The elimination of cells by programmed cell death (apoptosis) is a universal feature of development and aging in animals. Aberrant regulation of apoptotic cell death is also firmly established in the etiology and treatment of many human diseases including cancer, AIDS and neurodegenerative disorders. Despite an extensive body of knowledge, our understanding of this process is far from complete and many important issues remain unresolved. Our research seeks to understand the specification and execution of apoptosis in the genetic model, Drosophlia. Current evidence argues that in order to understand mechanisms that elicit cell killing, we need to understand the regulation and action of apical caspases (cysteinyl aspartate-specific proteinases). To investigate this problem, we propose continued genetic studies focused on events immediately proximal to apical caspase activation, which involve formation of a protein complex referred to as the 'apoptosome'. In worms, this complex (CED4/CED3) is phyiscally regulated through Bcl2-like proteins but, in mammals, formation of the apoptosome (APAF-1/CASPASE9) is intimately linked to mitochrondrial factors. Are these different modes of regulation just minor peculiarities? Or do they imply more profound variations in design of the intrinsic death machinery? Prompted, in part, by these questions, we propose genetic studies on the Drosophila 'apoptosomal counterparts, DRONC (a CARD-domain containing apical caspase) and DARK (the CED-4/APAF-1 ortholog). Toward this goal, we recently isolated 'clean' null alleles in the genes that encode both proteins. Promising observations implicate essential functions for both and strong interactions between them. Using sophisticated methods available in this animal model, these new mutations permit detailed exploration of the requirements for DARK and DRONC in cell death, development, and physiology. These efforts will contribute significant and converging information on the molecular basis of apoptosis in an important genetic model.
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