Cell Death: The Significance of Apoptosis

Wyllie, Andrew H.; Kerr, Judith; Currie, A. R.

doi:10.1016/s0074-7696(08)62312-8

Cited by 6,635 publications

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“…Apoptotic (or programmed) cell death, on the other hand, is considered quiescent and noninflammatory, and is generally thought of as more physiological than pathological. 22 Apoptosis is involved in both tissue differentiation and organ homeostasis and is of particular relevance to the immune system, as exemplified by thymocyte death during negative selection, as well as by death induced in virally infected cells by the action of granzymes released by CD8 þ T lymphocytes. Since apoptotic death is so central to organismal well being, mechanisms that mediate recognition and phagocytosis of apoptotic debris have co-evolved.…”

Section: Discussionmentioning

confidence: 99%

“…5 Cells undergoing apoptosis manifest a number of morphological and biochemical changes, including membrane blebbing, modification in plasma membrane configuration, cytoplasmic contraction and packaging of cytoplasmic proteins into membrane-bound vesicles. 22 Apoptotic cell specific molecular patterns (ACAMPs), comprising prominent autoantigens (such as DNA, histones and the ribonucleoprotiens Ro and La), appear upon membrane blebs in advance of cellular lysis and are readily accessible by specific autoreactive antibodies. 23 These appear to segregate into two different populations on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

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Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

et al. 2006

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Apoptotic cells are considered an important auto-antigenic source in diseases such as systemic lupus erythematosus (SLE). A human monoclonal antibody demonstrating exquisite specificity towards late-stage apoptotic cells was generated from an SLE patient. Polyreactive recognition of ribonucleoproteins Ro52 and Ro60 was observed. The antibody significantly diminished the phagocytosis of apoptotic cells and a concomitant decrease in transforming growth factor-b (TGF-b) secretion was observed. Light and heavy chain sequencing revealed the antibody to be in essentially germline configuration. Elicited anti-idiotypic antibodies bound distinct self-antigens and showed augmented reactivity towards apoptotic cells as well. Thus, near-germline encoded antibodies recognizing antigens externalized during the process of apoptosis can mediate a variety of potentially pathogenic effects; decreases in the phagocytic uptake of dying cells would constitute a disease-perpetuating event and stimulation of the idiotypic network could lead to intermolecular epitope spreading, increasing the range of molecular targets.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

et al. 2006

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“…1,2 This mode of death is critical for normal development as well as the maintenance of cellular homeostasis. 3 On the molecular level, members of a family of cysteine proteases, designated caspases, are responsible for programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

et al. 2004

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The activation of caspase-3 represents a critical step in the pathways leading to the biochemical and morphological changes that underlie apoptosis. Upon induction of apoptosis, the large (p17) and small (p12) subunits, comprising active caspase-3, are generated via proteolytic processing of a latent proenzyme dimer. Two copies of each individual subunit are generated to form an active heterotetramer. The tetrameric form of caspase-3 cleaves specific protein substrates within the cell, thereby producing the apoptotic phenotype. In contrast to the proenzyme, once activated in HeLa cells, caspase-3 is difficult to detect due to its rapid degradation. Interestingly, however, enzyme stability and therefore detection of active caspase-3 by immunoblot analysis can be restored by treatment of cells with a peptide-based caspase-3 selective inhibitor, suggesting that the active form can be stabilized through protein-inhibitor interaction. The heteromeric active enzyme complex is necessary for its stabilization by inhibitors, as expression of the large subunit alone is not stabilized by the presence of inhibitors. Our results show for the first time, that synthetic caspase inhibitors not only block caspase activity, but may also increase the stability of otherwise rapidly degraded mature caspase complexes. Consistent with these findings, experiments with a catalytically inactive mutant of caspase-3 show that rapid turnover is dependent on the activity of the mature enzyme. Furthermore, turnover of otherwise stable active site mutants of capase-3 is rescued by the presence of the active enzyme suggesting that turnover can be mediated in trans.

