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Title: Mcl-1 and Bcl-xLsequestration of Bak confers differential resistance to BH3-only proteins.
Austin Authors: Hockings, Colin;Alsop, Amber E;Fennell, Stephanie C;Lee, Erinna F;Fairlie, W Douglas;Dewson, Grant;Kluck, Ruth M
Affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia
Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia
Department of Chemical Engineering and Biotechnology, Cambridge, CB3 0AS, UK
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Melbourne, VIC, 3086, Australia
Issue Date: 2018 2018-02-19
Publication information: Cell death and differentiation 2018; 25(4): 721-734
Abstract: The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-xLinhibit 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-xLand 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-xLpreferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-xLcould 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.
DOI: 10.1038/s41418-017-0010-6
ORCID: 0000-0001-7894-7294
PubMed URL: 29459767
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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