title: Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression.
abstract: 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 Eμ-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 Eμ-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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Mérino
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc
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