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J. Biol. Chem., Vol. 280, Issue 12, 10988-10996, March 25, 2005

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B23 Regulates GADD45a Nuclear Translocation and Contributes to GADD45a-induced Cell Cycle G₂-M Arrest^*

Hua Gao, Shunqian Jin, Yongmei Song, Ming Fu, Minrong Wang, Zhihua Liu, Min Wu, and Qimin Zhan

From the State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Gadd45a is an important player in cell cycle G₂-M arrest in response to genotoxic stress. However, the underlying mechanism(s) by which Gadd45a exerts its role in the control of cell cycle progression remains to be further defined. Gadd45a interacts with Cdc2, dissociates the Cdc2-cyclin B1 complex, alters cyclin B1 nuclear localization, and thus inhibits the activity of Cdc2/cyclin B1 kinase. These observations indicate that Gadd45a nuclear translocation is closely associated with its role in cell cycle G₂-M arrest. Gadd45a has been characterized as a nuclear protein, but it does not contain a classical nuclear localization signal, suggesting that Gadd45a nuclear translocation might be mediated through different nuclear import machinery. Here we show that Gadd45a associates directly with B23 (nucleophosmin), and the B23-interacting domain is mapped at the central region (61–100 amino acids) of the Gadd45a protein using a series of Myc tag-Gadd45a deletion mutants. Deletion of this central region disrupts Gadd45a association with B23 and abolishes Gadd45a nuclear translocation. Suppression of endogenous B23 through a short interfering RNA approach disrupts Gadd45a nuclear translocation and results in impaired Gadd45a-induced cell cycle G₂-M arrest. These findings demonstrate a novel association of B23 and Gadd45a and implicate B23 as an important regulator in Gadd45a nuclear import.

Received for publication, November 10, 2004 , and in revised form, January 7, 2005.

^* This work is supported in part by National Key Basic Research Program of China Grant 2002CB513101, National Natural Science Foundation of China Grant 30225018, 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, Cancer Institute and Cancer Hospital, Beijing, 100021, China. Tel.: 86-10-67762694; Fax: 86-10-6771505; E-mail: Zhanqimin{at}chinalab.gov.cn.

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