Dying like Flies

complex: the low intrinsic protease activity of the pro-caspase is then sufficient to trigger intermolecular cleav-age and subsequent activation. Formation of such pro-44 Lincoln's Inn Fields London WC2A 3PX caspase complexes is mediated by the prodomains of the apical caspases that interact with adaptor molecules United Kingdom to form the " apoptosome. " The adaptor molecules serve as protein platforms that both mediate procaspase ag-gregation and couple caspase activation to various sig-Apoptosis is a peculiarly metazoan phenomenon. True, naling pathways. In C. elegans for example, the adaptor organized death of a kind is observed in some unicellular molecule CED-4 is required to activate the CED-3 cas-organisms, but only metazoans possess an elaborate pase and binds the prodomain of CED-3 via a conserved machinery evolved solely to destroy, dismantle, and dis-interaction domain christened CARD (caspase activa-pose of cells. Within the past few years, apoptosis has tion and recruitment domain). The interaction of CED-9 emerged as a key element in homeostasis, which to-with CED-4 quells CED-4's ability to activate CED-3. gether with cell proliferation and differentiation, regu-The closest known human homolog of CED-4 is Apaf1. lates the balance between cell loss and cell gain neces-Apaf1 activates caspase 9 via the proenzyme's CARD sary for the establishment and maintenance of metazoan domain. However, this activation requires holo-cyto-tissues. Insufficient or excessive apoptosis is now rec-chrome C, which is released from the intermembrane ognized as the cause or consequence of many human space of mitochrondria by an as-yet-unexplained mech-pathologies and, consequently, there is intense interest anism and appears to be an important trigger of apopto-in apoptosis as a pharmacological target. sis in vertebrates (Green and Reed, 1998). It is not known The past few years have seen significant advances in whether cytochrome c fulfills a similar pivotal role in our understanding of both the machinery that executes fomenting apoptosis in the nematode. However, even if apoptosis and the mechanisms by which this potentially it does, it is unlikely that any genetic analysis would catastrophic process is controlled. Much of our knowl-uncover a role for cytochrome c in apoptosis, given the edge stems from studies of the developmentally invari-essential role of cytochrome c in electron transport. ant nematode C. elegans. During its ontogeny, 1090 Nonetheless, the remarkable homology in basal apo-cells are born, of which 131 die by suicide. Genetic ptotic machineries of nematodes and mammals argues analysis has identified three principal genes that are for …