A first insight into the molecular mechanisms of apoptosis

Our 1993 paper entitled "The C. elegans Cell Death Gene ced-3 Encodes a Protein Similar to Mammalian Interleukin-l-13-Converting Enzyme" (Yuan et al., 1993) announced the discovery of a molecular mechanism for programmed cell death in the nematode Caenorhabditis elegans and led us to suggest that this mechanism is likely conserved in mammals. Our first glimpse of the impact this paper would have on the fields of biology and medicine came the day this paper was published: that day a number of pharmaceutical companies contacted one of us (H.R.H.) to ask how this finding could help them discover drugs. Nonetheless, its subsequent effect on the field of mammalian apoptosis was beyond our imagination at the time. In the past decade, the field of apoptosis has become enormous, with more than 10,000 published papers directed toward an understanding of CED-3-1ike proteases, now known as caspases, and more than 70,000 papers toward the understanding of apoptosis in general. Many of these latter papers use caspase activation as their primary marker for the process of apoptosis. The Yuan et al. (1993) paper, coupled with the companion paper by Miura et al. (1993), which showed that CED-3 expressed in mammalian cells could induce those cells to undergo apoptosis, not only provided the first insight concerning the molecular mechanisms of apoptosis but also established one of the first two (also see Vaux et al., 1992) direct links between the genetic analysis of programmed cell death in C. elegans and the field of mammalian apoptosis. That ced-3, a gene required for programmed cell death in C. elegans, encodes a protein resembling mammalian interleukin-l~ converting enzyme, a cysteine protease now termed caspase-1, strongly suggested that the CED-3 protein functions as a cysteine protease in regulating programmed cell death in worms, ced-3 had been identified by Hilary Ellis in a genetic screen for mutations that suppress the presence of persistent cell corpses caused by a mutation in ced-1, a gene required for the engulfment of dying cells (Ellis and Horvitz, 1986). In wild-type worms, cells undergoing programmed cell death are efficiently recognized, engulfed, and degraded by neighboring cells. The engulfment process is now known to be regulated by at least seven genes, which encode components of two parallel and partially redundant signal transduction pathways (e.g.,