Zhang Dongwei, Hirota Toru, Marumoto Tomotoshi, Shimizu Michio, Kunitoku Naoko, Sasayama Takashi, Arima Yoshimi, Feng Liping, Suzuki Misao, Takeya Motohiro, Saya Hideyuki
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Oncogene. 2004 Nov 18;23(54):8720-30. doi: 10.1038/sj.onc.1208153.
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.
极光激酶A（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，其过表达会在培养的人类和啮齿动物细胞中诱导非整倍体、中心体扩增和致瘤转化。然而，极光激酶A促进肿瘤发生的潜在机制和病理背景在很大程度上尚不清楚。在此，我们创建了一个转基因小鼠模型，使用Cre-loxP系统来研究极光激酶A过表达在乳腺发育和肿瘤发生中的作用。极光激酶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潜伏期后形成增生区域。在从转基因小鼠制备的小鼠胚胎成纤维细胞中诱导极光激酶A过表达也导致异常有丝分裂和双核细胞形成，随后发生凋亡。在这些过表达极光激酶A的细胞中，p53蛋白水平显著升高，并且通过缺失p53可显著抑制凋亡。鉴于在长时间潜伏期后，过表达极光激酶A的小鼠模型中未发现恶性肿瘤形成，过表达极光激酶A的乳腺上皮发生肿瘤还需要其他因素，如p53失活。我们的研究结果表明，该小鼠模型是研究极光激酶A的生理作用以及极光激酶A诱导致癌的遗传途径的有用系统。
