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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
Cho §,
Yong Hee
Lee §,
Hee-Sae
Park ,
Kanghyun
Ryoo ,
Keon Wook
Kang¶,
Jihyun
Park ,
Soo-Jung
Eom ,
Myung Jin
Kim ,
Tong-Shin
Chang ,
Soo-Yeon
Choi ,
Jaekyung
Shim ,
Youngho
Kim ,
Mi-Sook
Dong ,
Min-Jae
Lee ,
Sang Geon
Kim¶,
Hidenori
Ichijo**, and
Eui-Ju
Choi 
From the 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.

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:
ejchoi@mail.korea.ac.kr.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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