Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins
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
WEHI Research Division(s)
Cell Signalling And Cell Death; Molecular Genetics Of Cancer
PubMed ID
29459767
NHMRC Grants
NHMRC/1008434 NHMRC/1016701 NHMRC/1113133
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
An error has occurred. This application may no longer respond until reloaded. Reload 🗙