This timeline of cell death (Figure 1), illustrates how independent strands of research coalesced in the field known as apoptosis – currently the hottest field of biological research. Although the fact that cells die during normal development was recognized over 150 years ago,1 this was forgotten, only to be re-discovered several times until the influential review by Glucksmann in 1951.2 Even after this time, up until the late 1980's, study of physiological cell death processes, in which an organism's cells activate intrinsic mechanisms for the purpose of killing themselves, remained relatively obscure, usually with less than 10 papers published each year.
Initially, analysis of cell death was mainly morphological, and between the late 1800's and 1960's elegant figures were published illustrating the light (see reviews by Clarke and Clarke and Lockshin)82,83 and electron microscopic3 features of cell death, such as cell shrinkage, chromatin condensation, break-up of the cell and its engulfment.
Even well after the proposal of the term ‘apoptosis’ for cell death in 1972,8 interest remained low. The ‘modern’ era of cell death research, and the explosion of interest in the field, came with the identification of the biochemical and genetic processes that implement it, beginning with recognition of the first component of the cell death system, Bcl-2, in 1988.20 Since then, growth of the field has been exponential, and currently over 200 publications appear every week that refer to ‘apoptosis’. A genetic understanding of cell death has primarily come from study of C. elegans, in which 131 of the 1090 somatic cells formed in the hermaphrodite are fated to die during development.16 This started with the recognition of cell death in the worm in 1976,11 and generation of the first ced (cell death abnormal) mutants in 1983.14 In 1982, in a journal that unfortunately folded soon after, a paper appeared providing evidence that cell deaths in the worm were caused by a process that was specific for cell death, and had no other role, indicating that cell death in the worm is an active process whose only purpose is to remove unwanted cells.13 Similar conclusions were reached earlier in vertebrate systems, such as when Tata showed that cell deaths during tadpole metamorphosis could be inhibited by cycloheximide, and therefore required the cell's own proteins.6
At this time, the term most commonly used for the study of these cell death was ‘programmed cell death’, first used in 1965 to describe developmental cell deaths in insect systems by Lockshin and Williams.5 The term ‘apoptosis’ was proposed in 1972 by Kerr and colleagues,8 who realized that the morphology of cells dying due to toxins or hormones resembled that described for developmental cell death by Glucksmann.2 For Kerr, this did not mark the beginning of apoptosis research, because he had been studying it continuously since his first publication on cell death in 1965;4 rather, it marked the adoption of a new terminology, because until then he had used the terms such as ‘shrinkage necrosis’.
The first marker of physiological cell death that did not rely on morphology came with the recognition that cell death is usually accompanied by rapid activation of endonucleases.10 Subsequently, ‘ladders’ seen after electrophoresis of cleaved DNA9 were specifically associated with apoptosis.12 It took a further 17 years to identify the major endonuclease responsible (DFF/CAD).63,64 The observation that phosphatidyl serine is exposed on dying cells32 provided another convenient marker of apoptosis, and also gave an early lead into how dead cells are recognized prior to their engulfment. Although genetic analysis of cell death progressed most rapidly in the worm, with identification of more and more ced mutant lines,16,29 biochemical analysis of cell death was faster in mammals. While Bcl-2 was cloned in 1986,17,18 and its role in cell death was established in 1988,20 the first ced gene to be cloned and sequences was ced-4 in 1992.31
Comparisons of the morphological and anatomical features of developmental cell deaths in invertebrates and vertebrates have been made since 1969,7 but unification of the molecular processes of cell death did not occur until 1992, when it was shown that the human bcl-2 gene could inhibit developmental cell death in the worm.30 This united ‘apoptosis’ in vertebrates with ‘programmed cell death’ in invertebrates, showing them to be the same, evolutionarily conserved process, and it meant that discoveries based on genetics in C. elegans could be applied to analysis of apoptosis in mammalian cells.
