10018

BCL2L11

BAM|BIM|BOD;BCL2-like 11 (apoptosis facilitator);BCL2L11;BCL2-like 11 (apoptosis facilitator)

bcl-2 interacting mediator of cell death|bcl-2 interacting protein Bim|bcl-2-like protein 11|bcl-2-related ovarian death agonist

2q13

protein-coding

Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.

Overexpression of the transcriptional regulator Myc is thought to be the cause or a contributing factor in the development of a large number of human lymphomas and certain other cancers. Apoptotic cell death constitutes a tumor suppressive mechanism, particularly in the context of Myc overexpression. Accordingly, lymphoma development in Emu-Myc transgenic mice, which mimic the Myc/IgH chromosomal translocation that causes Burkitt lymphoma, is accelerated by concomitant overexpression of anti-apoptotic Bcl-2 family members or loss of pro-apoptotic BH3-only proteins, such as Bim. Bim binds with high affinity to all pro-survival Bcl-2-like proteins and can also interact with Bax/Bak, but it remains unclear which of these interactions are critical for its tumor suppressive function. We have previously generated knock-in mutant mice in which the BH3 region of Bim has been exchanged with that for Bad, Noxa or Puma so that it can only bind to select pro-survival Bcl-2-like proteins: Bim(Bad) binding to Bcl-2, Bcl-x(L) and Bcl-w, but not Mcl-1 or A1; Bim(Noxa) binding only to Mcl-1 and A1 and as a control, Bim(Puma), which can still bind all pro-survival Bcl-2-like proteins. We have now inter-crossed these Bim mutant mice with Emu-Myc transgenic mice, and found that both the Bim(Bad) and the Bim(Noxa) mutations but not the Bim(Puma) mutation greatly accelerate Myc-induced lymphoma development and increase leukemic burden. These results demonstrate that for optimal tumor suppressive activity, Bim must be able to interact with all and not just select pro-survival Bcl-2 family members.