Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis by phosphorylation of Mcl-1, promoting its degradation and freeing Bak from sequestration.
Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis by phosphorylation of Mcl-1, promoting its degradation and freeing Bak from sequestration.
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DOI：
10.1016/j.bcp.2011.10.008
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发表时间：
2012-01-15
影响因子：
5.8
通讯作者：
Chambers, Timothy C.
中科院分区：
文献类型：
--
作者：
Chu, Rong;Terrano, David T.;Chambers, Timothy C.
Mcl - 1是凋亡调节蛋白Bcl - 2家族中主要的抗凋亡成员之一。在本研究中，我们探讨了Mcl - 1在有丝分裂阻滞诱导的凋亡中的作用。长春碱处理KB - 3细胞最初导致Mcl - 1发生对磷酸酶敏感的迁移率变动，随后Mcl - 1蛋白表达缺失，而MG132可阻止这种情况，这表明磷酸化引发了蛋白酶体介导的降解。Mcl - 1磷酸化/降解是对微管抑制的特异性反应，在致死浓度的DNA损伤剂作用下不会发生。在因Bcl - xL过表达而使凋亡受阻的细胞中，长春碱处理导致Mcl - 1降解，这表明Mcl - 1降解不是凋亡的结果。在经历有丝分裂的同步化细胞中观察到Mcl - 1部分可逆的磷酸化，而如果同步化细胞用长春碱处理，则观察到更广泛的磷酸化以及随后Mcl - 1的降解。Mcl - 1磷酸化与细胞周期蛋白B的表达密切相关，特异性的细胞周期蛋白依赖性激酶（Cdk）抑制剂可阻断长春碱诱导的Mcl - 1磷酸化、其后续的降解，并提高有丝分裂阻滞后的细胞活力。免疫共沉淀研究表明，在未处理的细胞中，Mcl - 1与Bak形成复合物，但不与Bax或Noxa形成复合物，并且Bak随着Mcl - 1表达的缺失而被激活。这些结果表明，Cdk1/细胞周期蛋白B通过Mcl - 1磷酸化在有丝分裂阻滞诱导的凋亡中起关键作用，促进其降解并随后使Bak从隔离状态中释放出来。
Mcl-1 is one of the major anti-apoptotic members of the Bcl-2 family of apoptotic regulatory proteins. In this study we investigated the role of Mcl-1 in mitotic arrest-induced apoptosis. Vinblastine treatment of KB-3 cells initially resulted in a phosphatase-sensitive mobility shift in Mcl-1 and then subsequent loss of Mcl-1 protein expression which was prevented by MG132, suggesting that phosphorylation triggered proteosome-mediated degradation. Mcl-1 phosphorylation/degradation was a specific response to microtubule inhibition and did not occur in response to lethal concentrations of DNA damaging agents. Vinblastine treatment caused degradation of Mcl-1 in cells in which apoptosis was blocked by Bcl-xL overexpression, indicating that Mcl-1 degradation was not a consequence of apoptosis. A partial reversible phosphorylation of Mcl-1 was observed in synchronized cells traversing mitosis, whereas more extensive phosphorylation and subsequent degradation of Mcl-1 was observed if synchronized cells were treated with vinblastine. Mcl-1 phosphorylation closely paralleled cyclin B expression, and specific cyclin-dependent kinase (Cdk) inhibitors blocked vinblastine-induced Mcl-1 phosphorylation, its subsequent degradation, and improved cell viability after mitotic arrest. Co-immunoprecipitation studies indicated that Mcl-1 was complexed with Bak, but not Bax or Noxa, in untreated cells, and that Bak became activated in concert with loss of Mcl-1 expression. These results suggest that Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis via Mcl-1 phosphorylation, promoting its degradation and subsequently releasing Bak from sequestration.
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影响因子：
12.4
作者：
Opferman, J. T.
通讯作者：
Opferman, J. T.
影响因子：
4.8
作者：
Clohessy, JG;Zhuang, JG;Brady, HJM
通讯作者：
Brady, HJM
NBK/BIK 拮抗 MCL-1 和 BCL-XL，并响应蛋白质合成抑制激活 BAK 介导的细胞凋亡
影响因子：
10.5
作者：
Shimazu, Tsutomu;Degenhardt, Kurt;Inouye, Masayori
通讯作者：
Inouye, Masayori
DOI：
10.1073/pnas.0600447103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Vassilev, Lyubomir T.;Tovar, Christian;Chen, Li
通讯作者：
Chen, Li
影响因子：
5.8
作者：
Brantley-Finley, C;Lyle, CS;Chambers, TC
通讯作者：
Chambers, TC