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J. Biol. Chem., Vol. 281, Issue 25, 17457-17465, June 23, 2006

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Jab1 Induces the Cytoplasmic Localization and Degradation of p53 in Coordination with Hdm2^*

Wonkyung Oh¹, Eun-Woo Lee¹, Young Hoon Sung^¶, Mi-Ran Yang, Jaewang Ghim, Han-Woong Lee^¶2, and Jaewhan Song³

From the Department of Food Science and Biotechnology, Faculty of Life Sciences and Technology, Sungkyunkwan University, Suwon 440-746, the School of Biological Sciences, Seoul National University, Seoul 151-742, and the ^¶Department of Biochemistry, Yonsei University, Seoul 120-749, Korea

The biological mechanisms for maintaining the basal level of p53 in normal cells require nuclear exclusion and cytoplasmic degradation. Here, we showed that Jab1 facilitates p53 nuclear exclusion and its subsequent degradation in coordination with Hdm2. p53 was excluded from the nucleus in the presence of Jab1; this exclusion was prevented by leptomycin B treatment. Nuclear export of p53 was accompanied by a decrease in the levels of p53, as well as of its target proteins, which include p21 and Bax. Domain analyses of Jab1 showed that the N-terminal domain, 1-110, was capable of inducing cytoplasmic translocation of p53. Furthermore, 110-191 was required to facilitate the degradation of p53. Neither of these mutants incorporated into the CSN complex, indicating that Jab1 could affect the levels of p53 independent of intact CSN complex. Conversely, Jab1 was incapable of translocating and degrading two p53 mutants, W23S and 6KR, neither of which could be modified by Hdm2. Moreover, Jab1 did not affect the cellular localization or protein levels of p53 in p53 and Hdm2 double-null mouse embryo fibroblasts. We further observed that the ablation of endogenous Jab1 by small interfering RNA prevented Hdm2-mediated p53 nuclear exclusion. Under stressed conditions, which could sequester Hdm2 in its inactive state, Jab1 did not affect p53. Our studies implicate that Jab1 is required to remove post-translationally modified p53 and provide a novel target for p53-related cancer therapies.

Received for publication, February 27, 2006 , and in revised form, April 18, 2006.

^* This work was supported by 21C Frontier Functional Human Genome Project Grant FG05-22-02, Brain Research Center Frontier Grant M103KV010018-05K2201-01830 from Ministry of Science and Technology, and Science Research Center Grants R11-2000-080-09005-0 and R01-2002-000-00445-0 from the Korea Science and Engineering Foundation, and Simsan Grant KRF-2002-003-E00016 from Sungkyunkwan University. 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 To whom correspondence may be addressed: Dept. of Biochemistry, Yonsei University, Seoul 120-749, Korea. Tel.: 82-2-2123-2695; Fax: 82-2-362-9897; E-mail: hwl{at}yonsei.ac.kr. ³ To whom correspondence may be addressed: Dept. of Food Science and Biotechnology, Faculty of Life Science and Engineering, Sungkyunkwan University, Suwon 440-746, Korea. Tel.: 82-31-290-7807; Fax: 82-31-299-6435; E-mail: jso678{at}skku.edu.

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