Bak 被 Mcl-1 和 Bcl-x 隔离赋予对 BH3 仅有蛋白的差异抗性。
Mcl-1 and Bcl-x sequestration of Bak confers differential resistance to BH3-only proteins.
机构信息
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.
出版信息
Cell Death Differ. 2018 Mar;25(4):721-734. doi: 10.1038/s41418-017-0010-6. Epub 2018 Feb 19.
Abstract
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.
摘要
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。
相似文献
1
Mcl-1 and Bcl-x sequestration of Bak confers differential resistance to BH3-only proteins.Bak 被 Mcl-1 和 Bcl-x 隔离赋予对 BH3 仅有蛋白的差异抗性。
Cell Death Differ. 2018 Mar;25(4):721-734. doi: 10.1038/s41418-017-0010-6. Epub 2018 Feb 19.
2
Bax/Bak activation in the absence of Bid, Bim, Puma, and p53.在缺乏Bid、Bim、Puma和p53的情况下Bax/Bak激活。
Cell Death Dis. 2016 Jun 16;7(6):e2266. doi: 10.1038/cddis.2016.167.
3
Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism.双重抑制 Bcl-2 和 Bcl-xL 通过 GSK3 和 Bim 依赖性机制显著增强了 PI3K 抑制诱导的人髓系白血病细胞凋亡。
Cancer Res. 2013 Feb 15;73(4):1340-51. doi: 10.1158/0008-5472.CAN-12-1365. Epub 2012 Dec 12.
4
Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation.Mcl-1蛋白下调通过协同诱导Bak激活和Bax易位增强ABT-737的致死性。
Cancer Res. 2007 Jan 15;67(2):782-91. doi: 10.1158/0008-5472.CAN-06-3964.
5
Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak.促生存 Bcl-2 家族成员仅通过抑制 Bax 和 Bak 间接影响自噬。
Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8512-7. doi: 10.1073/pnas.1406425111. Epub 2014 May 27.
6
BH3-only activator proteins Bid and Bim are dispensable for Bak/Bax-dependent thrombocyte apoptosis induced by Bcl-xL deficiency: molecular requisites for the mitochondrial pathway to apoptosis in platelets.BH3 仅激活蛋白 Bid 和 Bim 在 Bcl-xL 缺乏诱导的由 Bak/Bax 依赖性血小板凋亡中是可有可无的：血小板凋亡中线粒体途径的分子需求。
J Biol Chem. 2011 Apr 22;286(16):13905-13. doi: 10.1074/jbc.M110.195370. Epub 2011 Mar 2.
7
Co-administration of the mTORC1/TORC2 inhibitor INK128 and the Bcl-2/Bcl-xL antagonist ABT-737 kills human myeloid leukemia cells through Mcl-1 down-regulation and AKT inactivation.mTORC1/TORC2抑制剂INK128与Bcl-2/Bcl-xL拮抗剂ABT-737联合使用可通过下调Mcl-1和使AKT失活来杀死人髓系白血病细胞。
Haematologica. 2015 Dec;100(12):1553-63. doi: 10.3324/haematol.2015.130351. Epub 2015 Oct 9.
8
Bim upregulation by histone deacetylase inhibitors mediates interactions with the Bcl-2 antagonist ABT-737: evidence for distinct roles for Bcl-2, Bcl-xL, and Mcl-1.组蛋白去乙酰化酶抑制剂上调Bim介导其与Bcl-2拮抗剂ABT-737的相互作用：Bcl-2、Bcl-xL和Mcl-1不同作用的证据
Mol Cell Biol. 2009 Dec;29(23):6149-69. doi: 10.1128/MCB.01481-08. Epub 2009 Oct 5.
9
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.BH3模拟物ABT-737靶向选择性Bcl-2蛋白，若Mcl-1被中和，则通过Bak/Bax有效诱导细胞凋亡。
Cancer Cell. 2006 Nov;10(5):389-99. doi: 10.1016/j.ccr.2006.08.027.
10
BH3-only protein bid participates in the Bcl-2 network in healthy liver cells.仅含BH3结构域的蛋白质Bid参与健康肝细胞中的Bcl-2网络。
Hepatology. 2009 Dec;50(6):1972-80. doi: 10.1002/hep.23207.
引用本文的文献
1
Computational design of potent and selective binders of BAK and BAX.BAK和BAX强效选择性结合剂的计算设计
Sci Adv. 2025 Sep 5;11(36):eadt4170. doi: 10.1126/sciadv.adt4170.
2
Structural basis of BAK sequestration by MCL-1 in apoptosis.MCL-1在细胞凋亡中隔离BAK的结构基础。
Mol Cell. 2025 Apr 17;85(8):1606-1623.e10. doi: 10.1016/j.molcel.2025.03.013. Epub 2025 Apr 4.
