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J. Biol. Chem., Vol. 283, Issue 21, 14506-14515, May 23, 2008

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The Association of GSK3β with E2F1 Facilitates Nerve Growth Factor-induced Neural Cell Differentiation^*

Fangfang Zhou¹, Long Zhang¹, Aijun Wang, Bo Song, Kai Gong, Lihai Zhang, Min Hu, Xiufang Zhang, Nanming Zhao, and Yandao Gong²

From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China and the Department of Stomatology, Chinese People's Liberation Army General Hospital, Beijing 100853, China

It is widely acknowledged that E2F1 and GSK3β are both involved in the process of cell differentiation. However, the relationship between E2F1 and GSK3β in cell differentiation has yet to be discovered. Here, we provide evidence that in the differentiation of PC12 cells induced by nerve growth factor (NGF), GSK3β was increased at both the mRNA and protein levels, whereas E2F1 at these two levels was decreased. Both wild-type GSK3β and its kinase-defective mutant GSK3β KM can inhibit E2F1 by promoting its ubiquitination through physical interaction. In addition, the colocalization of GSK3β and E2F1 and their subcellular distribution, regulated by NGF, were observed in the process of PC12 differentiation. At the tissue level, GSK3β colocalized and interacted with E2F1 in mouse hippocampus. Furthermore, GSK3β facilitated neurite outgrowth by rescuing the promoter activities of Cdk inhibitors p21 and p15 from the inhibition caused by E2F1. To summarize, our findings suggest that GSK3β can promote the ubiquitination of E2F1 via physical interaction and thus inhibit its transcription activity in a kinase activity independent manner, which plays an important role in the NGF-induced PC12 differentiation.

Received for publication, July 26, 2007 , and in revised form, March 20, 2008.

^* This work was supported by a grant from the Tsinghua-Yue-Yuen Medical Sciences Fund, Beijing Municipal Science and Technology Commission Grant H060920050430, the Tsinghua 985 Project, and the National Science Foundation of China (study of topographic specificity neurotropism and facial nerve plerosis). 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 Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China. Tel.: 86-10-62785049; Fax: 86-10-62794214; E-mail: gongyd{at}tsinghua.edu.cn.

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