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“…i) The in situ nick translation assay employing labeled triphosphonucleotides can be used to reveal DNA strand breaks, to detect the very early stages of apoptosis. The data presented indicate that flow cytometry can be applied in basic research on molecular and biochemical mechanisms of apoptosis, as well as in the clinic, where the ability to monitor early signs of apoptosis in samples from patients' tu- Key terms: Programmed cell death, DNA topoisomerases, DNA degradation, mitochondria, lysosomes, chromatin I. APOPTOSIS, PROGRAMMED CELL DEATH, AND NECROSIS The term apoptosis is used to describe the characteristic mode of cell death common to various cell types and often triggered by diverse environmental stimuli (2,36, 37,59,60). During this process, a cascade of specific biochemical events, the most prominent of which is the activation of an endogenous endonuclease that has affinity for internucleosomal (spacer) DNA regions, is paralleled by specific morphological changes in both the cell nucleus and cytoplasm (59,60).…”

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confidence: 99%

Features of apoptotic cells measured by flow cytometry

et al. 1992

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The present review describes several methods to characterize and differentiate between two different mechanisms of cell death, apoptosis and necrosis. Most of these methods were applied to studies of apoptosis triggered in the human leukemic HL‐60 cell line by DNA topoisomerase I or II inhibitors, and in rat thymocytes by either topoisomerase inhibitors or prednisolone. In most cases, apoptosis was selective to cells in a particular phase of the cell cycle: only Sphase HL‐60 cells and G0 thymocytes were mainly affected. Necrosis was induced by excessively high concentrations of these drugs. The following cell features were found useful to characterize the mode of cell death: (a) Activation of an endonuclease in apoptotic cells resulted in extraction of the low molecular weight DNA following cell permeabilization, which, in turn, led to their decreased stainability with DNA‐specific fluorochromes. Measurements of DNA content made it possible to identify apoptotic cells and to recognize the cell cycle phase specificity oaf the apoptotic process. (b) Plasma membrane integrity, which is lost in necrotic but not in apoptotic cells, was probed by the exclusion of propidium iodide (PI). The combination of PI followed by Hoechst 33342 proved to be an excellent probe to distinguish live, necrotic, early‐ and late‐apoptotic cells. (c) Mitochondrial transmembrane potential, assayed by retention of rhodamine 123 was preserved in apoptotic but not necrotic cells. (d) The ATP‐dependent lysosomal proton pump, tested by the supravital uptake of acridine orange (AO) was also preserved in apoptotic but not necrotic cells. (e) Bivariate analysis of cells stained for DNA and protein revealed markedly diminished protein content in apoptotic cells, most likely due to activation of endogenous proteases. Necrotic cells, having leaky membranes, had minimal protein content. (f) Staining of RNA allowed for the discrimination of G0 from G1 cells and thus made it possible to reveal that apoptosis was selective to G0 thymocytes. (g) The decrease in forward light shatter, paralleled either by no change (HL‐60 cells) or an increase (thymocytes) of right angle scatter, were early changes during apoptosis. (h) The sensitivity of DNA in situ to denaturation, was increased in apoptotic and necrotic cells. This feature, probed by staining with AO at love pH, provided a sensitive and early assay to discriminate between live, apoptotic and necrotic cells, and to evaluate the cell cycle phase specificity of these processes. (i) The in situ nick translation assay employing labeled triphosphonucleotides can be used to reveal DNA strand breaks, to detect the very early stages of apoptosis. The data presented indicate that flow cytometry can be applied in basic research on molecular and biochemical mechanisms of apoptosis, as well as in the clinic, where the ability to monitor early signs of apoptosis in samples from patients' tumors may be predictive of the outcome of some treatment protocols. © 1992 Wiley‐Liss, Inc.

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Cell Death: The Significance of Apoptosis

Cited by 6,635 publications

References 135 publications

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

Catalytic activity of caspase-3 is required for its degradation: stabilization of the active complex by synthetic inhibitors

Features of apoptotic cells measured by flow cytometry

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