Aurora A Is Essential for Early Embryonic Development and Tumor Suppression
Aurora A Is Essential for Early Embryonic Development and Tumor Suppression
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DOI：
10.1074/jbc.m805880200
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发表时间：
2008-11-14
影响因子：
4.8
通讯作者：
Chen, Junjie
中科院分区：
文献类型：
--
作者：
Lu, Lin-Yu;Wood, Jamie L.;Chen, Junjie
Aurora A是一种丝氨酸/苏氨酸激酶，在有丝分裂的各个阶段发挥作用。越来越多的证据表明Aurora A的基因扩增和过表达与肿瘤发生有关，提示Aurora A是一种癌基因。此外，Aurora A过表达已被用作阴性预后标志物，因为它与对常用于癌症治疗的抗有丝分裂剂的抗性相关。为了了解Aurora A的生理功能，我们产生了Aurora A敲除小鼠。Aurora A基因敲除小鼠在胚胎发育过程中早于16细胞期死亡。这些Aurora A无效胚胎在有丝分裂中有缺陷，特别是在纺锤体组装中，支持Aurora A在有丝分裂过渡期间的关键功能。有趣的是，Aurora A杂合性导致小鼠肿瘤发病率显著增加，表明Aurora A也可能作为单倍不足的肿瘤抑制因子。一致地，Aurora A杂合子小鼠胚胎成纤维细胞具有较高的非整倍体率。我们进一步发现，VX-680，一种极光激酶抑制剂，目前在II期临床试验的癌症治疗，可以诱导野生型小鼠胚胎成纤维细胞的非整倍体。我们的结论是，平衡的极光A水平是维持基因组稳定性的关键，人们需要充分意识到基于使用极光A特异性抑制剂的抗癌治疗的潜在副作用。
Aurora A is a serine/threonine kinase that functions in various stages of mitosis. Accumulating evidence has demonstrated that gene amplification and overexpression of Aurora A are linked to tumorigenesis, suggesting that Aurora A is an oncogene. In addition, Aurora A overexpression has been used as a negative prognostic marker, because it is associated with resistance to anti-mitotic agents commonly used for cancer therapy. To understand the physiological functions of Aurora A, we generated Aurora A knock-out mice. Aurora A null mice die early during embryonic development before the 16-cell stage. These Aurora A null embryos have defects in mitosis, particularly in spindle assembly, supporting critical functions of Aurora A during mitotic transitions. Interestingly, Aurora A heterozygosity results in a significantly increased tumor incidence in mice, suggesting that Aurora A may also act as a haploinsufficient tumor suppressor. Consistently, Aurora A heterozygous mouse embryonic fibroblasts have higher rates of aneuploidy. We further discovered that VX-680, an Aurora kinase inhibitor currently in phase II clinical trials for cancer treatment, could induce aneuploidy in wild type mouse embryonic fibroblasts. We conclude that a balanced Aurora A level is critical for maintaining genomic stability and one needs to be fully aware of the potential side effects of anti-cancer therapy based on the use of Aurora A-specific inhibitors.