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J Biol Chem, Vol. 274, Issue 52, 37117-37124, December 24, 1999
From the Laboratory of Drug Metabolism, Division of
Pharmacobiodynamics, Graduate School of Pharmaceutical Sciences,
Hokkaido University, N12W6, Kita-ku,
Sapporo, Hokkaido 060-0812, Japan
The purpose of this study was to clarify the
mechanism(s) responsible for the growth hormone (GH)-induced expression
of the CYP2C12 gene. To identify a functional GH-responsive
element (GHRE) in vivo, we performed the direct injection
of promoter-luciferase chimeric genes into female rat livers. The
results showed that the luciferase activity was decreased to
approximately 20% by the deletion of the sequence between nucleotides
Cooperative Regulation of CYP2C12 Gene Expression
by STAT5 and Liver-specific Factors in Female Rats*
4213 and 4161. Within this region, two copies of a possible GHRE
were present. The sequence of the GHRE was overlapped with that of an
interferon-
-activated sequence, known to be recognized by the signal
transducer and activator of transcription (STAT) proteins. In fact, a
supershift assay showed that STAT5 was capable of binding to the core
sequence of the GHRE. Furthermore, a luciferase assay with reporter
plasmids, 
4161/3781, mutated hepatocyte nuclear factor-4
(HNF-4), and mutated HNF-6, revealed that the GH-stimulated expression
of the CYP2C12 gene was regulated cooperatively by STAT5,
HNF-4, HNF-6, and the factor(s) that binds to the elements, 2C12-I
(4095 to 4074) and 2C12-II (4072 to 4045). The cooperative
regulation by STAT5 and the liver-enriched transcription factors
account for the GH-dependent and the liver-specific
expression of the CYP2C12 gene in female rats.
*
This work was supported in part by a Grant-in-Aid from the
Ministry of Education, Science, Sports and Culture of Japan, the Core
Research for Evolutional Science and Technology, and the Program for
Promotion of Fundamental Studies in Health Sciences of the Organization
for Drug ADR Relief, R & D Promotion and Product Review of Japan.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 all correspondence should be addressed: Laboratory of Drug
Metabolism, Division of Pharmacobiodynamics, Graduate School of
Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo,
Hokkaido 060-0812, Japan. Tel./Fax: 81-11-706-4978; E-mail: kamataki@pharm.hokudai.ac.jp.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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