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J Biol Chem, Vol. 275, Issue 4, 2322-2327, January 28, 2000
From the Phase II drug-metabolizing enzymes, such as
glutathione S-transferase and quinone reductase, play an
important role in the detoxification of chemical carcinogens. The
induction of these detoxifying enzymes by a variety of agents occurs at
the transcriptional level and is regulated by a cis-acting
element, called the antioxidant response element (ARE) or
electrophile-response element. In this study, we identified a signaling
kinase pathway that negatively regulates ARE-mediated gene expression.
Treatment of human hepatoma HepG2 and murine hepatoma Hepa1c1c7 cells
with tert-butylhydroquinone (tBHQ) stimulated the activity
of p38, a member of mitogen-activated protein kinase family. Inhibition
of p38 activation by its inhibitor, SB203580, enhanced the induction of
quinone reductase activity and the activation of ARE reporter gene by
tBHQ. In contrast, SB202474, a negative analog of SB203580, had little
effect. Consistent with this result, interfering with the p38 kinase
pathway by overexpression of a dominant-negative mutant of p38 or MKK3,
an immediate upstream regulator of p38, potentiated the activation of
the ARE reporter gene by tBHQ, whereas the wild types of p38 and MKK3
diminished such activation. In addition, inhibition of p38 activity
augmented the induction of ARE reporter gene activity by
tert-butylhydroxyanisole, sulforaphane, and
p38 Mitogen-activated Protein Kinase Negatively Regulates the
Induction of Phase II Drug-metabolizing Enzymes That Detoxify
Carcinogens*
,,,
Department of Pharmaceutics and
Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of
Pharmacy, University of Illinois, Chicago, Illinois 60612, § McArdle Laboratory for Cancer Research, University of
Wisconsin, Madison, Wisconsin 53706, and ¶ Department of
Microbiology and Immunology, Baylor College of Medicine,
Houston, Texas 77030
-naphthoflavone. Thus, p38 kinase pathway functions as a negative
regulator in the ARE-mediated induction of phase II detoxifying enzymes.
*
This work was supported in part by National Institutes of
Health Grants R01-CA73647 (to A. T. K.) and R01-AI38649 and
R01-AI42532 (to T. H. T.).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.
To whom correspondence should be addressed: Dept. of
Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical
Biotechnology MC870, College of Pharmacy, University of Illinois at
Chicago, 900 S. Ashland Ave., MBRB Rm. 3102, Chicago, IL 60607-7173. Tel.: 312-413-9646; Fax: 312-413-9303; E-mail: KongT@uic.edu.
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