While Bcl-2 was the first component of the apoptosis mechanism to be recognized, it had been cloned not because it was a cell death gene, but because it is translocated in follicular lymphoma, one of the most common cancers of blood cells in humans. Initially, it was assumed that bcl-2 may be like other oncogenes involved in translocations, such as abl and c-myc, and be a promoter of cell proliferation, but it turned out that when bcl-2 was over-expressed, it did not stimulate cell division, but prevented cells from dying when growth factor was removed.20 These experiments therefore not only identified Bcl-2 as a component of the apoptosis mechanism, but showed that inhibition of cell death could ultimately lead to cancer in humans. The realization that one of the roles of p53, the most commonly mutated gene in human cancers, is to cause apoptosis,25 further emphasized this link, as did the demonstration that p53 causes apoptosis via the mechanism that can be blocked by Bcl-2.84 Bcl-2 also provided the first experimental evidence linking inhibition of cell death with autoimmune disease, when it turned out that on certain genetic backgrounds transgenic mice expressing bcl-2 in their lymphocytes developed a disease resembling systemic lupus erythematosus.23 This link was further strengthened when the gene altered in lpr mice, which also develop a lupus-like autoimmune syndrome, turned out to be CD95 (Fas/APO-1),33 a TNF receptor family member24 that was known to signal apoptosis when crosslinked by antibodies.21,22 Furthermore, mice lacking bim, which encodes a so-called ‘BH3 only’ pro-apoptotic Bcl-2 homologue, also develop autoimmune disease.76
The effector proteases of apoptosis, now known as caspases, were first recognized when the ced-3 gene, which is essential for programmed cell death in the worm,16 was cloned and sequenced,35,36 and found to resemble the mammalian gene for the cysteine protease interleukin 1β converting enzyme, which had been cloned in 1992.85,86 Crystallography revealed that active caspases are heterotetramers formed from inactive zymogens.41,42 This focussed interest on what activates caspases, and what inhibits them.
Key findings have included the elucidation of a caspase activation pathway that originates in the plasma membrane, and proceeds from CD95, via the adaptor FADD, to activate caspase 8,44,45,57,58 and the findings that in C. elegans the adaptor CED-4 directly binds to and activates the caspase CED-3.67,68,70,71 Identification of mammalian homologues of these proteins (Apaf-1 and caspase 9)60,87 showed that a similar pathway operates in mammals, and revealed cytochrome c to be a molecule capable of activating Apaf-1.59 Many of the interactions between these cell death molecules involve related protein-protein interaction motifs termed death domains, death effector domains and caspase recruitment domains.62
While it is clear that anti-apoptotic Bcl-2 like proteins act upstream of caspases to prevent their activation, and pro-apoptotic Bcl-2 family members such as Bax34 promote caspase activity, debate remains about exactly how they work. Biochemical experiments using C. elegans proteins have suggested that CED-9 (the worm homologue of Bcl-2) inhibits cell death by directly binding to CED-4,65,66,67,68,69 but it is unclear whether similar direct interactions occur between their mammalian counterparts.
Solving the structure of Bcl-x,56 a Bcl-2 family member, raised the alternative possibility that these proteins act as membrane pores or ion channels, to somehow influence release of pro-apoptotic molecules such as cytochrome c from the mitochondria. From both structural studies, and genetics in C. elegans, it is, however, clear that anti-apoptotic Bcl-2 family members can be bound, and antagonized by, ‘BH3 only’ proteins such as Bim and Noxa in mammals,76,88 and EGL-1 in the worm,74 thus increasing the likelihood that a cell will undergo apoptosis. BH3 only proteins are key determinants of cell death in worms and vertebrates. All somatic developmental cell death in C. elegans require EGL-1,74 and in mammals p53-dependent apoptosis seems to be signalled in large part via Noxa.88 The discovery that the helical BH3 domain of one Bcl-2 family member can bind to a hydrophobic pocket on the surface of another73 has helped explain how pro-death Bcl-2 family proteins antagonize their anti-apoptotic cousins.
