Gene structure, alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim

Bim is a proapoptotic protein of the Bcl-2 family that shares only the shor t BH3 domain with other members. It has three isoforms, apparently produced by alternative splicing. The demonstration that Bim is essential for certa in apoptotic responses and to prevent overproduction of hematopoietic cells suggests that it may be a tumor suppressor. We have, therefore, investigat ed the organization of the mouse Bim gene, delineating its promoter and spl icing, and positioned the gene on both mouse and human chromosomes. Bim has six exons, but the third is a facultative intron that is spliced out in th e mRNAs for the smaller isoforms (Bim, and Bim,), but not that encoding the largest isoform (Bim(EL)). The 0.8-kb region 5' to exon 1, which contains a TATA-less promoter and binding sites for several transcription factors, c an drive expression of a reporter gene. Mouse Bim localizes to the distal t hird of Chromosome (Chr) 2, near the F-G boundary, and its: human counterpa rt to Chr 2q12 or q13. Deletions of these bands have been reported in ten t umors (eight hematopoietic), reinforcing the possibility that Bim is a tumo r suppressor. These findings should help to clarify the regulation of Bim e xpression and to assess whether mutations involving Bim contribute to neopl astic and other diseases.