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J. Biol. Chem., Vol. 278, Issue 48, 48092-48098, November 28, 2003

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p57^KIP2 Modulates Stress-activated Signaling by Inhibiting c-Jun NH₂-terminal Kinase/Stress-activated Protein Kinase^*

Tong-Shin Chang¶, Myung Jin Kim¶, Kanghyun Ryoo, Jihyun Park, Soo-Jung Eom, Jaekyung Shim||, Keiichi I. Nakayama**, Keiko Nakayama, Motowo Tomita, Katsuhiko Takahashi, Min-Jae Lee¶¶, and Eui-Ju Choi||||

From the National Creative Research Initiative Center for Cell Death, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea, ^**Division of Cell Biology, Department of Molecular and Cellular Biology and Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan, Department of Physiological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan, ^¶¶Department of Laboratory Animal Research, Samsung Biomedical Research Institute, Seoul 135-710, Korea, and the ^||Department of Molecular Biology, College of Natural Science, Sejong University, Seoul 143-747, Korea

p57^KIP2, a member of the Cip/Kip family of enzymes that inhibit several cyclin-dependent kinases, plays a role in many biological events including cell proliferation, differentiation, apoptosis, tumorigenesis and developmental changes. The human p57^KIP2 gene is located in chromosome 11p15.5, a region implicated in sporadic cancers and Beckwith-Wiedemann syndrome. We here report that p57^KIP2 physically interacts with and inhibits c-Jun NH₂-terminal kinase/stress-activated protein kinase (JNK/SAPK). The carboxyl-terminal QT domain of p57^KIP2 is crucial for the inhibition of JNK/SAPK. Overexpressed p57^KIP2 also suppressed UV- and MEKK1-induced apoptotic cell death. p57^KIP2 expression during C2C12 myoblast differentiation resulted in repression of the JNK activity stimulated by UV light. Furthermore, UV-stimulated JNK1 activity was higher in mouse embryonic fibroblasts derived from p57^–/– mice than in the cells from wild-type mice. Taken together, these findings suggest that p57^KIP2 modulates stress-activated signaling by functioning as an endogenous inhibitor of JNK/SAPK.

Received for publication, August 25, 2003

^* This work was supported by the Creative Research Initiatives Program of the Korean Ministry of Science and Technology (to E.-J. C). 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.

Present address: Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, MD 20892.

^¶ Both authors contributed equally to this work.

^|||| To whom correspondence should be addressed: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea. E-mail: ejchoi{at}korea.ac.kr.

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