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J. Biol. Chem., Vol. 276, Issue 41, 38010-38022, October 12, 2001
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From the Laboratory of Drug Metabolism, Graduate School of
Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo,
Hokkaido 060-0812, Japan
Human CYP3A7 and CYP3A4 are expressed in fetal
and adult livers, respectively, although the 5'-flanking regions of the
two genes show 90% homology. The purpose of this study was to clarify the mechanism(s) responsible for the transcriptional regulation of the
CYP3A7 gene in human hepatoma HepG2 cells that showed fetal phenotypes. Transfection studies using a series of the
CYP3A7 or CYP3A4 promoter-luciferase chimeric
genes identified a nuclear factor
Novel Transcriptional Regulation of the Human CYP3A7
Gene by Sp1 and Sp3 through Nuclear Factor
B-like Element*
B (NF-B)-like element between
nucleotides 
2326 and 2297 that conferred the transcriptional
activation of the CYP3A7 gene. A 1-base pair
mismatch within the corresponding region of the CYP3A4 gene
was sufficient for a differential enhancer activity. A gel shift assay
using nuclear extracts from HepG2 cells showed that Sp1 and Sp3 bound
to the NF-B-like element of the CYP3A7 but not
CYP3A4 gene. Specific activation of the CYP3A7
promoter by Sp1 and Sp3 was confirmed by a co-transfection of the
p3A7NF-B or p3A4NF-B reporter gene with Sp1 or Sp3 expression
plasmid into Drosophila cells, which lacked endogenous Sp
family. Additionally, introduction of mutations into binding sites for
hepatocyte nuclear factor 3
, upstream stimulatory factor 1, and a basic transcription element in the proximal promoter attenuated
luciferase activity to 20% of the level seen with the intact
CYP3A7 promoter. Thus, we conclude that the expression of
the CYP3A7 gene in HepG2 cells is cooperatively regulated
by Sp1, Sp3, hepatocyte nuclear factor 3, and upstream stimulatory
factor 1.
*
This work was supported in part by grants-in-aid from the
Ministry of Education, Science, Sports and Culture of Japan, from the
Program for Promotion of Fundamental Studies in Health Sciences of the
Organization for Drug ADR Relief, R&D Promotion, and from Product
Review of Japan and the Core Research for Evolutional Science and
Technology.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: Lab. of Drug
Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Tel. and Fax: 81-11-706-4978; E-mail:
kamataki@pharm.hokudai.ac.jp.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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