Aurora-A Kinase Is Essential for Bipolar Spindle Formation and Early Development
Aurora-A Kinase Is Essential for Bipolar Spindle Formation and Early Development
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DOI：
10.1128/mcb.01062-08
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发表时间：
2009-02-15
影响因子：
5.3
通讯作者：
Van Dyke, Terry
中科院分区：
文献类型：
--
作者：
Cowley, Dale O.;Rivera-Perez, Jaime A.;Van Dyke, Terry
Aurora-A是一种参与有丝分裂调控和致癌作用的保守激酶。Aurora-A以前被认为参与有丝分裂进入和纺锤体组装，尽管矛盾的结果阻碍了对Aurora-A在哺乳动物中的作用的清晰理解。我们在小鼠Aurora-A基因中开发了一种条件性无效突变，以研究Aurora-A在体外和体内原代细胞中的功能。我们在这里表明，培养的胚胎成纤维细胞中的条件性Aurora-A消融导致有丝分裂进入受损和有丝分裂停滞，双极纺锤体形成存在严重缺陷。生殖系Aurora-A缺乏导致胚泡阶段的胚胎死亡，伴有明显的细胞增殖失败、有丝分裂停滞和单极纺锤体形成。Aurora-A在妊娠中期胚胎中的缺失导致有丝分裂和凋亡细胞的增加。这些结果表明，小鼠Aurora-A促进，但不是绝对需要的，有丝分裂进入小鼠胚胎成纤维细胞，是必不可少的中心体分离和双极纺锤体形成在体外和体内。Aurora-A缺失增加细胞凋亡，表明靶向Aurora-A的分子治疗可能有效诱导肿瘤细胞凋亡。Aurora-A条件突变小鼠为进一步定义Aurora-A功能和预测Aurora-A治疗干预的效果提供了有价值的系统。
Aurora-A is a conserved kinase implicated in mitotic regulation and carcinogenesis. Aurora-A was previously implicated in mitotic entry and spindle assembly, although contradictory results prevented a clear understanding of the roles of Aurora-A in mammals. We developed a conditional null mutation in the mouse Aurora-A gene to investigate Aurora-A functions in primary cells ex vivo and in vivo. We show here that conditional Aurora-A ablation in cultured embryonic fibroblasts causes impaired mitotic entry and mitotic arrest with a profound defect in bipolar spindle formation. Germ line Aurora-A deficiency causes embryonic death at the blastocyst stage with pronounced cell proliferation failure, mitotic arrest, and monopolar spindle formation. Aurora-A deletion in mid-gestation embryos causes an increase in mitotic and apoptotic cells. These results indicate that murine Aurora-A facilitates, but is not absolutely required for, mitotic entry in murine embryonic fibroblasts and is essential for centrosome separation and bipolar spindle formation in vitro and in vivo. Aurora-A deletion increases apoptosis, suggesting that molecular therapies targeting Aurora-A may be effective in inducing tumor cell apoptosis. Aurora-A conditional mutant mice provide a valuable system for further defining Aurora-A functions and for predicting effects of Aurora-A therapeutic intervention.