Not all physiological cell deaths in animals are cell autonomous (i.e. cell ‘suicide’), sometimes one cell kills another cell (i.e. cell ‘murder’). In C. elegans, death of the male linker cell is non-cell autonomous,16 and in mammals, cytotoxic T cells (CTL) kill other host cells, especially those infected by viruses. Targets of CTL killing display the characteristic features of apoptosis,89 and it became clear why when the mechanisms involved in CTL killing were elucidated. CTL can kill by perforin-dependent, granule exocotysis, which involves granzyme B, a serine protease with a similar substrate specificity to the caspases,27,28 or via CD95L-CD95 interactions, which activate caspase 8.57,58 Knowledge of the enzymes involved in CTL killing therefore allowed unification of cell autonomous and non-cell autonomous cell deaths, and explained the shared apoptotic appearances.37
CTL killing illustrates the role of apoptosis in defense against viruses. But viruses have been selected that carry inhibitors of apoptosis. Several direct inhibitors of caspase activity were first found in viruses, and for some, cellular homologues were later identified. The first caspase inhibitor found was CrmA, a product of cowpox virus that was known to inhibit interleukin 1β converting enzyme (caspase 1),90 but is now known to also inhibit caspase 8, and thereby can block CD95 and TNFR signalled apoptosis.91 The gene for p35 was first found in baculoviruses,26 as were the first inhibitor of apoptosis (IAP) genes.40 Both p35 and IAPs act by binding directly to, and thereby inhibiting, active caspases.48,61 Several mammalian IAP homologues have been discovered,49,50,51,52,53,54 and one, c-IAP2, is commonly translocated in MALT lymphomas, where it is expressed as a fusion with the MLT/paracaspase gene product.75,79
In insects three different proteins, Reaper, HID and Grim,39,55,92 promote apoptosis by antagonizing the IAPs,72 and a mammalian protein, Smac/Diablo, has been found that inhibits mammalian IAPs in a similar way.77,78 The identification of a similar BIR-interacting N-terminal motif in processed caspase 9 revealed how Smac/Diablo can displace caspase 9 from IAPs.81 A tremendous effort is now being expended to discover even more about how apoptosis works, and to resolve some of the controversies that remain. It is still not clear how Bcl-2 family members work, or how cytokines prevent default activation of the cell death mechanisms, or even whether in mammalian cells prevention of caspase activity will allow long-term survival. The answers to such questions are not trivial, but will determine to what extent these wonderful, yet curiously delayed, discoveries in basic science will be easily applied to the development of novel therapeutic agents for the treatment of diseases in which cell death fails to occur or occurs inappropriately. The first non-peptide caspase inhibitory drugs are proving useful in animal models of sepsis,80 suggesting apoptosis-based therapies are not far away.
References
Vogt C . 1842 Untersuchungen uber die Entwicklungsgeschichte der Geburtshelerkroete (Alytes obstetricians) Solothurn: Jent und Gassman pp 130
Glucksmann A . 1951 Cell deaths inn normal vertebrate ontogeny Biol. Rev 26: 59–86
Bellairs R . 1961 Cell death in chick embryos as studied by electron microscopy J. Anat 95: 54–60
Kerr J . 1965 A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes J. Pathol. Bacteriol 90: 419–435
Lockshin R, Williams C . 1965 Programmed cell death. II. Endocrine presentation of the breakdown of the intersegmental muscles of silkworms J. Insect Physiol 11: 803–809
Tata JR . 1966 Requirement for RNA and protein synthesis for induced regression of the tadpole tail in organ culture Dev. Biol 13: 77–94
Whitten JM . 1969 Cell death during early morphogenesis: parallels between insect limb and vertebrate limb development Science 163: 1456–1457
Kerr JF, Wyllie AH, Currie AR . 1972 Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics Br. J. Cancer 26: 239–257
Hewish DR, Burgoyne LA . 1973 Chromatin sub-structure. The digestion of chromatin DNA at regularly spaced sites by a nuclear deoxyribonuclease Biochem. Biophys. Res. Comm 52: 504–510
Williams JR, Little JB, Shipley WU . 1974 Association of mammalian cell death with a specific endonucleolytic degradation of DNA Nature 252: 754–755
