Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim

Abstract

BH3 (Bcl-2 homology 3)-only proteins of the Bcl-2 family play an essential role in apoptosis. In this study, a novel human BH3-only protein, Bcl-2-interacting mediator (Bim)gamma, was identified during our study of regulation of prostate cancer cell death by Bcl-2 family proteins. Bimgamma 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 Bimgamma 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. Bimgamma mRNA displays a tissue-specific expression pattern distinct from those of the other Bim isoforms. Subcellular fractionation studies indicate that Bimgamma is localized both in intracellular membranes and cytosol. Interestingly, Bimgamma 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 Bimgamma inhibits clonal growth in prostate cancer cells and promotes apoptosis, which is inhibited by overexpressing Bcl-2. Because both Bimgamma 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.