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Identification and Characterization of Bim, a Novel Proapoptotic BH3-only Splice Variant of Bim¹

Department of Carcinogenesis, the University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957 [J-W. L., D. Cha., S-H. T., D. G. T.], and Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48226 [D. Cho.]

BH3 (Bcl-2 homology 3)-only proteins of the Bcl-2 family play an essentialrole in apoptosis. In this study, a novel human BH3-only protein, Bcl-2-interacting mediator (Bim), was identified during our study of regulation of prostate cancer cell death by Bcl-2 family proteins. Bim shares the highest amino acid sequence homology to BimEL and BimL, two proapoptotic BH3-only Bcl-2 proteins derived from alternative mRNA splicing. Genomic studies indicate that Bim is a novel splice variant of Bim and is generated as a result of the retention of a 126-bp intron of the bim gene. Bim mRNA displays a tissue-specific expression pattern distinct from those of the other Bim isoforms. Subcellular fractionation studies indicate that Bim is localized both in intracellular membranes and cytosol. Interestingly, Bim mRNA, similar to the BimEL protein, is up-regulated in the majority of the prostate cancer cell lines studied, whereas several other proapoptotic Bcl-2 proteins, including Bax, Bak, and Bad, are down-regulated in prostate cancer cells. Functional studies indicate that Bim inhibits clonal growth in prostate cancer cells and promotes apoptosis, which is inhibited by overexpressing Bcl-2. Because both Bim and BimEL are proapoptotic BH3-only proteins and both are up-regulated in prostate cancer cells, they may play a unique role in prostate cancer development.

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