficient for induction of cell death. J Biol Chem 272: 24494–24498.
Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y et al. (2001). Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem 44: 4313–4324.
Esposti MD, Erler JT, Hickman JA, Dive C . (2001). Bid, a widely expressed proapoptotic protein of the Bcl-2 family, displays lipid transfer activity. Mol Cell Biol 21: 7268–7276.
Feng W, Huang S, Wu H, Zhang M . (2007). Molecular basis of Bcl-xL's target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol 372: 223–235.
Fennell DA, Chacko A . (2008). Exploiting BH3 only protein function for effective cancer therapy. Front Biosci 13: 6682–6692.
Fernandez Y, Verhaegen M, Miller TP, Rush JL, Steiner P, Opipari Jr AW et al. (2005). Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res 65: 6294–6304.
Fernandez-Luna JL . (2008). Regulation of pro-apoptotic BH3-only proteins and its contribution to cancer progression and chemoresistance. Cell Signal 20: 1921–1926.
Fleischer A, Ayllon V, Dumoutier L, Renauld JC, Rebollo A . (2002). Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2. Oncogene 21: 3181–3189.
Garcia N, Salamanca F, Astudillo-de la Vega H, Curiel-Quesada E, Alvarado I, Penaloza R et al. (2005). A molecular analysis by gene expression profiling reveals Bik/NBK overexpression in sporadic breast tumor samples of Mexican females. BMC Cancer 5: 93.
Garcia-Saez AJ, Mingarro I, Perez-Paya E, Salgado J . (2004). Membrane-insertion fragments of Bcl-xL, Bax, and Bid. Biochemistry 43: 10930–10943.
Gartner A, Milstein S, Ahmed S, Hodgkin J, Hengartner MO . (2000). A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol Cell 5: 435–443.
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG et al. (2008). BAX activation is initiated at a novel interaction site. Nature 455: 1076–1081.
Giatromanolaki A, Koukourakis MI, Sowter HM, Sivridis E, Gibson S, Gatter KC et al. (2004). BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer. Clin Cancer Res 10: 5566–5571.
Gilley J, Coffer PJ, Ham J . (2003). FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162: 613–622.
Gillissen B, Essmann F, Hemmati PG, Richter A, Oztop I, Chinnadurai G et al. (2007). Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis. J Cell Biol 179: 701–715.
Grinberg M, Sarig R, Zaltsman Y, Frumkin D, Grammatikakis N, Reuveny E et al. (2002). tBID Homooligomerizes in the mitochondrial membrane to induce apoptosis. J Biol Chem 277: 12237–12245.
Gumienny TL, Lambie E, Hartwieg E, Horvitz HR, Hengartner MO . (1999). Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126: 1011–1022.
Guo B, Godzik A, Reed JC . (2001). Bcl-G, a novel pro-apoptotic member of the Bcl-2 family. J Biol Chem 276: 2780–2785.
Hacker G, Weber A . (2007). BH3-only proteins trigger cytochrome c release, but how? Arch Biochem Biophys 462: 150–155.
Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA et al. (2007). Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 14: 146–157.
Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ et al. (2001). Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA 98: 11318–11323.
Han J, Sabbatini P, White E . (1996). Induction of apoptosis by human Nbk/Bik, a BH3-containing protein that interacts with E1B 19K. Mol Cell Biol 16: 5857–5864.
Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJ . (2004). Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA 101: 15313–15317.
Hershko T, Ginsberg D . (2004). Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 279: 8627–8634.
Hetz C, Glimcher L . (2008). The daily job of night killers: alternative roles of the BCL-2 family in organelle physiology. Trends Cell Biol 18: 38–44.
Hinds MG, Day CL . (2005). Regulation of apoptosis: uncovering the binding determinants. Curr Opin Struct Biol 15: 690–699.
Hsu SY, Lin P, Hsueh AJ . (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. Mol Endocrinol 12: 1432–1440.
Huang DC, Strasser A . (2000). BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103: 839–842.