Sulston JE . 1976 Post-embryonic development in the ventral cord of Caenorhabditis elegans Philosoph. Trans. Roy. Soc. Lond. Series B: Biological Sci 275: 287–297
Wyllie AH . 1980 Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation Nature 284: 555–556
Horvitz HR, Ellis HM, Sternberg PW . 1982 Programmed cell death in nematode development Neurosci. Comment 1: 56–65
Hedgecock EM, Sulston JE, Thomson JN . 1983 Mutations affecting programmed cell deaths in the nematode Caenorhabditis elegans Science 220: 1277–1279
Duke RC, Cohen JJ . 1986 IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells Lymphokine Res 5: 289–299
Ellis HM, Horvitz HR . 1986 Genetic control of programmed cell death in the nematode C. elegans Cell 44: 817–829
Tsujimoto Y, Croce CM . 1986 Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma Proc. Natl. Acad. Sci. USA 83: 5214–5218
Cleary ML, Smith SD, Sklar J . 1986 Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation Cell 47: 19–28
Pearson GR, Luka J, Petti L, Birkenbach M, Braun D, Kieff E . 1987 Identification of an Epstein-Barr virus early gene encoding a second component of the restricted early antigen complex Virology 160: 151–161
Vaux DL, Cory S, Adams JM . 1988 Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells Nature 355: 440–442
Yonehara S, Ishii A, Yonehara M . 1989 A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor J. Exp. Med 169: 1747–1756
Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, Debatin KM, Krammer PH . 1989 Monoclonal antibody-mediated tumor regression by induction of apoptosis Science 245: 301–305
Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S, Harris AW . 1991 Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease Proc. Natl. Acad. Sci. USA 88: 8661–8665
Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S . 1991 The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis Cell 66: 233–243
Yonish RE, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M . 1991 Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6 Nature 353: 345–347
Clem RJ, Fechheimer M, Miller LK . 1991 Prevention of apoptosis by a baculovirus gene during infection of insect cells Science 254: 1388–1390
Poe M, Blake JT, Boulton DA, Gammon M, Sigal NH, Wu JK, Zweerink HJ . 1991 Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity J. Biol. Chem 266: 98–103
Odake S, Kam CM, Narasimhan L, Poe M, Blake JT, Krahenbuhl O, Tschopp J, Powers JC . 1991 Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins Biochemistry 30: 2217–2227
Hengartner MO, Ellis RE, Horvitz HR . 1992 Caenorhabditis elegans gene ced-9 protects cells from programmed cell death Nature 356: 494–499
Vaux DL, Weissman IL, Kim SK . 1992 Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2 Science 258: 1955–1957
Yuan J, Horvitz HR . 1992 The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death Development 116: 309–320
Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM . 1992 Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages J. Immunol 148: 2207–2216
Watanabe FR, Brannan CI, Copeland NG, Jenkins NA, Nagata S . 1992 Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis Nature 356: 314–317
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
Miura M, Zhu H, Rotello R, Hartweig EA, Yuan J . 1993 Induction of apoptosis in fibroblasts by IL-1_-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3 Cell 75: 653–660
Yuan JY, Shaham S, Ledoux S, Ellis HM, Horvitz HR . 1993 The C. elegans cell death gene ced 3 encodes a protein similar to mammalian interleukin 1 beta converting enzyme Cell 75: 641–652
Vaux DL, Haecker G, Strasser A . 1994 An evolutionary perspective on apoptosis Cell 76: 777–779
Hengartner MO, Horvitz HR . 1994 C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2 Cell 76: 665–676
White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H . 1994 Genetic control of programmed cell death in Drosophila Science 264: 677–683
Birnbaum MJ, Clem RJ, Miller LK . 1994 An apoptosis inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motoif J. Virol 68: 2521–2528
Walker NPC, Talanian RV, Brady KD, Dang LC, NJ B, Ferenz CR, Franklin S, Ghayur T, Hackett MC, Hamill LD, Herzog L, Hugunin M, Houy W, Mankovich JA, McGuiness L, Orlewicz E, Paskind M, Pratt CA, Reis P, Summani A, Terranova M, Welch JP, Xiong L, Möller A, Tracey DE, Kamen R, Wong WW . 1994 Cystal structure of the cysteine protease interleukin-1-β-converting enzyme: A (p20/p10)2 homodimer Cell 78: 343–352
