BIM - A NOVEL MEMBER OF THE BCL-2 FAMILY THAT PROMOTES APOPTOSIS

Certain members of the Bcl-2 family inhibit apoptosis while others fac ilitate this physiological process of cell death, An expression screen for proteins that bind to Bcl-2 yielded a small novel protein, denote d Bim, whose only similarity to any known protein is the short (nine a mino acid) BH3 motif shared by most Bcl-2 homologues. Bim provokes apo ptosis, and the BH3 region is required for Bcl-2 binding and for most of its cytotoxicity. Like Bcl-2, Bim possesses a hydrophobic C-terminu s and localizes to intracytoplasmic membranes, Three Bim isoforms, pro bably generated by alternative splicing, all induce apoptosis, the sho rtest being the most potent, Wild-type Bcl-2 associates with Bim in vi vo and modulates its death function, whereas Bcl-2 mutants that lack s urvival function do neither, Significantly, Bcl-x(L) and Bcl-w, the tw o closest homologues of Bcl-2, also bind to Bim and inhibit its activi ty, but more distant viral homologues, adenovirus E1B19K and Epstein-B arr virus BHRF-1, can do neither, Hence, Bim appears to act as a 'deat h ligand' which can only neutralize certain members of the pro-surviva l Bcl-2 sub-family.