Control of Apoptosis by Proteases

The discussion in this chapter confirms an important role for proteases in mammalian cell death. Available evidence indicates that interleukin-1β converting enzyme (ICE)/CED-3 (the product of a gene necessary for programmed cell death in the nematode Caenorhabditis elegans) proteases are essential components of a common cell death mechanism that is triggered in response to diverse stimuli. The discovery that CED-3 belongs to the interleukin-1β converting enzyme (ICE) family of cysteine proteases has led to intense interest in the role of these enzymes in apoptosis. It is now generally accepted that members of this family do, in fact, play key roles in at least some models of mammalian cell death, although the precise nature of their involvement remains obscure. Other proteases that have been implicated in apoptosis in vertebrates are the serine protease granzyme B and members of the calpain cysteine protease family. The identification of some of the potential victims of proteolysis by these enzymes has provided important insights into the actual pathways that may be altered to produce the apoptotic phenotype. Despite the finding that inhibitors of ICE/CED-3 proteases prevent apoptosis in several models, serious issues regarding the suitability of these enzymes as targets for therapeutic intervention remain to be addressed.