Drosophila Apoptosis and Bcl-2 Genes

(Igaki et al., 2000) unveils the long anticipated, missing piece of the apoptosome in flies. On page 703 in this issue, in a paper by Colussi et al., Ku-mur, Richardson, and colleagues characterize the first Drosophila members of the Bcl-2 gene family whose function is important for programmed cell death (PCD). The founding member of this gene family was identified as the proto-oncogene upregulated by t(14;18) translocations in B cell follicular lymphomas. Since this discovery, and its link to the regulation of cell death, the Bcl-2 family of proteins has grown to include more than twenty members of death-suppressing and-promoting molecules found in the genomes of worms, mammals, viruses, and now flies (Gross et al., 1999; Vander Heiden and Thompson, 1999). Central components of the apoptosis machinery in worms, mammals and flies are schematized in Fig. 1. In C. elegans , both Ced-3 and Ced-4 are required for all PCD during worm development. Ced-3 encodes a founding member of the caspase family (cysteine proteases) while Ced-4 promotes the activation of Ced-3 through direct physical interaction. The upstream death regulator, Ced-9, protects cells from death by forming a complex with Ced-4, thus preventing the activation of Ced-3 by Ced-4. A pro-apoptotic protein with limited Bcl-2 similarity, Egl-1, can interact with Ced-9 to derepress Ced-4 and permit activa-In mammals the Ced-4 homologue, Apaf-1, together with cytochrome c released from mitochondria, promotes oligomerization and activation of the mammalian apical caspase, caspase-9. Activated caspase-9 subsequently processes downstream effector caspases (e.g., caspase-3) thus initiating a caspase cascade leading to apoptosis. In this pathway, the Bcl-2 family of proteins is thought to act upstream of caspase activation, perhaps regulating the initial phase of caspase processing, while in other situations (e.g., death receptor signaling), Bcl-2 proteins may function to amplify or propagate an already initiated caspase cascade. The Bcl-2 related proteins can form homo-and hetero-dimers through their conserved domains (BH domains). This ability to dimerize, and the relative abundance of the pro-and anti-apoptotic members, are thought to be important determinants regulating the propensity of a given cell to convert death signals into an apoptotic response (re-How do the mammalian Bcl-2 proteins function to regulate cell death? Since human Bcl-2 can partially reverse cell death defects found in Ced-9 mutant worms, Ced-9 and Bcl-2 are thought to share at least some functional properties (Vaux et al., 1992; Hengartner and Horvitz, 1994). Thus, one proposed mechanism draws on possible …