APOPTOSIS Drosophila Bcl-2 Family Member

Abstract: Three essential components of the programmed cell death or apoptosis pathway have been defined in Caenorhabditis elegans. The components are the caspases represented by CED-3 in C.elegans, the Apaf-1 caspase activator proteins represented by CED-4, and the Bcl-2 family of regulators of caspase activation represented by CED-9. Homologs of CED-3 and CED-4 have been previously identified in Drosophila. Igaki et al. have identified Drob-1, the first Drosophila member of the CED-9/Bcl-2 family of apoptotic regulators. Drob-1, with eight predicted helices, four Bcl-2-homology domains, and a COOH-terminal hydrophobic tail, was most similar to the proapoptotic Mtd/Bok member of the Bcl-2 family. A proapoptotic role for Drob-1 was established by misexpression in the developing retina and by transfection into Drosophila S2 cells. The retinas showed gene-dosage dependent reduction in the number of photoreceptor neurons and the transfected S2 cells underwent cell death with morphological features of apoptosis and increased caspase activity. Drob-1 also initiated a caspase-independent pathway for apoptosis as the apoptotic activity of Drob-1 in the S2 cells was unaffected by caspase inhibitors. The ability of Drob-1 to cause apoptosis appeared to be dependent on localization to mitochondrial membranes because deletion of the COOH-terminal hydrophobic sequence resulted in loss of apoptotic activity in transfected S2 cells. Identification and characterization of Drob-1 as a caspase-dependent and caspase-independent mediator of apoptosis may help clarify the mechanisms by which the Bcl-2/CED-9 family members regulate cell death.

Igaki, T., Kanuka, H., Inohara, N., Sawamoto, K., Núñez, G., Okano, H., and Miura, M. (2000) Drob-1, a Drosophila member of the Bcl-2/CED-9 family that promotes cell death. Proc. Natl. Acad. Sci. U.S.A. 97: 674-679. [Abstract] [Full Text]