© 1994 by Oxford University Press
Journal of the National Cancer Institute, Vol. 86, No. 17, 1286-1296,
September 7, 1994
© 1994 Oxford University Press
Mechanisms of Apoptosis: Integration of Genetic, Biochemical, and Cellular Indicators
*Children's Leukaemia and Cancer Research Centre, University of New South Wales, Prince of Wales Children's Hospital Sydney, New South Wales, Australia
Correspondence to: Bernard W. Stewart, Ph.D., Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Randwick, Sydney, NSW 2031, Australia.
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 G 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. [J Natl Cancer Inst 86: 1286–1296, 1994]
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