Hubner A, Barrett T, Flavell RA, Davis RJ . (2008). Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell 30: 415–425.
Hunter JJ, Bond BL, Parslow TG . (1996). Functional dissection of the human Bc12 protein: sequence requirements for inhibition of apoptosis. Mol Cell Biol 16: 877–883.
Hur J, Bell DW, Dean KL, Coser KR, Hilario PC, Okimoto RA et al. (2006). Regulation of expression of BIK proapoptotic protein in human breast cancer cells: p53-dependent induction of BIK mRNA by fulvestrant and proteasomal degradation of BIK protein. Cancer Res 66: 10153–10161.
Hur J, Chesnes J, Coser KR, Lee RS, Geck P, Isselbacher KJ et al. (2004). The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proc Natl Acad Sci USA 101: 2351–2356.
Imaizumi K, Tsuda M, Imai Y, Wanaka A, Takagi T, Tohyama M . (1997). Molecular cloning of a novel polypeptide, DP5, induced during programmed neuronal death. J Biol Chem 272: 18842–18848.
Inohara N, Ding L, Chen S, Nunez G . (1997). Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16: 1686–1694.
Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J et al. (2003). Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4: 321–328.
Kamer I, Sarig R, Zaltsman Y, Niv H, Oberkovitz G, Regev L et al. (2005). Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122: 593–603.
Kammouni W, Wong K, Ma G, Firestein GS, Gibson SB, El-Gabalawy HS . (2007). Regulation of apoptosis in fibroblast-like synoviocytes by the hypoxia-induced Bcl-2 family member Bcl-2/adenovirus E1B 19-kd protein-interacting protein 3. Arthritis Rheum 56: 2854–2863.
Karbowski M, Youle RJ . (2003). Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 10: 870–880.
Karst AM, Li G . (2007). BH3-only proteins in tumorigenesis and malignant melanoma. Cell Mol Life Sci 64: 318–330.
Kaufmann T, Tai L, Ekert PG, Huang DC, Norris F, Lindemann RK 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.
Kelekar A, Thompson CB . (1998). Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 8: 324–330.
Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T . (2001). Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2: 330–335.
Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH . (2004). BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med 199: 113–124.
Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M . (2003). Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 46: 4259–4264.
Kluck RM, Esposti MD, Perkins G, Renken C, Kuwana T, Bossy-Wetzel E et al. (1999). The pro-apoptotic proteins, Bid and Bax, cause a limited permeabilization of the mitochondrial outer membrane that is enhanced by cytosol. J Cell Biol 147: 809–822.
Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S et al. (2000). Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis. Nat Cell Biol 2: 1–6.
Krajewska M, Zapata JM, Meinhold-Heerlein I, Hedayat H, Monks A, Bettendorf H et al. (2002). Expression of Bcl-2 family member Bid in normal and malignant tissues. Neoplasia 4: 129–140.
Ku B, Woo JS, Liang C, Lee KH, Hong HS, E X et al. (2008). Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68. PLoS Pathog 4: e25.
Kudla G, Montessuit S, Eskes R, Berrier C, Martinou JC, Ghazi A et al. (2000). The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment. J Biol Chem 275: 22713–22718.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR et al. (2005). BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525–535.
Lama D, Sankararamakrishnan R . (2008). Anti-apoptotic Bcl-X(L) protein in complex with BH3 peptides of pro-apoptotic Bak, Bad, and Bim proteins: comparative molecular dynamics simulations. Proteins 73: 492–514.
Lanave C, Santamaria M, Saccone C . (2004). Comparative genomics: the evolutionary history of the Bcl-2 family. Gene 333: 71–79.
Lee JH, Soung YH, Lee JW, Park WS, Kim SY, Cho YG et al. (2004). Inactivating mutation of the pro-apoptotic gene BID in gastric cancer. J Pathol 202: 439–445.
Lee SH, Soung YH, Lee JW, Kim HS, Lee JH, Park JY et al. (2003). Mutational analysis of Noxa gene in human cancers. Apmis 111: 599–604.
Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ . (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183–192.
Leu JI, Dumont P, Hafey M, Murphy ME, George DL . (2004). Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6: 443–450.
Ley R, Ewings KE, Hadfield K, Cook SJ . (2005). Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ 12: 1008–1014.
Li H, Zhu H, Xu CJ, Yuan J . (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.
Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G et al. (1998). Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72: 8586–8596.
Lieberman HB, Hopkins KM, Nass M, Demetrick D, Davey S . (1996). A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene. Proc Natl Acad Sci USA 93: 13890–13895.
Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X et al. (2004). Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116: 527–540.
Liu H, Huang Q, Shi B, Eksarko P, Temkin V, Pope RM . (2006). Regulation of Mcl-1 expression in rheumatoid arthritis synovial macrophages. Arthritis Rheum 54: 3174–3181.
Liu H, Toman RE, Goparaju SK, Maceyka M, Nava VE, Sankala H et al. (2003a). Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 278: 40330–40336.
Liu X, Dai S, Zhu Y, Marrack P, Kappler JW . (2003b). The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity 19: 341–352.
Liu Z, Lu H, Jiang Z, Pastuszyn A, Hu CA . (2005). Apolipoprotein l6, a novel proapoptotic Bcl-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells. Mol Cancer Res 3: 21–31.
Lorand L, Graham RM . (2003). Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4: 140–156.
Losonczi JA, Olejniczak ET, Betz SF, Harlan JE, Mack J, Fesik SW . (2000). NMR studies of the anti-apoptotic protein Bcl-xL in micelles. Biochemistry 39: 11024–11033.
Lu Y, Lemon W, Liu PY, Yi Y, Morrison C, Yang P et al. (2006). A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med 3: e467.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.
Ma C, Ying C, Yuan Z, Song B, Li D, Liu Y et al. (2007). dp5/HRK is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons. J Biol Chem 282: 30901–30909.
Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA et al. (2007a). BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3: 374–376.
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P et al. (2007b). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26: 2527–2539.
Marani M, Tenev T, Hancock D, Downward J, Lemoine NR . (2002). Identification of novel isoforms of the BH3 domain protein Bim, which directly activate Bax to trigger apoptosis. Mol Cell Biol 22: 3577–3589.
Marshansky V, Wang X, Bertrand R, Luo H, Duguid W, Chinnadurai G 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. J Immunol 166: 3130–3142.
Matsui H, Asou H, Inaba T . (2007). Cytokines direct the regulation of Bim mRNA stability by heat-shock cognate protein 70. Mol Cell 25: 99–112.
McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D . (1999). Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell 96: 625–634.
Mestre-Escorihuela C, Rubio-Moscardo F, Richter JA, Siebert R, Climent J, Fresquet V et al. (2007). Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood 109: 271–280.
Michalak EM, Villunger A, Adams JM, Strasser A . (2008). In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ 15: 1019–1029.
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590.
Mok CL, Gil-Gomez G, Williams O, Coles M, Taga S, Tolaini M et al. (1999). Bad can act as a key regulator of T cell apoptosis and T cell development. J Exp Med 189: 575–586.
Morales AA, Olsson A, Celsing F, Osterborg A, Jondal M, Osorio LM . (2004). Expression and transcriptional regulation of functionally distinct Bmf isoforms in B-chronic lymphocytic leukemia cells. Leukemia 18: 41–47.
Mund T, Gewies A, Schoenfeld N, Bauer MK, Grimm S . (2003). Spike, a novel BH3-only protein, regulates apoptosis at the endoplasmic reticulum. FASEB J 17: 696–698.
Nakajima K, Hirose H, Taniguchi M, Kurashina H, Arasaki K, Nagahama M et al. (2004). Involvement of BNIP1 in apoptosis and endoplasmic reticulum membrane fusion. EMBO J 23: 3216–3226.