Wilson KP, Black J, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA, Livingston DJ . 1994 Structure and mechanism of interleukin-1-beta converting enzyme Nature 370: 270–275
Alderson MR, Tough TW, Davis ST, Braddy S, Falk B, Schooley KA, Goodwin RG, Smith CA, Ramsdell F, Lynch DH . 1995 Fas ligand mediates activation-induced cell death in human T lymphocytes J. Exp. Med 181: 71–77
Tewari M, Dixit VM . 1995 Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product J. Biol. Chem 270: 3255–3260
Enari M, Hug H, Nagata S . 1995 Involvement of an ICE-like protease in Fas-mediated apoptosis Nature 375: 78–81
Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D . 1995 A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain J. Biol. Chem 270: 7795–7798
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM . 1995 FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis Cell 81: 505–512
Xue D, Horvitz HR . 1995 Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein Nature 377: 248–251
Roy N, Mahadevan MS, Mclean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besnerjohnston A, Lefebvre C, Kang XL, Salih M, Aubry H, Tamai K, Guan XP, Ioannou P, Crawford TO, Dejong PJ, Surh L, Ikeda JE, Korneluk RG, Mackenzie A . 1995 The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy Cell 80: 167–178
Hay BA, Wassarman DA, Rubin GM . 1995 Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death Cell 83: 1253–1262
Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV . 1995 The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral-inhibitor of apoptosis proteins Cell 83: 1243–1252
Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL . 1996 Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors Proc. Natl. Acad. Sci. USA 93: 4974–4978
Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Chertonhorvat G, Farahani R, Mclean M, Ikeda JE, Mackenzie A, Korneluk RG . 1996 Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes Nature 379: 349–353
Duckett CS, Nava VE, Gedrich RW, Clem RJ, Vandongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB . 1996 A conserved family of cellular genes related to the baculovirus IAP gene and encoding apoptosis inhibitors EMBO J 15: 2685–2694
Grether ME, Abrams JM, Agapite J, White K, Steller H . 1995 The head involution defective gene of Drosophila melanogaster functions in programmed cell death Genes Dev 9: 1694–1708
Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SC, Fesik SW . 1996 X-ray and NMR structure of human Bcl-x(1), an inhibitor of programmed cell death Nature 381: 335–341
Boldin MP, Goncharov TM, Goltsev YV, Wallach D . 1996 Involvement of MACH, a novel MORTI/FADD-interacting protease, in Fas/APO-1 and TNF receptor-induced cell death Cell 85: 803–815
Muzio M, Chinnaiyan AM, Kischkel FC, Orourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM . 1996 FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex Cell 85: 817–827
Liu XS, Kim CN, Yang J, Jemmerson R, Wang XD . 1996 Induction of apoptotic program in cell-free extracts – requirement for dATP and cytochrome c Cell 86: 147–157
Zou H, Henzel WJ, Liu XS, Lutschg A, Wang XD . 1997 Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 Cell 90: 405–413
Deveraux QL, Takahashi R, Salvesen GS, Reed JC . 1997 X-linked IAP is a direct inhibitor of cell-death proteases Nature 388: 300–304
Hofmann K, Bucher P, Tschopp J . 1997 The CARD domain – a new apoptotic signalling motif Trends Biochem. Sci 22: 155–156
Liu XS, Zou H, Slaughter C, Wang XD . 1997 DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis Cell 89: 175–184
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S . 1998 A caspase-activated DNAse that degrades DNA during apoptosis, and its inhibitor ICAD Nature 391: 43–50
Spector MS, Desnoyers S, Hoeppner DJ, Hengartner MO . 1997 Interaction between the C. elegans cell-death regulators CED-9 and CED-4 Nature 385: 6553–656
James C, Gschmeissner S, Fraser A, Evan GI . 1997 CED-4 induces chromatin condensation in Schizosaccharomyces pombe and is inhibited by direct physical association with CED-9 Curr. Biol 7: 246–252
Wu DY, Wallen HD, Nunez G . 1997 Interaction and regulation of subcellular localization of CED-4 by CED-9 Science 275: 1126–1129
