Biochemical determinants of apoptosis and necrosis
Section snippets
Introduction: distinctions between apoptosis and necrosis
The term `apoptosis' was originally coined by Kerr et al. (1972)to describe a pattern of morphological alterations associated with normal programmed cell death and certain pathological processes in vivo. These changes include cell shrinkage and loss of contact with neighboring cells, formation of cytoplasmic vacuoles, plasma and nuclear membrane blebbing, and chromatin condensation, and an important feature was that they could be readily distinguished from those occurring during `accidental'
Molecular regulation of apoptosis: lessons from Caenorhabditis elegans
For years the study of apoptosis relied solely upon somewhat subjective assessments of cellular morphology, which left many scientists understandably sceptical about the pathway's relevance. This skepticism was ameliorated somewhat when endonuclease activation emerged as a biochemical indicator of apoptosis. However, in the absence of any information about the genetic control of the process, investigators remained unconvinced that apoptosis represented a mechanistically unique cell death
Triggers for apoptosis
Numerous extracellular stimuli can initiate apoptosis (Fig. 2). However, it appears that they can be grouped into two general categories based upon their overall mechanisms of action. In the first group are polypeptides homologous to the receptor for tumor necrosis factor (TNF) and CD95/Fas, which are directly coupled to the cell death machinery. Members of this family interact physically with caspases via regions in their cytoplasmic domains known as the `death domains,' and receptor
Mechanisms of caspase activation
Other genetic studies in C. elegans revealed that ced-9 and ced-4 function upstream of ced-3 in the apoptotic pathway, suggesting that caspase activation might be rate-limiting for apoptosis (Hengartner and Horvitz, 1994a). However, precisely how caspase activation is triggered in whole cells remained unclear. Early clues came from Korsmeyer's laboratory, who demonstrated that a substantial fraction of cellular bcl-2 protein localizes to mitochondria (Hockenbery et al., 1990). Subsequent work
Biochemical determinants of apoptosis and necrosis
Even though the morphological alterations associated with each response are (by definition) distinct, accumulating evidence indicates that certain key biochemical mechanisms are shared by the two responses. Early work from Cotter's laboratory using a panel of toxicants demonstrated that low to moderate concentrations trigger apoptosis and higher levels necrosis (Lennon et al., 1991), and more recent work established a similar dose-dependent relationship between apoptosis and necrosis in
Conclusions
As a result of the work outlined above and other studies, a clear-cut distinction between apoptosis and necrosis no longer exists at the biochemical level, because overexpression of BCL-2 can delay cell death in either case. The effects of bcl-2 appear due in part to direct effects on the mitochondria, which lead to stabilization of membrane potential, preservation of ATP production, prevention of oxidative stress and sustained intracellular Ca2+ alterations, and modulation of intracellular GSH
Acknowledgements
Supported by grants from the National Cancer Institute (CA69676) and the National Heart, Lung, and Blood Institute (HL60537).
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