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J. Biol. Chem., Vol. 281, Issue 39, 28943-28950, September 29, 2006

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Gadd45a Interacts with Aurora-A and Inhibits Its Kinase Activity^*

Shujuan Shao¹, Yang Wang¹, Shunqian Jin^¶1, Yongmei Song, Xiaoxia Wang^||, Wenhong Fan^**, Zhiying Zhao, Ming Fu, Tong Tong, Lijia Dong, Feiyue Fan^||, Ningzhi Xu, and Qimin Zhan²

From the State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China, ^¶Department of Radiation Oncology, Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, Dalian Medical University, Dalian 116027, China, ^||Institute of Radiation Medicine, Tianjing 300192, China, and ^**Department of Neurobiology, Institute of Basic Medical Sciences, Beijing 100850, China

Centrosome stability is required for successful mitosis in mammalian cells. Amplification of the centrosome leads to chromosomal missegregation and generation of aneuploidy, which are closely associated with cell transformation and tumorigenesis (Doxsey, S. J. (2001) Nat. Cell Biol. 3, E105-E108; Hinchcliffe, E. H., and Sluder, G. (2001) Genes Dev. 15, 1167-1181; Pihan, G. A., Purohit, A., Wallace, J., Malhotra, R., Liotta, L., and Doxsey, S. J. (2001) Cancer Res. 61, 2212-2219). However, there are currently limited insights into mechanism(s) for this critical biological event. Here we show that Gadd45a, a DNA damage-inducible protein that is regulated by tumor suppressors p53 and BRCA1, participates in the maintenance of centrosome stability. Mouse embryonic fibroblasts derived from gadd45a knock-out mice exhibit centrosome amplification (designated as increased centrosome numbers). Introduction of exogenous Gadd45a into mouse embryonic fibroblasts isolated from gadd45a-null mice substantially restored the normal centrosome profile. In contrast to p21^waf1/cip1, which ensures coordinated initiation of centrosome, Gadd45a had no significant effect on centrosome duplication in S phase. Interestingly Gadd45a was found to physically associate with Aurora-A protein kinase, whose deregulated expression results in centrosome abnormality. Furthermore Gadd45a was demonstrated to strongly inhibit Aurora-A kinase activity and to antagonize Aurora-A-induced centrosome amplification. These findings identify a novel mechanism for Gadd45a in the maintenance of centrosome stability and broaden understandings of p53- and BRCA1-regulated signaling pathways in maintaining genomic fidelity.

Received for publication, January 10, 2006 , and in revised form, June 12, 2006.

^* This work was supported in part by National Fundamental Research Program of China Grant 2002CB513101, National Natural Science Foundation of China Grants 30225018 and 30400074, and National Institutes of Health Grant R01 CA93640. 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.

¹ These authors made equal contributions to this work.

² To whom correspondence should be addressed: State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Cancer Inst. and Cancer Hospital, Beijing 100021, China. Tel.: 86-10-67762694; Fax: 86-10-67715058; E-mail: Zhanqimin{at}pumc.edu.cn.

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