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J. Biol. Chem., Vol. 283, Issue 9, 5888-5898, February 29, 2008

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ECRG2 Disruption Leads to Centrosome Amplification and Spindle Checkpoint Defects Contributing Chromosome Instability^*

Xiaolong Cheng, Zheng Shen^¶, Jianyi Yang, Shih-Hsin Lu^||, and Yongping Cui¹

From the Key Laboratory of Cellular Physiology, Ministry of Education, and the Department of Cell Biology & Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, China, the ^¶State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 10008, China, and the ^||Department of Etiology and Carcinogenesis, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China

Cancer cells contain an abnormal number of chromosomes (aneuploidy), which is a prevalent form of genetic instability in human cancers. Abnormal amplification of centrosomes and defects of spindle assembly checkpoint are the major causes of chromosome instability in cancer cells. Here we present biochemical evidence to suggest a role of ECRG2, a novel tumor suppressor gene, in maintaining chromosome stability. ECRG2 localized to centrosomes during interphase and kinetochores during mitosis. Further analysis revealed that ECRG2 participates in centrosome amplification in a p53-dependent manner. Depletion of ECRG2 not only destabilized p53, down-regulated p21, and increased the cyclin E/CDK2 activity, thus initiating centrosome amplification, but also abolished the ability of p53 localize to centrosomes. Overexpression of ECRG2 restored the p53-dependent suppression of centrosome duplication. Furthermore, ECRG2-depleted cells show severely disrupted spindle phenotype but fail to maintain the mitotic arrest due to minimal BUBR1 protein levels. Taken together, our results indicate that ECRG2 is important for ensuring centrosome duplication, spindle assembly checkpoint, and accurate chromosome segregation, and its depletion may contribute to chromosome instability and aneuploidy in human cancers.

Received for publication, October 1, 2007 , and in revised form, December 27, 2007.

^* This work was supported by National Nature Science Foundation of China Grant 30500588 and Nature Science Foundation of Shanxi Grant 20051089 (to Y. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Dept. of Cell Biology & Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, China. Fax: 86-351-4135895; E-mail: cuiy0922{at}yahoo.com.

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