Nakamura M, Ishida E, Shimada K, Nakase H, Sakaki T, Konishi N . (2005). Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas. Acta Neuropathol 110: 402–410.
Nakano K, Vousden KH . (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7: 683–694.
Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI et al. (2006). The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Res 66: 6412–6420.
Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR et al. (2007). Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 104: 19512–19517.
Nikrad M, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS . (2005). The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther 4: 443–449.
Obata T, Toyota M, Satoh A, Sasaki Y, Ogi K, Akino K et al. (2003). Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Clin Cancer Res 9: 6410–6418.
Oberstein A, Jeffrey PD, Shi Y . (2007). Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 282: 13123–13132.
O'Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ et al. (2009). Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 113: 299–305.
O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S et al. (1998). Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17: 384–395.
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T et al. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288: 1053–1058.
Okami J, Simeone DM, Logsdon CD . (2004). Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res 64: 5338–5346.
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681.
Oltvai ZN, Milliman CL, Korsmeyer SJ . (1993). Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609–619.
Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.
Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J et al. (2000). Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 9: 2528–2534.
Pompeia C, Hodge DR, Plass C, Wu YZ, Marquez VE, Kelley JA et al. (2004). Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res 64: 3465–3473.
Ponassi R, Biasotti B, Tomati V, Bruno S, Poggi A, Malacarne D et al. (2008). A novel Bim-BH3-derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity. Cell Cycle 7: 3211–3224.
Porzio O, Massa O, Cunsolo V, Colombo C, Malaponti M, Bertuzzi F et al. (2007). Missense mutations in the TGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes. Mutation in brief no. 982. Online. Hum Mutat 28: 1150.
Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A . (1999). The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3: 287–296.
Puthalakath H, 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 Differ 9: 505–512.
Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE et al. (2001). Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293: 1829–1832.
Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V et al. (2005). Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 65: 6282–6293.
Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP et al. (2003). Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci USA 100: 9324–9329.
Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G . (2008). BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27: 1366–1375.
Real PJ, Sanz C, Gutierrez O, Pipaon C, Zubiaga AM, Fernandez-Luna JL . (2006). Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells. FEBS Lett 580: 5905–5909.
Regula KM, Ens K, Kirshenbaum LA . (2002). Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes. Circ Res 91: 226–231.
Reis PP, Rogatto SR, Kowalski LP, Nishimoto IN, Montovani JC, Corpus G et al. (2002). Quantitative real-time PCR identifies a critical region of deletion on 22q13 related to prognosis in oral cancer. Oncogene 21: 6480–6487.
Renshaw SA, Dempsey CE, Barnes FA, Bagstaff SM, Dower SK, Bingle CD et al. (2004). Three novel Bid proteins generated by alternative splicing of the human Bid gene. J Biol Chem 279: 2846–2855.
Rodolfo C, Mormone E, Matarrese P, Ciccosanti F, Farrace MG, Garofano E et al. (2004). Tissue transglutaminase is a multifunctional BH3-only protein. J Biol Chem 279: 54783–54792.
Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M et al. (2008). Essential role for Nix in autophagic maturation of erythroid cells. Nature 454: 232–235.
Sanz C, Mellstrom B, Link WA, Naranjo JR, Fernandez-Luna JL . (2001). Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic Hrk gene in hematopoietic progenitor cells. EMBO J 20: 2286–2292.
Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M et al. (1997). Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275: 983–986.
Scatizzi JC, Bickel E, Hutcheson J, Haines III GK, Perlman H . (2006). Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis. Arthritis Rheum 54: 3182–3193.
Scatizzi JC, Hutcheson J, Bickel E, Haines III GK, Perlman H . (2007). Pro-apoptotic Bid is required for the resolution of the effector phase of inflammatory arthritis. Arthritis Res Ther 9: R49.
Schendel SL, Azimov R, Pawlowski K, Godzik A, Kagan BL, Reed JC . (1999). Ion channel activity of the BH3 only Bcl-2 family member, BID. J Biol Chem 274: 21932–21936.
