A License to Kill

Much of our knowledge of the basal mechanism underly-44 Lincoln's Inn Fields ing programmed cell death derives from the elegant London WC2A 3PX studies of Horvitz and colleagues on developmental cell United Kingdom death in the developmentally deterministic nematode worm Caenorhabditis elegans. During development of Apoptosis is the descriptive name given to the process the hermaphrodite worm, 1090 cells are born and 131 of programmed cell death in vertebrates. During die. Mutants defective in this death program define three apoptosis, a cell activates an intrinsic suicide mecha-principal genes (ced genes) that orchestrate each cell nism that systematically trashes the cell: its surface death. ced-3 and ced-4 act to kill target cells, while membrane begins to bleb and express pro-phagocytic ced-9 acts to suppress the killer genes. ced-9 is a struc-signals, the cell shrinks and severs contact with its tural and functional homolog of the human proto-onco-neighbors, chromatin becomes condensed and cleaved gene bcl-2, one of a family of genes intimately involved (ensuring genetic death of the affected cell), and eventu-in the regulation of vertebrate apoptosis. ced-4 has no ally the whole cell fragments into membrane-bound vesi-known function or homolog. ced-3 encodes a cysteine cles that are rapidly ingested by neighboring cells. The protease that is related to an emerging family of verte-apoptotic process is extremely rapid (typically between brate cysteine proteases of which the prototype is the a few minutes and a few hours), and the apoptotic debris eponymous interleukin-1␤-converting enzyme (ICE) is cleared with similar rapidity. (Yuan et al., 1993). ICE is well characterized as the Up until some 4 years ago, apoptosis held much the activator of the inflammatory cytokine interleukin-1␤ same status among serious scientists as aromatherapy through cleavage of the inactive 31 kDa interleukin-1␤ does among physicians—an interesting and amusing precursor at Asp116↓Ala117. concept, decorative, but definitely not mainstream. Of The mammalian ICE-related protease family now course, all that has now changed. Nowadays, the fero-comprises some nine known members. These include cious pace (and funding) of research into apoptosis is the Ced-3-like subfamily members CPP32␤ (also known matched only by a deep sense of frustration that, despite as Yama and Apopain), Mch2, Mch3 (also known as elucidation of many of the important players in the cell ICE-LAP-3 and CMH-1), and Mch4; the ICE subfamily death process, very little hangs together to give a coher-members ICE, ICE rel III, and ICE rel II (also known as ent …