アクティブボード・２００６年１１月
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研究発表を行った学会； 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress.
　　　２００６年６月１８日〜２３日 (Kyoto)
タイトル； Suppression of centrosome amplification after DNA damage depends on p27 accumulation.
発表者；杉原　英志　氏
　　　（熊本大学　大学院医学薬学研究部　腫瘍医学分野）
Abstract；
The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by CDK2/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors, p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after γ-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27–/– and p27+/– mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ATM-p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 siRNA, indicating that downregulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.