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.
Cell Death Differ. 2018 Mar;25(4):721-734. doi: 10.1038/s41418-017-0010-6. Epub 2018 Feb 19.
The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x 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-x 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-x preferentially sequestered Bid while Mcl-1 preferentially sequestered Bak. Notably, Bcl-x could sequester Bak in response to the BH3 mimetic ABT-737, despite this molecule targeting Bcl-x. These findings highlight the importance of Bak sequestration in resistance to anti-cancer treatments, including BH3 mimetics.
生存促进 Bcl-2 家族蛋白 Mcl-1 和 Bcl-x 通过隔离 BH3 仅蛋白（如 Bid 和 Bim）（模式 1）或效应蛋白 Bak 和 Bax（模式 2）来抑制细胞凋亡。为了更好地理解模式 1 和模式 2 在阻止细胞死亡中的作用，以及如何克服对细胞死亡的抵抗，我们研究了 Bcl-2 家族蛋白的规定混合物。在 Bim 和 Bak 混合物中，Bcl-x 和 Mcl-1 不仅隔离了 Bid，而且还隔离了因 Bid 激活而形成的 Bak。相比之下，在 Bid 和 Bak 混合物中，Bcl-x 优先隔离 Bid，而 Mcl-1 优先隔离 Bak。值得注意的是，尽管 ABT-737 靶向 Bcl-x，但 Bcl-x 仍能响应 BH3 模拟物 ABT-737 隔离 Bak。这些发现强调了 Bak 隔离在抵抗抗癌治疗（包括 BH3 模拟物）中的重要性。
