INTERACTION BETWEEN THE C-ELEGANS CELL-DEATH REGULATORS CED-9 AND CED-4

Programmed cell death (apoptosis) is an evolutionarily conserved proce ss used by multicellular organisms to eliminate cells that are not nee ded or are potentially detrimental to the organism(1,2). Members of th e Bcl-2 family of mammalian proteins are intimately involved in the re gulation of apoptosis, but, their precise mechanism of action remains unresolved(3-5). In Caenorhabditis elegans, the Bcl-2 homologue CED-9 prevents cell death by antagonizing the death-promoting activities of CED-3, a member of the Caspase family of death proteases, and of CED-4 , a protein with no known mammalian homologue(6-9). Here we show that CED-9 interacts physically with CED-4. Mutations that reduce or elimin ate CED-9 activity also disrupt its ability to bind CED-4, suggesting that this interaction is important for CED-9 function. Thus, CED-9 mig ht control C. elegans cell death by binding to and regulating CED-4 ac tivity. We propose that mammalian Bcl-2 family members might control a poptosis in a similar way through interaction and regulation of CED-4 homologues or analogues.