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J. Biol. Chem., Vol. 283, Issue 6, 3392-3400, February 8, 2008

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NF-B-inducing Kinase Phosphorylates and Blocks the Degradation of Down Syndrome Candidate Region 1^*

Eun Jung Lee, Su Ryeon Seo, Ji Won Um, Joongkyu Park, Yohan Oh, and Kwang Chul Chung¹

From the Department of Biology, College of Science, Yonsei University, Seoul 120-749 and the Department of Molecular Bioscience, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Kangwon-do 200-701, Korea

Down syndrome, the most frequent genetic disorder, is characterized by an extra copy of all or part of chromosome 21. Down syndrome candidate region 1 (DSCR1) gene, which is located on chromosome 21, is highly expressed in the brain of Down syndrome patients. Although its cellular function remains unknown, DSCR1 expression is linked to inflammation, angiogenesis, and cardiac development. To explore the functional role of DSCR1 and the regulation of its expression, we searched for novel DSCR1-interacting proteins using a yeast two-hybrid assay. Using a human fetal brain library, we found that DSCR1 interacts with NF-B-inducing kinase (NIK). Furthermore, we demonstrate that NIK specifically interacts with and phosphorylates the C-terminal region of DSCR1 in immortalized hippocampal cells as well as in primary cortical neurons. This NIK-mediated phosphorylation of DSCR1 increases its protein stability and blocks its proteasomal degradation, the effects of which lead to an increase in soluble and insoluble DSCR1 levels. We show that an increase in insoluble DSCR1 levels results in the formation of cytosolic aggregates. Interestingly, we found that whereas the formation of these inclusions does not significantly alter the viability of neuronal cells, the overexpression of DSCR1 without the formation of aggregates is cytotoxic.

Received for publication, August 13, 2007 , and in revised form, November 29, 2007.

^* This work was supported by Grants from the Brain Research Center of the 21st Century Frontier Research Program Technology M103KV010011-06K2201-01110 (to K. C. C.), from National Research Laboratory Program Grant R04-2007-000-20014-0 (to K. C. C.) of Korea Science and Engineering Foundation (KOSEF) funded by Ministry of Science, Republic of Korea, and in part by Basic Research Grant from KOSEF R01-2007-000-20089-0 (to K. C. C.), by Grant A060440 from the Korea Health 21R&D Project (to K. C. C.), Ministry of Health & Welfare, and by the Korea Research Foundation Grant KRF-2004-005-E0017 (to K. C. C. and S. R. S.). 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 To whom correspondence should be addressed: Dept. of Biology, College of Science, Yonsei University, Shinchon-dong 134, Seodaemun-gu, Seoul 120-749, Korea. Tel.: 82-2-2123-2653; Fax: 82-2-312-5657; E-mail: kchung{at}yonsei.ac.kr.