Physiology in MedicineApoptosis: definition, mechanisms, and relevance to disease☆
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Apoptosis and other death forms
Apoptosis can be differentiated from other forms of cell death, termed necrosis, that may occur in response to injury by toxins, physical stimuli, or ischemia. Swelling of cells and disruption of membranes are prominent features of necrosis, and the nuclear chromatin undergoes lysis, not condensation, in this mode of cell death (Figure 1). Because large groups of cells are involved and cellular contents are lost early into the extracellular space, necrotic tissues evoke vigorous inflammatory
Biological significance of apoptosis
For the vast majority of normal cells undergoing apoptosis, little is known about the signals that commit cells to death. Cells may emanate signals that cause neighboring cells to die. Although this seems to be the way some cells are eliminated during development, for example, during morphogenesis of fingers and toes, understanding of the nature of apoptosis-inducing signals and the principles that determine their location and timing is incomplete. Systemic factors may also be necessary to
Caenorhabditis elegans: a worm’s tale of cell death
Apoptosis was first characterized during genetic studies on the nematode worm Caenorhabditis elegans. Programmed cell death during C. elegans development involves the activation of selective death genes that kill exactly 131 cells, leaving 959 cells intact in the worm (2). Further studies revealed that apoptosis consists of three successive stages: (1) commitment to death triggered by extracellular or intracellular signals; (2) execution of cell killing by activation of intracellular proteases;
Apoptosis and disease pathogenesis
In the normal state, cell proliferation and cell death are at equilibrium. Alterations in the rate of cell death or proliferation, or both, can be involved in disease pathogenesis. Abnormalities of apoptosis have been implicated in diverse disease processes (Table 3). Failure of normally required apoptosis in some cell populations as well as abnormally increased apoptosis may result in disease. Some disease processes may depend on both failed and excessive apoptosis during different stages of
Future directions
Evolving recognition that programmed cell death is an important feature of disease will certainly increase further the burgeoning interest in apoptosis research. Although it is clear that apoptosis or its inhibition is involved in disease pathogenesis and in the expression of disease symptoms, there is much room for intensive research to arrive at a deeper understanding. Techniques that allow for accurate and quantitative detection of apoptosis need to be developed. There is also a need to
References (191)
- et al.
Genetic control of programmed cell death in the nematode C. elegans
Cell
(1986) - et al.
Sequence of metabolic changes during X-ray–induced apoptosis
Exp Cell Res
(1999) - et al.
Induction of apoptosis and secondary necrosis in rat dorsal root ganglion cell cultures by oxidized low density lipoprotein
Neurosci Lett
(1996) - et al.
Measurement of cell death
Meth Cell Biol
(1998) - et al.
A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V
J Immunol Meth
(1995) - et al.
Thyroxine enhancement and the role of reactive oxygen species in tadpole tail apoptosis
Free Rad Biol Med
(1999) Apoptosis (programmed cell death) and other reasons for elimination of neurons and axons
Brain Dev
(1995)- et al.
Neuronal death in the central nervous system during development
Biomed Pharmacother
(1998) - et al.
Programmed cell death in animal development
Cell
(1997) - et al.
Programmed cell death during mammary gland involution
Meth Cell Biol
(1995)
Intact, injured, necrotic and apoptotic cells after focal cerebral ischemia in the rat
J Neurol Sci
Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation
J Biol Chem
Apoptosis and thyroiditis
Clin Immunol Immunopathol
Immune cell signaling defects in lupusactivation, anergy and death
Immunol Today
Caenorhabditis elegans CED-4 stimulates CED-3 processing and CED-3–induced apoptosis
Curr Biol
The death inhibitory molecules CED-9 and CED-4L use a common mechanism to inhibit the CED-3 death protease
J Biol Chem
Anchorage dependence, integrins, and apoptosis
Cell
Estrogen causes cell death of estrogen receptor stably transfected cells via apoptosis
J Steroid Biochem Mol Biol
Apoptosis by death factor
Cell
A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain
J Biol Chem
The death domain motif found in Fas (Apo-1) and TNF receptor is present in proteins involved in apoptosis and axonal guidance
FEBS Lett
The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation
Cell
FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis
Cell
TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex
Immunity
Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3
Cell
Human ICE/CED-3 protease nomenclature. Letter
Cell
A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis
J Biol Chem
The CARD domaina new apoptotic signalling motif
Trends Biochem Sci
Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock
Cell
Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis
J Biol Chem
Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally
Immunity
Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade
Curr Biol
Activation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway by overexpression of caspase-8 and its homologs
J Biol Chem
Differential requirement for caspase 9 in apoptotic pathways in vivo
Cell
Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9
Cell
Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis
J Biol Chem
Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3
Cell
Apaf1 is required for mitochondrial pathways of apoptosis and brain development
Cell
Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development
Cell
Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization
Mol Cell
Apoptosisa basic biological phenomenon with wide-ranging implications in tissue kinetics
Br J Cancer
Apoptosisan overview
Br Med Bull
Mechanisms of cell death in hypoxia/reoxygenation injury
Oncogene
Methods for detecting and quantifying apoptosis
Curr Top Dev Biol
A cautionary note on the use of the TUNEL stain to determine apoptosis
Neuroreport
Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death. Involvement of serine but not cysteine proteases
Am J Pathol
Survival factors and apoptosis
Adv Biochem Eng Biotechnol
Apoptosis in the human uterine endometrium during the menstrual cycle
J Clin Endocrinol Metab
Deletion of cells by apoptosis during castration-induced involution of the rat prostate
Virchows Arch B Cell Pathol
Apoptosis. Its nature and implications for dermatopathology
Am J Dermatopathol
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2021, Developmental and Comparative ImmunologyCitation Excerpt :The signaling pathways (intrinsic or extrinsic) of apoptosis are complex in nature, of which always involves the activation of effectors, belonged to the family proteases known as caspases (Wang et al., 2011). Condensation of nuclei, chromatin agglutination, DNA fragmentation, cellular shrinkage, swelling and disintegration of mitochondria are some of the typical features of apoptosis (Saikumar et al., 1999; Gulbins et al., 2000). Previous studies already proved that Mycoplasmas infection induced apoptosis in cells (Sokolova et al., 1998).
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Research grant support was provided to Drs. P. Saikumar, National Institutes of Health (NIH) Grant DK 54472 and Morrison Trust Grant; J. M. Weinberg, NIH Grant DK 34275, Department of Veteran’s Affairs, and Office of Naval Research Grant N00014-95-1-584; and M. A. Venkatachalam, NIH Grants DK37139 and DK48417.