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J. Biol. Chem., Vol. 282, Issue 42, 30901-30909, October 19, 2007

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dp5/HRK Is a c-Jun Target Gene and Required for Apoptosis Induced by Potassium Deprivation in Cerebellar Granule Neurons^*

Chi Ma¹, Chunyi Ying¹, Zhongmin Yuan, Bin Song, Dan Li, Yulin Liu, Bingquan Lai, Wenming Li, Ruzhu Chen, Yick-Pang Ching^¶, and Mingtao Li²

From the Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, China and the ^¶Department of Pathology and Biochemistry, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China

In cerebellar granule neurons, a BH3-only Bcl-2 family member, death protein 5/harakiri, is up-regulated in a JNK-dependent manner during apoptosis induced by potassium deprivation. However, it is not clear whether c-Jun is directly involved in the induction of dp5. Here, we showed that the up-regulation of dp5, but not fas ligand and bim, after potassium deprivation was suppressed by the expression of a dominant negative form of c-Jun. Deletion analysis of the 5'-flanking sequence of the dp5 gene revealed that a major responsive element responsible for the induction by potassium deprivation is an ATF binding site located at -116 to -109 relative to the transcriptional start site. Mutation of this site completely abolished promoter activation. Furthermore, a gel shift assay showed that a specific complex containing c-Jun and ATF2 recognized this site and increased in potassium-deprived cerebellar granule neurons. Chromatin immunoprecipitation demonstrated that c-Jun was able to bind to this site in vivo. Finally, we demonstrated that knockdown of Dp5 by small interfering RNA rescued neurons from potassium deprivation-induced apoptosis. Taken together, these results suggest that dp5 is a target gene of c-Jun and plays a critical role in potassium deprivation-induced apoptosis in cerebellar granule neurons.

Received for publication, September 8, 2006 , and in revised form, April 2, 2007.

^* This work was supported by National Natural Science Foundation of China Grants 30570562, 30629002, and U0632006; Natural Science Foundation of Guangdong Province Grants 5100982 and 2006B50103001; Y. P. C was supported by Hong Kong University/NFSC Young Research Award. 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 two authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology, Zhongshan Medical College, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, China. Tel.: 86-20-87331553; Fax: 86-20-87331653; E-mail: limt{at}mail.sysu.edu.cn.

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