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Cell Death in the Third Millennium Cell Death and Differentiation (2000) 7, 2±7 ã 2000 Macmillan Publishers Ltd All rights reserved 1350-9047/00 $15.00 www.nature.com/cdd Editorial Cell death in the third millennium RA Lockshin*,1, B Osborne2 and Z Zakeri3 setting, signaling and transduction are often not linear but are dependent on very specific aspects of cell history and current 1 Department of Biological Science, St. John's University, Jamaica, New York, state. The phase in which researchers expected a linear NY 11439, USA sequence of events, for instance from signal to transduction to 2 Veterinary/Animal Science, University of Massachusetts, Amherst, gene activation to caspase activation, is over: The role of a Massachusetts, MA 10013, USA given protein may be entirely contextual. Secondly, as the 3 Department of Biology, Queens College of CUNY, Flushing, New York, NY linear sequences are more precisely defined, it has become 11367, USA apparent that there are many variants to both the broad * Corresponding author: RA Lockshin, Department of Biological Science, St. schemes and the more subtle details. Both of these limitations John's University, Jamaica, New York, NY 11439, USA suggest that it is now time to bring the molecular biology to bear on the somewhat messier situations of apoptosis in vivo and in the situations of sedentary, large, highly differentiated post-mitotic cells, which rarely follow a conventional Although one can delineate some trends in current thinking, sequence of apoptosis. We need to accept the idea that the we should reflect on the ability of working scientists to predict model of apoptosis based on cells of hematopoietic origin is the future. It is poor.* Therefore, though trends now seem to an extremely important paradigm, but it is not universal. be identifiable with relative clarity, we recognize that fields change rapidly, and we acknowledge that the topic discussed here represents a certain level of hubris. Nevertheless, the Cells and cell deaths in context last 10 years have seen some remarkable changes. From an The role of context may be illustrated by a few examples. original description of apoptosis as inherently a phenomenon Different TNF receptors play different roles in NFkB of morphology, we have moved to a much more comprehen- dependent and independent pathways. TNFRI often induces sive understanding of the molecular origins of that morphol- apoptotic signals but in other circumstances is anti- ogy, including at least partial understanding of the roles of apoptotic.24 In chick and duck embryos, both condensation proteases and nucleases in creating the hallmarks of of cartilage to form a digit and cell death result from the apoptosis. Many of these advances derive from the cloning interactions of BMP, FGFB, and noggin, but the reason for the and identification of Caenorhabditis genes, which opened the different responses remains unknown.25 Even the paradig- entire horizon of proteases, and led directly to identification of matic inducer of apoptosis, myc, is now consigned to a subtler the role of mitochondria in apoptosis.1±10 Similarly, identifica- role: rather than causing apoptosis in some circumstances, tion of pro- and anti-apoptosis mechanisms in human cells myc sensitizes a cell to many inducers of apoptosis; `myc (fas and p53; bcl2) and in bacteria and viruses (p35, crmA) increases the probability of apoptosis'.26,27 has allowed us to glimpse intracellular signaling. For a few specific situations, we can now trace a complete sequence controlling the survival of a cell.11 ± 23 Nevertheless, the clarity Types of cell death: caspases, proteases, of these sequences is a bit meretricious. The inherent and autophagic cell death elegance and simplicity of these concepts (albeit not of the For several years a major discussion point was definition of sequences ± the simplicity is in the linearity of the scheme) the type of cell death: apoptosis, programmed, active, belie at least two orders of complication. The first of these is physiological, necrotic. Elucidation of some of the that, in real life as opposed to a very controlled laboratory molecular pathways has resolved some of these issues, but has indicated that there is sufficient variation that one needs either to take a larger view of the meaning of the *Our sense of the reliability of predictions derives from an experience word `apoptosis' or to consider apoptosis to be one of a one of us (RA Lockshin) had as an undergraduate and graduate at a family of physiological cell deaths. For instance, in the last well known institution. He twice got very high grades from prominent 10 years caspases have been identified as major players scientists for totally missing the point. In one, he reviewed the brand- in apoptosis, and have even