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  • Title: Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins.
    Author: Hockings C, Alsop AE, Fennell SC, Lee EF, Fairlie WD, Dewson G, Kluck RM.
    Journal: Cell Death Differ; 2018 Mar; 25(4):721-734. PubMed ID: 29459767.
    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.
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