Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension

The Bcl-2 family of proteins plays a central regulatory role in apoptosis, We have identified a novel, widely expressed Bcl-2 member which we have nam ed Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apopt otic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4, Unlike Bcl-2, however, the C-terminal membrane anchor region is pre ceded by a unique 250 amino acid insertion containing two tandem repeats. N o interaction of Bcl-rambo with either anti-apoptotic (Bcl-2, Bcl-x(L), Bcl -w, A1, MCL-1, E1B-1SK, and BHRF1) or pro-apoptotic (Bax, Bak, Bik, Bid, Bi m, and Bad) members of the Bcl-2 family was observed. In mammalian cells, B cl-rambo was localized to mitochondria, and its overexpression induces apop tosis that is specifically blocked by the caspase inhibitors, IAPs, whereas inhibitors controlling upstream events of either the 'death receptor' (FLI P, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. Surprisingly, the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain and not by the Bcl-2 homology region. T hus, Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.