been proposed as the defining new Medawar and Burnet clonal selection theory, which he dismissed element of apoptosis,28 but we also now recognize that the as the old Landsteiner theory with a modern vocabulary. In the other, he had unearthed a relatively obscure reference that contended that, if certainly powerful caspase pathway is not necessary to kill baby guinea pigs were thymectomized, they would appear to do all cells. Although the discovery of the caspase-mitochondrial right (as did rats) but eventually they became cachectic and died. With pathways unequivocally counts as one of the triumphs of appropriate scorn, he noted that better animal husbandry would this decade,29 ± 37 we are now beginning to recognize limits resolve the problem. He thereby learned that senior scientists are not 38 ± 41 routinely clairvoyant. In the legalistic sense currently preferred in and complications that we need to explore. This is North America, Europe and elsewhere, the above remarks constitute typical of a rapidly-moving and exciting field: the brilliance the legal disclaimer. of the concept draws many researchers who, while not Editorial 3 undermining the concept, realize that it must be nuanced. neighbors, or anomie. Several cell biologists have For instance, the protease that initiates degradation of emphasized the importance of cell shape on cell chromatin is likely not to be a caspase.42,43 In many metabolism.57 ± 60 These issues are of minimal importance instances cells in which caspases are blocked or knocked in the case of cells that normally move freely in the body out will die, even though they do not acquire apoptotic and are studied in suspension culture, but they may be morphology. They look more like cells with elaborately very meaningful for sedentary tissues in vivo and therefore developed autophagy, a form of death that is encountered, should be considered for all clinical evaluations. Other more commonly than acknowledged, in large postmitotic genes previously attracting interest include genes affecting epithelial and other cells, including insect organs and structure, such as transglutaminase, those now considered mammary epithelium. In these cells, lysosomal and to participate in the suppression of inflammation, such as perhaps other proteases are activated, though the role of TRPM-2 (SGP2), and genes involved in, or regulating, cell proteasomal proteases remains equivocal.44,45 There is cycle. Their stories are not yet complete, and deserve growing recognition that autophagic death is not a caspase further attention. Caspases are important enzymes, but, like death and that, in cells destined to die (such as neurons in most biomolecules that are discovered in conjunction with a the absence of NGF) inhibition of caspases may prevent specific important process, their role is undoubtedly more development of apoptotic morphology but neither autop- complex than we picture. For instance, caspases arose in hagy nor death of the cell.46 There are autophagic evolution from molecules that presumably had other pathways even in thymocytes.47 In other instances, functions61±65 and we have not yet assessed those other granzymes play more complex and subtle roles than the functions and determined their importance. Do mammalian original `bludgeoning' model suggested.48,49 We have come cells really carry a complex of more than one dozen full circle, now returning to the investigation of autophagic proenzymes solely to anticipate their death and graceful death that was popular 30 ± 40 years ago. Levi-Montalcini exit? In Dictyostelium, caspase inhibitors interfere with and Aloe noted in 1981 that the types of death of neurons development but not apoptosis. Insect cells, which have depended on their state of differentiation50 and Schweichel caspases and display caspase-mediated cell death in vitro, and Merker51 and Potten52 attempted to classify different show little sign of activating these enzymes during the types of death. These and other variations help to paradigmatic programmed cell death of their metamorpho- understand why caspase or apaf-1 knockouts, for sis,66 and a functional role for bcl-2 like molecules has not instance, may yield only modest phenotypes. First, cells been convincingly demonstrated. In neurons, different may follow parallel or complementary pathways to death, caspases function under different conditions: why? so that knockout of the normal system simply routes the cell through another pathway. Second, embryonic develop- ment is highly redundant and embryos are wonderfully The morphology and molecular biology of adept at compensating for deficits by using secondary cell death controls or even other cells to accomplish the same end. The mechanics and consequences of the morphological For autophagic cell death,
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