System-level deficiencies in Aurora B control in cancers.
System-level deficiencies in Aurora B control in cancers.
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Aurora B 控制癌症的系统级缺陷。
DOI：
10.1080/15384101.2016.1185850
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发表时间：
2016
期刊：
影响因子：
4.3
通讯作者：
T.
中科院分区：
文献类型：
--
作者：
Abe;Y.;Hirota;T.
染色体分离机制的缺陷导致产生含有异常数目染色体的非整倍体细胞。由4个核心亚基（极光B激酶、INCENP、存活素和Borealin/Dasra）组成的染色体过客复合物（CPC）主要通过释放不正确的着丝粒-微管附着来确保忠实的染色体分离。早期的研究发现，通过低剂量的抑制剂治疗对极光B活性的部分抑制已经诱导染色体分离错误，而需要更有效的抑制来影响极光B介导的组蛋白H3磷酸化、染色体组装和运动以及胞质分裂。1这些结果表明，染色体分离的保真度取决于Aurora B的完全活性。尽管癌细胞通常具有升高的染色体错误分离率，但这种病理状况的分子基础一直是一个长期存在的问题。异染色质蛋白1（HP 1）通过INCENP与CPC结合，从而在有丝分裂中被募集到着丝粒。2，3这种HP 1-CPC结合的意义直到最近才被发现，当时发现HP 1对Aurora B的变构效应。4 HP 1使Aurora B的体外底物加工速率加倍，并且这种激酶活性的增强是Aurora B磷酸化细胞中动粒底物所必需的。值得注意的是，在所有测试的癌细胞系中，HP 1结合的CPC的分数显著降低，这导致了极光B活性不足是癌症的普遍特征的结论。这些发现的必然结果是，HP 1介导的完整Aurora B活性支持故障安全染色体分离，并且事实上，在非转化细胞中HP 1与CPC结合的破坏增加了染色体错误分离的速率，而没有可检测地影响由Aurora B调节的其他有丝分裂事件。4从CPC上去除HP 1降低了Aurora B的活性，并干扰了动粒底物的磷酸化，但它也损害了Aurora B在着丝粒上的富集。4这些结果与CPC装载到着丝粒上受多个正反馈回路调节的概念一致，涉及Aurora B活性本身。5例如，Aurora B通过调节Haspin激酶介导的组蛋白H3-磷酸化Thr 3，从而在着丝粒募集CPC，从而增强CPC的着丝粒积累。此外，由于已知极光B促进凝聚蛋白I的染色质缔合，从而赋予着丝粒物理稳定性，因此极光B活性在着丝粒处的累积对于维持该位点的结构完整性一定是重要的。因此，CPC的“支架”可能变得非结构化，而没有HP 1的变构效应。基于这些观察，一个合理的观点是CPC的正确着丝粒定位和功能是由Aurora B的自我调节机制控制的（图1）。非转化细胞有一个强大的机制，通过增加极光B招聘到错位的染色体7纠正附着错误的发现可能强调了这种系统级控制的重要性。在广泛的癌细胞中，极光B在着丝粒的定义定位明显受损到不同程度，而是保持不脱离染色体臂（未发表的观察，安倍晋三Y和广田T）。根据控制Aurora B定位的正反馈环，这种不明确的着丝粒定位可以通过发现Aurora B的活性由于癌细胞中HP 1结合的降低而降低来合理地解释。4值得注意的是……
Defects in chromosome segregation machinery give rise to generation of aneuploid cells containing abnormal number of chromosomes. The chromosomal passenger complex (CPC) composed of 4 core subunits, Aurora B kinase, INCENP, Survivin and Borealin/Dasra ensures faithful chromosome segregation primarily by releasing incorrect kinetochore-microtubule attachments. Earlier studies have found that a partial inhibition of Aurora B activity by a low-dose of inhibitor treatment already induces chromosome segregation errors, whereas more potent inhibition is needed to affect Aurora B-mediated histone H3 phosphorylation, chromosome assembly and movement and cytokinesis. 1 These results have implied that fidelity of chromosome segregation depends on full activity of Aurora B. Although cancer cells, in general, have elevated rates of chromosome missegregation, molecular basis underlying such pathological conditions has been a longstanding question. The heterochromatin protein 1 (HP1) associates with CPC through INCENP and thereby is recruited to centromeres in mitosis. 2, 3 The significance of this HP1-CPC association was unclear until recently, when an allosteric effect of HP1 on Aurora B was found. 4 HP1 doubled the substrate-processing rate of Aurora B in vitro, and this enhancement of the kinase activity is required for Aurora B to phosphorylate kinetochore substrates in cells. Remarkably, the fraction of HP1-bound CPC was significantly decreased in all the cancer cell lines tested, which led to the conclusion that insufficient Aurora B activity is a widespread feature of cancers. A corollary of these findings was that HP1-mediated full Aurora B activity supports the fail-safe chromosome segregation and indeed, disruption of HP1 binding to the CPC in non-transformed cells increased the rate of chromosome missegregation, without detectably affecting other mitotic events regulated by Aurora B. 4 Deprivation of HP1 from the CPC lowered Aurora B activity and perturbed the phosphorylation of kinetochore substrates, but it also impaired the enrichment of Aurora B at centromeres. 4 These results are consistent with the notion that CPC loading onto centromeres is regulated by multiple positive feedback loops, involving Aurora B activity itself. 5 For instance, Aurora B enhances centromeric accumulation of the CPC by regulating Haspin kinase-mediated histone H3-phospho-Thr3, which in turn recruits the CPC at centromeres. Moreover, because Aurora B is known to promote chromatin association of condensin I, which confers physical stability to centromeres, 6 accumulation of Aurora B activity at centromeres must be important to maintain the structural integrity at that site. Thus the “scaffolds” for CPC may become unstructured without an allosteric effect of HP1. Based on these observations, a reasonable view would be that the proper centromeric localization and function of the CPC are controlled by self-regulating mechanisms of Aurora B (Fig. 1). The finding that non-transformed cells have a robust mechanism to correct attachment errors by increasing Aurora B recruitment to misaligned chromosomes 7 may underscore the importance of this systemlevel control.In a wide range of cancer cells, defined localization of Aurora B at centromeres is noticeably impaired to various extents, and it is instead remained undetached from chromosome arms (unpublished observations, Abe Y and Hirota T). In light of positive feedback loops controlling localization of Aurora B, this ill-defined centromeric localization can be reasonably explained by the finding that the activity of Aurora B is low by decreased HP1 binding in cancer cells. 4 It is noteworthy to …