Bim must be able to engage all pro-survival Bcl-2 family members for efficient tumor suppression
Details
Publication Year 2012-07, Volume 31, Issue #28, Page 3392-3396
Journal Title
ONCOGENE
Publication Type
Journal Article
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 El-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 proapoptotic 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-xL 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 El-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. Oncogene (2012) 31, 3392-3396; doi: 10.1038/onc.2011.508; published online 14 November 2011
Publisher
NATURE PUBLISHING GROUP
Keywords
B-CELL LYMPHOMAGENESIS; TRANSGENIC MICE; C-MYC; MEMBRANE PERMEABILIZATION; PROTEINS; DEATH; PUMA; EXPRESSION; LEUKEMIA; DRIVEN
WEHI Research Division(s)
Molecular Genetics Of Cancer
Rights Notice
© 2013 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Creation Date: 2012-07-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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