Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins
- Author(s)
- Hockings, C; Alsop, AE; Fennell, SC; Lee, EF; Fairlie, WD; Dewson, G; Kluck, RM;
- Details
- Publication Year 2018-02-19,Volume 25,Issue #4,Page 719-732
- Journal Title
- Cell Death and Differentiation
- Publication Type
- Journal Article
- Abstract
- The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xL inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-xL and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim. In contrast, in a Bid and Bak mixture, Bcl-xL preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xL could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-xL. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.
- Publisher
- Springer Nature
- Research Division(s)
- Cell Signalling And Cell Death; Molecular Genetics Of Cancer
- PubMed ID
- 29459767
- Publisher's Version
- https://doi.org/10.1038/s41418-017-0010-6
- NHMRC Grants
- NHMRC/1008434, NHMRC/1016701, NHMRC/1113133,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-02-28 10:12:06
Last Modified: 2018-05-07 09:40:03