Chinnaiyan AM, O'Rourke K, Lane BR, Dixit VM . 1997 Interaction of CED-4 with CED-3 and CED-9 – a molecular framework for cell death Science 275: 1122–1126
Ottilie S, Wang Y, Banks S, Chang J, Vigna NJ, Weeks S, Armstrong RC, Fritz LC, Oltersdorf T . 1997 Mutational analysis of the interacting cell death regulators CED-9 and CED-4 Cell Death Differ 4: 526–533
Seshagiri S, Miller LK . 1997 Caenorhabditis elegans CED-4 stimulates CED-3 processing and CED-3-induced apoptosis Curr. Biol 7: 455–460
Irmler M, Hofmann K, Vaux DL, Tschopp J . 1997 Direct physical interaction between the Caenorhabditis elegans death proteins CED-3 and CED-4 FEBS Lett 406: 189–190
Vucic D, Kaiser WJ, Harvey AJ, Miller LK . 1997 Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs) Proc. Natl. Acad. Sci. USA 94: 10183–10188
Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW . 1997 Structure of Bcl-x(l)-Bak peptide complex – recognition between regulators of apoptosis Science 275: 983–986
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
Dierlamm J, Baens M, Woldarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P . 1999 The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas Blood 93: 3601–3609
Bouillet P, Metcalf D, Huang DCS, Tarlinton DM, Kay TWH, Kontgen F, Adams JM, Strasser A . 1999 Proapoptotic Bcl-2 relative BIM required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity Science 286: 1735–1738
Du CY, Fang M, Li YC, Li L, Wang XD . 2000 Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition Cell 102: 33–42
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL . 2000 Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins Cell 102: 43–53
Uren AG, O'Rourke K, Aravind L, Pisabarro MT, Seshagiri S, Koonin EV, Dixit VM . 2000 Identification of paracaspases and metacaspases: Two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma Molec. Cell 6: 961–967
Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson DW, Karl IE . 2000 Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte Nat. Immunol 1: 496–501
Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai JJ, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi YG, Alnemri ES . 2001 A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis Nature 410: 112–116
Clarke PG, Clarke S . 1996 Nineteenth century research on naturally occurring cell death and related phenomena Anat. Embryol 193: 81–99
Lockshin RA . 1997 The early modern period in cell death Cell Death Differ 4: 347–351
Chiou SK, Rao L, White E . 1994 Bcl 2 blocks p53 dependent apoptosis Mol. Cell. Biol 14: 2556–2563
Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J, Elliston KO, Ayala JM, Casano FJ, Chin J, Ding GJ, Egger LA, Gaffney EP, Limjuco G, Paylha OC, Raju SM, Rolando AM, Salley JP, Yanin TT, Lee TD, Shively JE, MacCross JE, Mumford RA, Schmidt JA, Tocci MJ . 1992 A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes Nature 356: 768–774
Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van NK, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, Huebner K, Black RA . 1992 Molecular cloning of the interleukin-1 beta converting enzyme Science 256: 97–100
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang XD . 1997 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade Cell 91: 479–489
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N . 2000 Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis Science 288: 1053–1058
Clouston WM, Kerr JF . 1985 Apoptosis, lymphocytotoxicity and the containment of viral infections Med. Hypoth 18: 399–404
Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, Pickup DJ . 1992 Viral inhibition of inflammation: Cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme Cell 69: 597–604
Muzio M, Salvesen GS, Dixit VM . 1997 FLICE induced apoptosis in a cell-free system – cleavage of caspase zymogens J. Biol. Chem 272: 2952–2956
Chen P, Nordstrom W, Gish B, Abrams JM . 1996 Grim, a novel cell death gene in Drosophila Genes Deve 10: 1773–1782
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Vaux, D. Apoptosis Timeline. Cell Death Differ 9, 349–354 (2002). https://doi.org/10.1038/sj.cdd.4400990
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DOI: https://doi.org/10.1038/sj.cdd.4400990
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