Mechanisms of Apoptosis: Integration of Genetic, Biochemical, and Cellular Indicators

Abstract

Apoptosis, or programmed cell death, is defined by morphologic change resulting in nonpathologic cell loss and is relevant to a wide spectrum of biology. The process is best characterized in the nematode Caenorhabditis elegans where ced genes mediate the death of specific cells during development. Some corresponding genes have been identified in mammalian cells. Expression of the mammalian bcl-2 gene (homologous to ced-9) suppresses apoptosis in many systems. The ced-3 gene is homologous to a mammalian protease. Increased levels of the tumor suppressor p53 due to DNA damage may result in either blockage of the cell cycle at G1 or apoptosis. Mutation of p53 is associated with decreased cell death from radiation and cytotoxic drugs. Initiation of the apoptotic pathway may occur as a consequence of conflicting growth signals. Hierarchical relationships variously between bcl-2, p53, myc, and other genes indicate a complex pattern of regulation. Stimuli resulting in apoptosis may cause production of free radicals and increased intracellular calcium concentration. The relationship of these changes to the hallmark of apoptosis, internucleosomal fragmentation of DNA, is unclear, and "laddering" of DNA is not always evident. Apoptotic DNA degradation probably occurs sequentially, initially involving breakage into 50 kilobases or larger fragments. The nuclease(s) responsible have not been identified, but deoxyribonuclease I is implicated. The association between nuclease activation and chromatin condensation is complex, and programmed cell death may be subject to cytoplasmic regulation. Available data suggest that clearer understanding of apoptosis will result in better cancer therapy.

Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study

“…Some authors have suggested that CCB may have a negative influence on apoptosis, programmed cell death, which has been under investigation regarding its role in oncogenesis [26]. Transmembrane calcium signals influence and cause cell differentiation and apoptosis [27,28].…”

Apoptosis after ischemia-reperfusion in human liver allografts

“…[1][2][3] Apoptosis typically occurs in single cells, eventually eliminated by phagocytosis 4 in the absence of an inflammatory reaction. One of the most characteristic events of apoptosis is the internucleosomal fragmentation of nuclear DNA, 5 which might be revealed either by Southern blotting techniques, which show a characteristic ladder pattern caused by the migration of DNA fragments corresponding to nucleosomes or multiples of nucleosomes, 6 or by in situ techniques of end labeling the nuclear DNA fragments, 7 such as the TUNEL 8 or other ISEL 9,10 assays.…”

The translational inhibitor cycloheximide represses growth factor depletion-induced apoptosis in an alb-SV40T transgenic rat liver cell line

“…Described as a counterpart of mitosis, transgene has been described by this laboratory. Several apoptosis has been the focus of a large number of studcell lines have been established from the livers of two of ies since it was first described by Kerr et al [1][2][3][4][5][6] Affecting these rats. One of these cell lines, L37, exhibits a large single or small groups of cells, apoptosis exhibits nuclear/cytoplasmic ratio and a well-differentiated cyto-changes in cellular ultrastructure that are distinct plasm containing numerous organelles.…”