Part I General Principles of Cell Death

1 ,2 Several months later, one of the key genes governing the commitment to apoptosis in Caenorhabditis elegans – CED3 – was demonstrated to show homology with ICE.3 These publications initiated a successful search by many groups over the ensuing years for mammalian ICE homologs that should govern cell death. Today these proteases are known as caspases.4 Of the 11 caspases in humans, 7 are considered to be involved primarily in apoptosis, three are considered to be involved primarily in proinflammatory cytokine activation, and one is involved in keratinocyte differentiation (Figure 1-1). How cells learned to employ closely related proteases to execute two opposing phenotypes – apoptosis and inflammation – is strongly debated, and this chapter incorporates some discussion on this tricky issue. Confirmation of the important roles of the caspases in the inflammatory cytokine response comes from gene ablation experiments in mice. Animals ablated in caspase-1 or -11 are deficient in cytokine processing,5,6 but without any overt apoptotic phenotype. The phenotypes of the apoptotic caspase knockouts are often gross and are sometimes antiapoptotic and vary from early embryonic lethality (caspase-8), to perinatal lethality (caspase-3 and -9),7,8,9 to relatively mild with defects in the process of normal oocyte ablation (caspase-2).10 Techniques in biochemistry and cell biology have allowed us to place the apoptotic caspases in two converging pathways (Figure 1-2). This core pathway probably represents a minimal apoptotic program, but almost certainly the apparent simplicity is complicated by cell-specific additions that help to fine tune individual cell fates. Moreover, recent evidence clearly implicates caspase-8 in nonlethal roles in the control of cell proliferation.11,12