Mechanisms underlying the Hallmark features of the execution-phase of apoptosis

Jason C. Mills

Research output: Contribution to journalReview articlepeer-review

8 Scopus citations


As can easily be assessed from the other chapters in this volume (or by any literature search with "apoptosis" as a key word), the study of apoptotic death has mushroomed in the last few years, and many processes and mechanisms specific to apoptosis have been discovered and characterized. The explosion of interest has also naturally led to an impressive proliferation of terms. As it can be helpful to organize all the new findings within a few set categories, the first aim of this chapter was to define more specifically the terms relating to the progression of an individual cell through the time course of death. The time course can be summarized as follows: the initiation phase - (during which the cell responds to numerous types of signals, with cell-type-specific signal transduction pathways, to transduce the signal for apoptosis to the commitment phase); the commitment phase (during which the cell uses a limited number of evolutionarily conserved pathways to integrate the barious initiation phase signals into a decision to refrain from apoptosis or commit irreversibly to it, thereby triggering the execution-phase), and the execution-phase (during which the cell invokes multiple parallel pathways that lead to the hallmark features of apoptosis). The second aim of this chapter was to review recent advances in study of specifically the execution-phase, as this is the stage when all the defining (evolutionarily important) features of apoptosis occur, and there is great potential for fruitful research into identifying the mechanisms responsible for these features. Thus, in this chapter the execution-phase was grouped into nuclear and extranuclear events, and those were further subdivided into upstream and downstream processes. It was noted that the caspase family of proteases comprises the best-characterized upstream regulators in extranuclear and especially nuclear events. Downstream nuclear events were also discussed. These included: DNA fragmentation, which has been well studied and has seen recent great advances with the identification of caspase-inducible endonucleases, and chromatin condensation, which is a process that is still largely uncharacterized. Downstream extranuclear events were discussed, with special attention paid to cell blebbing and apoptotic body formation as part of general cell shrinkage. These morphologic changes have seen recent advances with the identification of caspase-activated kinases necessary for apoptotic body formation and characterization of the possible cellular mechanism underlying apoptotic contraction and blebbing. Other downstream extranuclear events were discussed and included: changes in the cell's interaction with its environment, a field that has seen some progress with the identification of several caspase-mediated changes in membrane-associated proteins; changes in cytoskeleton and cytoskeleton-associated proteins, which have been recently shown to occur in the form of microtubule disassembly and protein phosphatase 2A activation; changes in cellular energetics, which have not been as well studied in the execution-phase itself but the importance of which is hinted at by the dependence of the execution-phase on ATP (as possibly generated preferentially by glycolysis). All the recent advances in the study of the execution-phase discussed in this chapter serve only to highlight how complicated and multifaceted this stage of apoptosis is. Many of the mechanisms underlying the telltale execution-phase morphologic events, especially those mediating extranuclear events, have undoubtedly not even been identified, let alone characterized. Thus, the future seems bright for those interested in discovering how a cell brings about this fascinating, final act of altruism.

Original languageEnglish
Pages (from-to)1-38
Number of pages38
JournalAdvances in Cell Aging and Gerontology
Issue numberC
StatePublished - Dec 1 2001


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