TY - JOUR
T1 - Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models
AU - Zhang, Dongwei
AU - Hirota, Toru
AU - Marumoto, Tomotoshi
AU - Shimizu, Michio
AU - Kunitoku, Naoko
AU - Sasayama, Takashi
AU - Arima, Yoshimi
AU - Feng, Liping
AU - Suzuki, Misao
AU - Takeya, Motohiro
AU - Saya, Hideyuki
N1 - Funding Information:
We thank Dr Kimi Araki (Kumamoto University) for providing pCAG-CAT-lacZ plasmid; Mr Takenobu Nakagawa (Kumamoto University) for technical assistance; Drs Izumu Saito and Yumi Kanegae (University of Tokyo) for providing adenoviral luciferase and AxCANCre virus; members of the Saya lab for valuable suggestions; and members of the Gene Technology Center at Kumamoto University for their contributions to the technical assistance. This work was supported by the Research for the Future program of the Japan Society for the promotion of Science and by a grant for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to HS).
PY - 2004/11/18
Y1 - 2004/11/18
N2 - 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 apopiosis 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.
AB - 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 apopiosis 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.
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U2 - 10.1038/sj.onc.1208153
DO - 10.1038/sj.onc.1208153
M3 - Article
C2 - 15480417
AN - SCOPUS:9944220985
SN - 0950-9232
VL - 23
SP - 8720
EP - 8730
JO - Oncogene
JF - Oncogene
IS - 54
ER -