A role for IκB kinase 2 in bipolar spindle assembly
A role for IκB kinase 2 in bipolar spindle assembly
复制标题
DOI：
10.1073/pnas.0706493104
复制
发表时间：
2007-10-23
影响因子：
11.1
通讯作者：
Chanda, Sumit K.
中科院分区：
文献类型：
--
作者：
Irelan, Jeffrey T.;Murphy, Thomas J.;Chanda, Sumit K.
κ B激酶2 （IKK2或IKK β）是IKK复合体的一个组成部分，它协调细胞对多种细胞外刺激的反应，包括细胞因子、微生物感染和应激。在响应外部刺激时，该复合物被激活，导致I κ B蛋白的磷酸化和随后的蛋白酶体介导的降解。这一事件触发nf - κ B转录因子的核输入，激活调节多种基本生物过程的基因转录，包括免疫反应、细胞存活和发育。在这里，我们定义了IKK2在正常有丝分裂过程和维持纺锤体双极性中的重要作用。化学和遗传干扰IKK2促进多极纺锤体的形成和染色体错分离。IKK2的缺失导致Aurora A蛋白稳定性的降低，并导致Aurora A底物（有丝分裂马达KIF11）的过度激活。这些数据支持IKK2在有丝分裂过程中作为Aurora a信号拮抗剂的功能。此外，我们的研究结果表明IKK2在维持基因组稳定性中的直接作用，并强调了靶向这种激酶进行治疗干预的致癌后果的潜力。
I kappa B kinase 2 (IKK2 or IKK beta) is a component of the IKK complex that coordinates the cellular response to a diverse set of extracellular stimuli, including cytokines, microbial infection, and stress. In response to an external stimulus, the complex is activated, resulting in the phosphorylation and subsequent proteasome-mediated degradation Of I kappa B proteins. This event triggers the nuclear import of the NF-kappa B transcription factor, which activates the transcription of genes that regulate a variety of fundamental biological processes, including immune response, cell survival, and development. Here, we define an essential role for IKK2 in normal mitotic progression and the maintenance of spindle bipolarity. Chemical and genetic perturbation of IKK2 promotes the formation of multipolar spindles and chromosome missegregation. Depletion of IKK2 results in the deregulation of Aurora A protein stability and coincident hyperactivation of a putative Aurora A substrate, the mitotic motor KIF11. These data support a function for IKK2 as an antagonist of Aurora A signaling during mitosis. Additionally, our results indicate a direct role for IKK2 in the maintenance of genome stability and underscore the potential for oncogenic consequences in targeting this kinase for therapeutic intervention.