Schmitz R, Thomas RK, Harttrampf AC, Wickenhauser C, Schultze JL, Hansmann ML et al. (2006). The major subtypes of human B-cell lymphomas lack mutations in BCL-2 family member BAD. Int J Cancer 119: 1738–1740.
Schmutte C, Tombline G, Rhiem K, Sadoff MM, Schmutzler R, von Deimling A et al. (1999). Characterization of the human Rad51 genomic locus and examination of tumors with 15q14–15 loss of heterozygosity (LOH). Cancer Res 59: 4564–4569.
Schumacher B, Schertel C, Wittenburg N, Tuck S, Mitani S, Gartner A et al. (2005). C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ 12: 153–161.
Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC et al. (2007). NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci USA 104: 19500–19505.
Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA et al. (2002). A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2: 55–67.
Seo YW, Shin JN, Ko KH, Cha JH, Park JY, Lee BR et al. (2003). The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death. J Biol Chem 278: 48292–48299.
Shaw J, Kirshenbaum LA . (2008). Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy. Autophagy 4: 427–434.
Shaw J, Yurkova N, Zhang T, Gang H, Aguilar F, Weidman D et al. (2008). Antagonism of E2F-1 regulated Bnip3 transcription by NF-kappaB is essential for basal cell survival. Proc Natl Acad Sci USA 105: 20734–20739.
Shibue T, Suzuki S, Okamoto H, Yoshida H, Ohba Y, Takaoka A et al. (2006). Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. EMBO J 25: 4952–4962.
Shibue T, Takeda K, Oda E, Tanaka H, Murasawa H, Takaoka A et al. (2003). Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 17: 2233–2238.
Shibue T, Taniguchi T . (2006). BH3-only proteins: integrated control point of apoptosis. Int J Cancer 119: 2036–2043.
Shimizu S, Tsujimoto Y . (2000). Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity. Proc Natl Acad Sci USA 97: 577–582.
Shore GC, Viallet J . (2005). Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. Hematology Am Soc Hematol Educ Program, 226–230.
Sinha S, Colbert CL, Becker N, Wei Y, Levine B . (2008). Molecular basis of the regulation of Beclin 1-dependent autophagy by the gamma-herpesvirus 68 Bcl-2 homolog M11. Autophagy 4: 989–997.
Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL . (2001). HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61: 6669–6673.
St Onge RP, Udell CM, Casselman R, Davey S . (1999). The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Mol Biol Cell 10: 1985–1995.
Strohecker AM, Yehiely F, Chen F, Cryns VL . (2008). Caspase cleavage of HER-2 releases a Bad-like cell death effector. J Biol Chem 283: 18269–18282.
Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S et al. (2006). Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma. Cell Death Differ 13: 619–627.
Subramanian T, Vijayalingam S, Lomonosova E, Zhao LJ, Chinnadurai G . (2007). Evidence for involvement of BH3-only proapoptotic members in adenovirus-induced apoptosis. J Virol 81: 10486–10495.
Sunters A, Fernandez de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA et al. (2003). FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278: 49795–49805.
Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A 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 KO, Tan KM, Chan SL, Yee KS, Bevort M, Ang KC et al. (2001). MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains. J Biol Chem 276: 2802–2807.
Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P et al. (2005). Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7: 227–238.
Tang G, Ding K, Nikolovska-Coleska Z, Yang CY, Qiu S, Shangary S et al. (2007). Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic Bcl-2 proteins. J Med Chem 50: 3163–3166.
Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P, Macleod KF . (2007). BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 27: 6229–6242.
Tsai SC, Pasumarthi KB, Pajak L, Franklin M, Patton B, Wang H et al. (2000). Simian virus 40 large T antigen binds a novel Bcl-2 homology domain 3-containing proapoptosis protein in the cytoplasm. J Biol Chem 275: 3239–3246.
Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J et al. (2001). Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 3: 183–191.
U M, Miyashita T, Shikama Y, Tadokoro K, Yamada M . (2001). Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family. FEBS Lett 509: 135–141.
van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. (2006). The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10: 389–399.
Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S et al. (2000). BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20: 5454–5468.
Verma S, Zhao LJ, Chinnadurai G . (2001). Phosphorylation of the pro-apoptotic protein BIK: mapping of phosphorylation sites and effect on apoptosis. J Biol Chem 276: 4671–4676.
Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ et al. (2003). p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036–1038.
Vogler M, Dinsdale D, Dyer MJ, Cohen GM . (2009). Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 16: 360–367.
Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA . (2008). Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death. J Biol Chem 283: 21540–21549.
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F et al. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284: 339–343.
Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ . (1996). BID: a novel BH3 domain-only death agonist. Genes Dev 10: 2859–2869.
Wang Z, Malone MH, He H, McColl KS, Distelhorst CW . (2003). Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem 278: 23861–23867.
Wang Z, Sun Y . (2008). Identification and characterization of two splicing variants of human Noxa. Anticancer Res 28: 1667–1674.
Weber A, Paschen SA, Heger K, Wilfling F, Frankenberg T, Bauerschmitt H et al. (2007). BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins. J Cell Biol 177: 625–636.
Wick W, Petersen I, Schmutzler RK, Wolfarth B, Lenartz D, Bierhoff E et al. (1996). Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. Oncogene 12: 973–978.
Willis SN, Adams JM . (2005). Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17: 617–625.
Wolff S, Erster S, Palacios G, Moll UM . (2008). p53's mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell Res 18: 733–744.
Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J et al. (2008). Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9: 405–414.
Xie X, Xia W, Li Z, Kuo HP, Liu Y, Ding Q et al. (2007). Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models. Cancer Cell 12: 52–65.
Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R, Hosokawa H et al. (2008). Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. J Exp Med 205: 1109–1120.
Yan N, Gu L, Kokel D, Chai J, Li W, Han A et al. (2004). Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell 15: 999–1006.
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ . (1995). Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80: 285–291.
Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B et al. (1999). Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400: 886–891.
Yoshida K, Komatsu K, Wang HG, Kufe D . (2002). c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage. Mol Cell Biol 22: 3292–3300.
You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M et al. (2006). FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 203: 1657–1663.
Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L et al. (2006). Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8: 1124–1132.
Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L . (2003). PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci USA 100: 1931–1936.
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B . (2001). PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7: 673–682.
Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC et al. (2002). Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8: 725–730.
Zeng X, Overmeyer JH, Maltese WA . (2006). Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J Cell Sci 119: 259–270.
Zha H, Aime-Sempe C, Sato T, Reed JC . (1996a). 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.
Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ . (1997). BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J Biol Chem 272: 24101–24104.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ . (1996b). 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.
Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ . (2000). Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290: 1761–1765.
Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB et al. (2008). Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283: 10892–10903.
Zhang H, Heim J, Meyhack B . (1999). Novel BNIP1 variants and their interaction with BCL2 family members. FEBS Lett 448: 23–27.
Zhong Q, Gao W, Du F, Wang X . (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121: 1085–1095.
Zhou XM, Liu Y, Payne G, Lutz RJ, Chittenden T . (2000). Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem 275: 25046–25051.
Zhu H, Zhang L, Dong F, Guo W, Wu S, Teraishi F et al. (2005). Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 24: 4993–4999.
Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ . (2005). A role for proapoptotic BID in the DNA-damage response. Cell 122: 579–591.
Zinkel SS, Ong CC, Ferguson DO, Iwasaki H, Akashi K, Bronson RT et al. (2003). Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev 17: 229–239.
Acknowledgements
GC received grant support from the National Cancer Institute Grants CA-33616, CA-116262 and CA-73803. We thank John Tavis, Ling-jun Zhao and Carolyn Mulhall for reading the paper.
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Lomonosova, E., Chinnadurai, G. BH3-only proteins in apoptosis and beyond: an overview. Oncogene 27 (Suppl 1), S2–S19 (2008). https://doi.org/10.1038/onc.2009.39
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