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J. Biol. Chem. 276 (16): 12749-12755

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Glutathione S-Transferase Mu Modulates the Stress-activated Signals by Suppressing Apoptosis Signal-regulating Kinase 1*

Ssang-Goo ChoDagger §, Yong Hee LeeDagger §, Hee-Sae ParkDagger , Kanghyun RyooDagger , Keon Wook Kang, Jihyun ParkDagger , Soo-Jung EomDagger , Myung Jin KimDagger , Tong-Shin ChangDagger , Soo-Yeon ChoiDagger , Jaekyung ShimDagger , Youngho KimDagger , Mi-Sook DongDagger , Min-Jae Lee||, Sang Geon Kim, Hidenori Ichijo**, and Eui-Ju ChoiDagger Dagger Dagger

From the Dagger  National Creative Research Initiative Center for Cell Death, Graduate School of Biotechnology, Korea University, Anam-dong, Sungbuk-ku, Seoul 136-701, South Korea, the  College of Pharmacy, Seoul National University, Seoul 151-742, South Korea, the || Seoul National University Hospital Clinical Research Institute, #28 Yongon-dong, Chongno-ku, Seoul 110-799, South Korea, and the ** Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that can activate the c-Jun N-terminal kinase and the p38 signaling pathways. It plays a critical role in cytokine- and stress-induced apoptosis. To further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the yeast two-hybrid method. The yeast two-hybrid assay indicated that mouse glutathione S-transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently confirmed that mGSTM1-1 physically associated with ASK1 both in vivo and in vitro. The in vitro binding assay indicated that the C-terminal portion of mGSTM1-1 and the N-terminal region of ASK1 were crucial for binding one another. Furthermore, mGSTM1-1 suppressed stress-stimulated ASK1 activity in cultured cells. mGSTM1-1 also blocked ASK1 oligomerization. The ASK1 inhibition by mGSTM1-1 occurred independently of the glutathione-conjugating activity of mGSTM1-1. Moreover, mGSTM1-1 repressed ASK1-dependent apoptotic cell death. Taken together, our findings suggest that mGSTM1-1 functions as an endogenous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insofar as mGSTM1-1 may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.

* 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. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Dagger Dagger To whom correspondence should be addressed: Graduate School of Biotechnology, Korea University, Seoul, 136-701, South Korea. Tel.: 82-2-3290-3446; Fax: 82-2-927-9028; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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