Identification of Caspases as cell death proteins

First evidence for the involvement of cystein proteases in apoptosis evolved when Horvitz et al. (Cell, vol. 75, pp641, 1993) reported significant sequence similarity between the Caenorhabditis elegans death gene ced-3 and the mammalian interleukin-1-converting enzyme (ICE). In the nematode Caenorhabditis elegans, pathways of programmed cell death were already intensively studied at this time. Among others, the gene ced-3 was known to play an essential role in the initiation/execution of the cell death program. Now it was suggested that the mammalian ced-3 homolog ICE (known as the activator of the cytokine IL-1) could play a key role in programmed cell death in vertebrates. This was confirmed by the observation that overexpression of ICE induces apoptosis and that the ICE inhibitors cow pox viral serpin CrmA and baculovirus p35 block ICE-induced apoptosis. Following the identification of ICE as the mammalian counterpart of the C. elegans death gene ced-3, nine other mammalian aspartate specific cysteine proteases were identified and cloned. All those caspases (as they are called now) show homology to ICE and Ced-3: this homology was used in the identification/cloning of several of the caspase family members (Alnemri, E.S., 1997, J. Cell. Biochem., 64: 33-42).