Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models
Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models
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DOI：
10.1038/sj.onc.1208153
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发表时间：
2004-11-18
期刊：
影响因子：
8
通讯作者：
Saya, H
中科院分区：
文献类型：
--
作者：
Zhang, DW;Hirota, T;Saya, H
Aurora-A是一种丝氨酸/苏氨酸有丝分裂激酶，据报道在多种人类癌症中过表达，并且其过表达在培养的人类和啮齿动物细胞中诱导非整倍体、中心体扩增和致瘤性转化。然而，Aurora-A促进肿瘤发生的潜在机制和病理环境在很大程度上是未知的。在这里，我们创建了一个转基因小鼠模型，研究Aurora-A过表达的乳腺和肿瘤发生的发展中的参与使用Cre-loxP系统。Aurora-A的条件性表达导致乳腺上皮中双核细胞形成和凋亡显著增加。存活的乳腺上皮细胞在短暂的潜伏期后组成增生区。在转基因小鼠制备的小鼠胚胎成纤维细胞中诱导Aurora-A过表达也导致异常有丝分裂和双核细胞形成，随后是凋亡。p53蛋白水平在这些Aurora-A-过表达的细胞中显著增加，并且通过缺失p53而显著抑制凋亡。鉴于在长时间潜伏期后，Aurora-A过表达小鼠模型中没有发现恶性肿瘤形成，因此Aurora-A过表达乳腺上皮的肿瘤发生需要其他因素，例如p53失活。我们的研究结果表明，这种小鼠模型是一个有用的系统，研究极光-A的生理作用和极光-A诱导的致癌作用的遗传途径。
Aurora-A, a serine/threonine mitotic kinase, was reported to be overexpressed in various human cancers, and its overexpression induces aneuploidy, centrosome amplification and tumorigenic transformation in cultured human and rodent cells. However, the underlying mechanisms and pathological settings by which Aurora-A promotes tumorigenesis are largely unknown. Here, we created a transgenic mouse model to investigate the involvement of Aurora-A overexpression in the development of mammary glands and tumorigenesis using a Cre-loxP system. The conditional expression of Aurora-A resulted in significantly increased binucleated cell formation and apoptosis in the mammary epithelium. The surviving mammary epithelial cells composed hyperplastic areas after a short latency. Induction of Aurora-A overexpression in mouse embryonic fibroblasts prepared from the transgenic mice also led to aberrant mitosis and binucleated cell formation followed by apoptosis. The levels of p53 protein were remarkably increased in these Aurora-A-overexpressing cells, and the apoptosis was significantly suppressed by deletion of p53. Given that no malignant tumor formation was found in the Aurora-A-overexpressing mouse model after a long latency, additional factors, such as p53 inactivation, are required for the tumorigenesis of Aurora-A-overexpressing mammary epithelium. Our findings indicated that this mouse model is a useful system to study the physiological roles of Aurora-A and the genetic pathways of Aurora-A-induced carcinogenesis.