The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions
The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions
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DOI：
10.4161/cc.6.20.4807
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发表时间：
2007-10-15
期刊：
影响因子：
4.3
通讯作者：
Dobbelaere, Dirk A.
中科院分区：
文献类型：
--
作者：
Blazkova, Hana;von Schubert, Conrad;Dobbelaere, Dirk A.
I kappa B激酶(IKK)复合体控制炎症、免疫反应、细胞存活和正常细胞和肿瘤细胞的增殖等过程。通过激活核因子kappaB，IKK复合体促进了G(1)/S的转变，并首次提出了IKKα也调节进入有丝分裂的证据。然而，在什么阶段需要IKK，以及IKK是否也通过有丝分裂和胞质分裂促进进展，目前还没有确定。在这项研究中，我们使用一种有效的IKK的变构小分子抑制剂BMS-345541，在G(2)期和有丝分裂期间特异性地抑制IKK。我们发现BMS-345541影响几个有丝分裂细胞周期的转变，包括有丝分裂进入、前中期到后期进展和胞质分裂。在S时相释放的细胞中加入BMS-345541可阻断Aurora A、B、C的激活、CDK1的激活和组蛋白H3的磷酸化。此外，用BMS-345541处理有丝分裂细胞会导致Cyclin B1和Securin早熟、染色体分离缺陷和胞质分裂不正确。BMS-345541还被发现超越了诺康唑抑制细胞中的纺锤体检查点。使用BMS-345541进行的体外激酶分析表明，这些作用主要不是由于BMS-345541对有丝分裂酶如CDK1、极光A或B、PIK1或NEK2的直接抑制作用。这项研究指出了IKK在细胞周期进程中的一个新的潜在作用。由于细胞周期的失调是肿瘤形成和发展的标志之一，新发现的BMS-345541功能水平可能有助于细胞周期控制的研究，并可能为未来的治疗设计提供有价值的线索。
The I kappa B kinase (IKK) complex controls processes such as inflammation, immune responses, cell survival and the proliferation of both normal and tumor cells. By activating NF kappa B, the IKK complex contributes to G(1)/S transition and first evidence has been presented that IKK alpha also regulates entry into mitosis. At what stage IKK is required and whether IKK also contributes to progression through mitosis and cytokinesis, however, has not yet been determined. In this study, we use BMS-345541, a potent allosteric small molecule inhibitor of IKK, to inhibit IKK specifically during G(2) and during mitosis. We show that BMS-345541 affects several mitotic cell cycle transitions, including mitotic entry, prometaphase to anaphase progression and cytokinesis. Adding BMS-345541 to the cells released from arrest in S-phase blocked the activation of Aurora A, B and C, Cdk1 activation and histone H3 phosphorylation. Additionally, treatment of the mitotic cells with BMS-345541 resulted in precocious cyclin B1 and securin degradation, defective chromosome separation and improper cytokinesis. BMS-345541 was also found to override the spindle checkpoint in nocodazole-arrested cells. In vitro kinase assays using BMS-345541 indicate that these effects are not primarily due to a direct inhibitory effect of BMS-345541 on mitotic kinases such as Cdk1, Aurora A or B, PIk1 or NEK2. This study points towards a new potential role of IKK in cell cycle progression. Since deregulation of the cell cycle is one of the hallmarks of tumor formation and progression, the newly discovered level of BMS-345541 function could be useful for cell cycle control studies and may provide valuable clues for the design of future therapeutics.