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J. Biol. Chem., Vol. 283, Issue 8, 4682-4689, February 22, 2008

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Ubiquitination and Degradation of Homeodomain-interacting Protein Kinase 2 by WD40 Repeat/SOCS Box Protein WSB-1^*

Dong Wook Choi¹, Yu-Mi Seo¹, Eun-A Kim, Ki Sa Sung², Jang Won Ahn, Sang-Joon Park, Seung-Rock Lee^¶3, and Cheol Yong Choi⁴

From the Department of Biological Science, Sungkyunkwan University, 300 Chunchundong, Suwon 440-746, the Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Jangdong 100, Daejeon 305-600, and the ^¶Department of Biochemistry, Center for Aging and Geriatrics, Chonnam National University Medical School, Hakdong 5, Gwangju 501-746, Republic of Korea

Homeodomain-interacting protein kinase 2 (HIPK2) is a member of the nuclear protein kinase family, which induces both p53- and CtBP-mediated apoptosis. Levels of HIPK2 were increased by UV irradiation and cisplatin treatment, thereby implying the degradation of HIPK2 in cells under normal conditions. Here, we indicate that HIPK2 is ubiquitinated and degraded by the WD40-repeat/SOCS box protein WSB-1, a process that is blocked under DNA damage conditions. Yeast two-hybrid screening was conducted to identify the proteins that interact with HIPK2. WSB-1, an E3 ubiquitin ligase, was characterized as an HIPK2-interacting protein. The coexpression of WSB-1 resulted in the degradation of HIPK2 via its C-terminal region. Domain analysis of WSB-1 showed that WD40-repeats and the SOCS box were required for its interaction with and degradation of HIPK2, respectively. In support of the degradation of HIPK2 by WSB-1, HIPK2 was polyubiquitinated by WSB-1 in vitro and in vivo. The knockdown of endogenous WSB-1 with the expression of short hairpin RNA against WSB-1 increases the stability of endogenous HIPK2 and resulted in the accumulation of HIPK2. The ubiquitination and degradation of HIPK2 by WSB-1 was inhibited completely via the administration of DNA damage reagents, including Adriamycin and cisplatin. These findings effectively illustrate the regulatory mechanisms by which HIPK2 is maintained at a low level, by WSB-1 in cells under normal conditions, and stabilized by genotoxic stresses.

Received for publication, October 29, 2007 , and in revised form, December 3, 2007.

^* This work was supported in part by the Korea Science and Engineering Foundation (KOSEF) funded by the Korea government (Grants M10533010002-07N3301-00210 and R01-2006-000-10917-0). 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 Both authors contributed equally to this work.

² Recipient of a Seoul Science Fellowship.

³ Supported by KOSEF Grant RO1-2004-000-10242-0.

⁴ To whom correspondence should be addressed: Tel.: 82-31-290-7010; Fax: 82-31-290-7015; E-mail: choicy{at}skku.ac.kr.

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