This series of articles summarizes the current understanding of the increasingly recognized importance of apoptosis in the neoplastic process. The remarkable relationship of apoptosis to many other physiological processes, including development, viral resistance, cachexia, immune responses, cellular generation of reactive oxygen species, and neurodegeneration, is touched on in these reports, as well. An improved understanding of the control of apoptosis therefore has many potential rewards.
The first two articles, by Junying Yuan and David Hockenbery, describe the basics of the cellular control of apoptosis. Junying Yuan describes the central finding that two of the three key genes controlling the programmed cell death pathway in nematodes have been found to be similar to mammalian genes that demonstrate important effects on apoptosis. In each case, a single gene from C. elegans has shown similarity to multiple related mammalian genes, suggesting that evolution, while conserving the lynchpins of the program, has enhanced the overall complexity. Ced-9 is an inhibitor of developmental cell death in nematodes, and a family of related genes, which includes the prototype bcl-2, inhibits apoptosis in mammalian cells. However, although bcl-2 can substitute for ced-9 in nematodes, they are not completely functionally equivalent, since one specific point mutant of ced-9 results in a gain of function, whereas the corresponding mutation in bcl-2 results in a loss of function.
Ced-3 is required for developmental cell death in nematodes, and, as with ced-9, similar mammalian genes with similar effects on cell death have been identified. In mammals, these genes form the interleukin-lp-converting enzyme (ICE) family of cysteine proteases, which cleave substrates following aspartate residues. The importance of this family of cysteine proteases in mammalian cell death is suggested by the findings that (1) expression leads to cell death; (2) inhibition by a specific protease inhibitor, crm A, inhibits apoptosis in a standard paradigm of