Bim: a novel member of the Bcl-2 family that promotes apoptosis

Abstract

Certain members of the Bcl-2 family inhibit apoptosis while others facilitate this physiological process of cell death. An expression screen for proteins that bind to Bcl-2 yielded a small novel protein, denoted Bim, whose only similarity to any known protein is the short (nine amino acid) BH3 motif shared by most Bcl-2 homologues. Bim provokes apoptosis, and the BH3 region is required for Bcl-2 binding and for most of its cytotoxicity. Like Bcl-2, Bim possesses a hydrophobic C-terminus and localizes to intracytoplasmic membranes. Three Bim isoforms, probably generated by alternative splicing, all induce apoptosis, the shortest being the most potent. Wild-type Bcl-2 associates with Bim in vivo and modulates its death function, whereas Bcl-2 mutants that lack survival function do neither. Significantly, Bcl-x L and Bcl-w, the two closest homologues of Bcl-2, also bind to Bim and inhibit its activity, but more distant viral homologues, adenovirus E1B19K and Epstein-Barr virus BHRF-1, can do neither. Hence, Bim appears to act as a 'death ligand' which can only neutralize certain members of the pro-survival Bcl-2 sub-family.

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

“…To analyse Bim sensitivity, Bim S was expressed in the cell lines by transient transfection. Bim S is a constitutively active isoform of Bim that is not subject to post-translational modification and activation; all Bim isoforms are presumed to induce apoptosis by the same mechanism (O'Connor et al, 1998;Puthalakath et al, 1999). Transfection of Bax was included as an additional marker of mitochondrial sensitivity.…”

BH3-only proteins: key regulators of neuronal apoptosis

“…Bim EL , Bim L and Bim S are the major variants (see Figure 1a), generated as a result of alternate splicing of bim transcripts. 34 All three proteins are proapoptotic but differ in their potency such that Bim S 4Bim L 4Bim EL . Bim EL and Bim L contain a region, not present in Bim S (Figure 1a), that allows them to interact, in certain cell types, with LC8 (dynein light chain 1), a component of the dynein motor complex associated with the microtubule cytoskeleton.…”

“…Numbers refer to amino-acid residues in the mouse Bim protein. 34 The positions of the LC8 binding domain (LC8 BD), BH3 domain and hydrophobic transmembrane domain (TM) are indicated. The region unique to Bim EL (shaded) is shown together with the ERK/JNK phosphorylation site at serine 65.…”

Bcl-xS and Bax induce different apoptotic pathways in PC12 cells

“…The anti-apoptotic members of the Bcl-2 family include Bcl-2, Bcl-x L , Bcl-W, Mcl-1, B¯1/ A1, E1B 19k, Epstein-Barr virus BHRF1, and Caenorhabditis elegans Ced-9. Pro-apoptotic members include Bax, Bak, Bad, Bik, Bid, Bim, Hrk, Bok/Mtd, Blk and Bcl-x S (for review see Hegde et al, 1998;Hsu et al, 1997;Kelekar and Thompson, 1998;O'Connor et al, 1998;Strasser et al, 1997 and references therein). The homology between members of the Bcl-2 family resides mainly within four conserved domains, designated Bcl-2 homology (BH) domains BH1, BH2, BH3 and BH4.…”