3
Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors.解析MCL-1与BAK相互作用中的分子特异性及其对设计强效MCL-1抑制剂的意义。
Cell Death Differ. 2025 Feb 3. doi: 10.1038/s41418-025-01454-2.
4
Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5.仅含BH3结构域的蛋白BNIP5对BAK介导的细胞凋亡的抑制作用。
Cell Death Differ. 2025 Feb;32(2):320-336. doi: 10.1038/s41418-024-01386-3. Epub 2024 Oct 15.
5
Profiling protein-protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia.分析蛋白质-蛋白质相互作用，预测 B 细胞淋巴瘤-2 同源物-3 模拟物对急性髓系白血病的疗效。
Nat Biomed Eng. 2024 Nov;8(11):1379-1395. doi: 10.1038/s41551-024-01241-3. Epub 2024 Jul 18.
6
The C-terminal sequences of Bcl-2 family proteins mediate interactions that regulate cell death.Bcl-2 家族蛋白的 C 末端序列介导了调节细胞死亡的相互作用。
Biochem J. 2024 Jul 17;481(14):903-922. doi: 10.1042/BCJ20210352.
7
A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.一种新型抑制 BAK 抗体可用于评估癌细胞中非激活的 BAK。
Cell Death Differ. 2024 Jun;31(6):711-721. doi: 10.1038/s41418-024-01289-3. Epub 2024 Apr 6.
8
The Role of FNDC5/Irisin in Cardiovascular Disease.FNDC5/鸢尾素在心血管疾病中的作用。
Cells. 2024 Feb 2;13(3):277. doi: 10.3390/cells13030277.
9
Apoptotic mitochondrial poration by a growing list of pore-forming BCL-2 family proteins.越来越多的形成孔的 BCL-2 家族蛋白导致线粒体凋亡穿孔。
Bioessays. 2023 Mar;45(3):e2200221. doi: 10.1002/bies.202200221. Epub 2023 Jan 17.
10
Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins.线粒体 E3 泛素连接酶 MARCHF5 独立于 BH3 仅蛋白控制 BAK 的凋亡活性。
Cell Death Differ. 2023 Mar;30(3):632-646. doi: 10.1038/s41418-022-01067-z. Epub 2022 Sep 28.
本文引用的文献
1
Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia.维奈托克治疗既往治疗的慢性淋巴细胞白血病患者。
Clin Cancer Res. 2017 Aug 15;23(16):4527-4533. doi: 10.1158/1078-0432.CCR-16-0955. Epub 2017 Jan 18.
2
Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance.BCL-xL在亚细胞膜上对BH3蛋白的紧密隔离导致细胞凋亡抗性。
Cell Rep. 2016 Dec 20;17(12):3347-3358. doi: 10.1016/j.celrep.2016.11.064.
3
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.MCL1 抑制剂 S63845 在多种癌症模型中具有良好的耐受性和疗效。
Nature. 2016 Oct 27;538(7626):477-482. doi: 10.1038/nature19830. Epub 2016 Oct 19.
4
Physiological restraint of Bak by Bcl-xL is essential for cell survival.Bcl-xL对Bak的生理性抑制对于细胞存活至关重要。
Genes Dev. 2016 May 15;30(10):1240-50. doi: 10.1101/gad.279414.116. Epub 2016 May 19.
5
Mito-priming as a method to engineer Bcl-2 addiction.线粒体启动作为一种构建对Bcl-2成瘾的方法。
Nat Commun. 2016 Feb 2;7:10538. doi: 10.1038/ncomms10538.
6
In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-XL and Mcl-1 but in the absence of active BH3-only proteins.在未转化的细胞中，Bak在抗凋亡蛋白Bcl-XL和Mcl-1缺失时激活，但前提是不存在活性的仅含BH3结构域的蛋白。
Cell Death Dis. 2015 Nov 26;6(11):e1996. doi: 10.1038/cddis.2015.341.
7
Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells.组成型BAK激活作为恶性淋巴造血细胞药物敏感性的决定因素。
Genes Dev. 2015 Oct 15;29(20):2140-52. doi: 10.1101/gad.267997.115.
8
An interconnected hierarchical model of cell death regulation by the BCL-2 family.BCL-2家族对细胞死亡调控的相互关联的层级模型。
Nat Cell Biol. 2015 Oct;17(10):1270-81. doi: 10.1038/ncb3236. Epub 2015 Sep 7.
9
Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax.双向嵌合体表明，大多数仅含BH3结构域的蛋白质可直接激活Bak和Bax，且对Bak和Bax无偏好性。
Cell Death Dis. 2015 Apr 23;6(4):e1735. doi: 10.1038/cddis.2015.105.
10
Dissociation of Bak α1 helix from the core and latch domains is required for apoptosis.Bakα1 螺旋与核心和闩锁结构域的解离是细胞凋亡所必需的。
Nat Commun. 2015 Apr 16;6:6841. doi: 10.1038/ncomms7841.
Zotero 插件