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J. Biol. Chem., Vol. 277, Issue 32, 28601-28608, August 9, 2002
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,
,
,
, and
**
From the Membrane-associated prostaglandin (PG)
E2 synthase (mPGES) is an inducible terminal enzyme
in the biosynthetic pathway for prostaglandin E2, which
participates in many biological processes. In this study, we
investigated the molecular mechanism controlling the inducible
expression of mPGES. The mouse mPGES gene consisted of
three exons, and its 5'-proximal promoter contained consensus motifs
for the binding of several transcription factors. Transgenic expression
in mice of the mouse mPGES promoter flanked by a reporter gene resulted in stimulus-dependent induction of the
reporter in tissues where mPGES was intrinsically induced. Deletion and site-specific mutation analyses of the 5'-flanking region demonstrated that stimulus-inducible expression of mouse and human mPGES required tandem GC boxes adjacent to the initiation site. The stimulus-induced GC box binding activity was present in nuclear extracts of cells, in
which the proximal GC box was essential for binding. An 80-kDa stimulus-inducible nuclear protein that bound to this GC box was identified as the transcription factor Egr-1 (for early
growth response-1). These results suggest that
Egr-1 is a key transcription factor in regulating the inducible
expression of mPGES.
Department of Pharmacology, National
Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai,
Suita, Osaka 565-8565, Japan, the § Department of Health
Chemistry, School of Pharmaceutical Sciences, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, and the
¶ Department of Pharmacology, School of Pharmaceutical Sciences,
Kitasato University, Shirokane 5-9-1, Minato-ku,
Tokyo 108-8641, Japan
The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBankTM/EBI Data Bank with accession number(s) AB083340.
Present address: Kitasato Institute, Tokyo 108-8642, Japan.
**
To whom correspondence should be addressed. Tel.: 81-6-6833-5012;
Fax: 81-6-6872-8090; E-mail: tanabe@ri.ncvc.go.jp.
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