Molecular cloning and characterization of six novel isoforms of human Bim,a member of the proapoptotic Bcl-2 family

Bim protein is one of the BH3-only proteins, members of the Bcl-2 family th at have only one of the Bcl-2 homology regions, BH3. BH3-only proteins are essential initiators Of apoptotic cell death. Thus far, three isoforms of B im have been reported, i.e. Bim(EL), Bim(L) and Bim(s). Here we report the cloning and characterization of six novel isoforms of human Bim, designated as Bim alpha1, alpha2, and beta1-beta4, which are generated by alternative splicing. Unlike the three known isoforms, none of these novel isoforms co ntained a C-terminal hydrophobic region. Among the novel isoforms, only Bim alpha1 and alpha2 contained a BH3 domain and were proapoptotic, although l ess potent than the classical isoforms. These two isoforms localized, at le ast in part, in mitochondria when transiently expressed in HeLa cells as a green fluorescent protein-fused form. These results suggest that the BH3 do main is necessary for induction of apoptosis and mitochondrial localization but not sufficient for the full proapoptotic activity. While the classical isoforms were always predominantly expressed in transformed cells, express ion profiles of him isoforms were highly variable among normal tissues at l east in humans, suggesting a tissue-specific transcriptional regulation of bim. (C) 2001 Federation of European Biochemical Societies. Published by El sevier Science B.V. All rights reserved.