Role of Bcl-2 family members in invertebrates

Proteins belonging to the Bcl-2 family function as regulators of 'life-or-death' decisions in response to various intrinsic and extrinsic stimuli. In mammals, cell death is controlled by pro- and anti-apoptotic members of the Bcl-2 family, which function upstream of the caspase cascade. Structural and functional homologues of the Bcl-2 family proteins also exist in lower eukaryotes, such as nematodes and flies. In nematodes, an anti-apoptotic Bcl-2 family protein, CED-9, functions as a potent cell death inhibitor, and a BH3-only protein, EGL-1, acts as an inhibitor of CED-9 to facilitate the spatio-temporal regulation of programmed cell death. On the other hand, the Drosophila genome encodes two Bcl-2 family proteins, Drob-1/Debcl/dBorg-1/dBok and Buffy/dBorg-2, both of which structurally belong to the pro-apoptotic group, despite abundant similarities in the cell death mechanisms between flies and vertebrates. Drob-1 acts as a pro-apoptotic factor in vitro and in vivo, and Buffy/dBorg-2 exhibits a weak anti-apoptotic function. The ancestral role of the Bcl-2 family protein may be pro-apoptotic, and the evolution of the functions of this family of proteins may be closely linked with the contribution of mitochondria to the cell death pathway. (C) 2003 Elsevier B.V. All rights reserved.