ABSTRACT
The detailed cascade of genetic elements involved in the mammalian apoptotic process was first defined from initial studies in Caenorhabditis elegans. During the development of this nematode, cells are deleted by an invariant process morphologically and functionally analogous to apoptosis (Ellis et al., 1991). Mutational analysis lead to the discovery of various genes which act as either positive or negative regulators of apoptosis. Of these, ced-3, ced-4 and ced-9 appear to be essential for the execution and regulation of cell death (reviewed in Hengartner and Horvitz, 1994a). Both ced-3 and ced-4 have pro-apoptotic effects and mutants lacking either of these genes contain additional cells, normally deleted
† Corressponding Author: (08) 8222 3738. Fax: (08) 8222 3139. e-mail: sharad.kumar@imvs.sa.gov.au
during development (Ellis and Horvitz, 1986). The ced-9 gene antagonises the function of ced-3 and ced-4 to protect cells from apoptosis, as demonstrated in ced-9 loss-of-function mutants where the majority of cells arrest early in development resulting in embryonic lethality (Hengartner et al., 1992). The first evidence to suggest that the cell death pathways in C. elegans and mammalian cells may contain common regulatory elements arose from the discovery that ced-9 shares both structural and sequence homologies with the mammalian bcl-2 gene (Hengartner and Horvitz, 1994b). Bcl-2 has been shown to prevent apoptosis both in vitro and in vivo in a wide variety of cell types (reviewed in Korsmeyer, 1992) and, when overexpressed, may partially restore functional loss in a ced-9 mutant (Vaux et al., 1992; Hengartner and Horvitz, 1994b). Further similarities between the C. elegans and mammalian death pathways were demonstrated by the discovery that ced-3 exhibits significant homology to interleukin-1β-converting enzyme (ICE) (caspase-1) (Yuan et al., 1993). ICE was the first identified member of a family of aspartate-specific cysteine pro teases (Thornberry et al., 1992; Cerretti et al., 1992) recently designated caspases (Alnemri et al., 1996) which, like CED-3 appear essential for the execution of active cell death. Subsequent studies have revealed several more mammalian ICE/CED-3 homologs: Nedd2/ICH-l (caspase-2) (Kumar et al., 1994; Wang et al., 1994), CPP32/Yama/apopain (caspase-3) (FernandesAlnemri et al., 1994; Nicholson et al., 1995; Tewari et al., 1995b), ICErelII/TX/ICH2 (caspase-4) (Faucheu et al., 1995; Kamens et al., 1995; Munday et al., 1995), ICErelIII/TY (caspase-5) (Munday et al, 1995; Faucheu et al., 1996); Mch2 (caspase-6) (FernandesAlnemri et al., 1995a); ICE-Lap3/Mch3 (caspase-7) (Fernandes-Alnemri et al., 1995b; Duan et al., 1996a), MACH/FLICE/Mch5 (caspase-8) (Boldin et al., 1996; Fernandes-Alnemri et al., 1996; Muzio et al., 1997), ICE-Lap6/Mch6 (caspase-9) (Duan et al., 1996b; Srinivasula et al., 1996b), Mch4 (caspase-10) (Fernandes-Alnemri et al., 1996) and ICH3 (caspase-11) (Wang et al., 1996). In addition, two novel murine caspase homologs have recently been identified and characterised (Van de Craen et al., 1997).
