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J. Biol. Chem., Vol. 279, Issue 30, 31296-31303, July 23, 2004

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Interaction between Glucose-regulated Destruction Domain of DNA Topoisomerase II and MPN Domain of Jab1/CSN5^*

Jisoo Yun, Akihiro Tomida, Toshiwo Andoh, and Takashi Tsuruo¶||

From the Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1,Yayoi, Bunkyo-ku, Tokyo 113-0032, the Department of Bioengineering, Faculty of Engineering, Soka University, 1-236 Tangi-Cho, Hachioji, Tokyo 192-0003, and ^¶Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1, Toshima-ku, Tokyo 170-8455, Japan

DNA topoisomerase (topo) II, an essential enzyme for cell proliferation, is targeted to a proteasome-dependent degradation pathway when human tumor cells are glucose-starved. Here we show that the topo II destabilization depends on the newly identified domain, GRDD (glucose-regulated destruction domain), which was mapped to the N-terminal 70–170 amino acid sequence. Indeed, the deletion of GRDD conferred a stable feature on topo II, whereas the fusion of GRDD rendered green fluorescent protein unstable under glucose starvation conditions. Nuclear localization was a prerequisite for GRDD function, because the inhibition of nuclear translocation resulted in the suppression of GRDD-mediated topo II degradation. Further, GRDD was identified as an interactive domain for Jab1/CSN5, which promoted the degradation of topo II in a manner dependent on the MPN (Mpr1p/Prd1p N terminus) domain. Depleting Jab1/CSN5 by antisense oligonucleotide and treating cells with the CSN-associated kinase inhibitor, curcumin, inhibited topo II degradation induced by glucose starvation. These findings demonstrate that GRDD can act as a stress-activated degron for regulating topo II stability, possibly through interaction with the MPN domain of Jab1/CSN5.

Received for publication, February 9, 2004 , and in revised form, April 30, 2004.

^* This work was supported in part by a grant-in-aid for scientific research on priority areas for cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

^|| To whom correspondence should be addressed. Tel.: 81-3-5841-7861; Fax: 81-3-5841-8487; E-mail: ttsuruo{at}iam.u-tokyo.ac.jp.

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