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J. Biol. Chem., Vol. 276, Issue 42, 38703-38714, October 19, 2001
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From the Department of Pediatrics, Division of Pediatric
Gastroenterology, Nutrition and Liver Diseases, Mount Sinai School
of Medicine, New York, New York 10029
Ileal reclamation of bile salts, a critical
determinant of their enterohepatic circulation, is mediated primarily
by the apical sodium-dependent bile acid transporter
(ASBT=SLC10A2). We have defined mechanisms involved in the
transcriptional regulation of ASBT. The ASBT gene extends over 17 kilobases and contains five introns. Primer extension analysis
localized two transcription initiation sites 323 and 255 base pairs
upstream of the initiator methionine. Strong promoter activity is
imparted by both a 2.7- and 0.2-kilobase 5'-flanking region of ASBT.
The promoter activity is cell line specific (Caco-2, not Hep-G2,
HeLa-S3, or Madin-Darby canine kidney cells). Four distinct specific
binding proteins were identified by gel shift and cross-linking studies
using Caco-2 or rat ileal nuclear extracts. Two AP-1 consensus sites
were identified in the proximal promoter. DNA binding and promoter
activity could be abrogated by mutation of the proximal AP-1 site.
Supershift analysis revealed binding of c-Jun and c-Fos to this
AP-1 element. Co-expression of c-Jun enhanced promoter activity in
Caco-2 cells and activated the promoter in Madin-Darby canine kidney
cells. Region and developmental stage-specific expression of ASBT in the rat intestine correlated with the presence of one of these DNA-protein complexes and both c-Fos and c-Jun proteins. A specific AP-1 element regulates transcription of the rat ASBT gene.
The Role of AP-1 in the Transcriptional Regulation of the Rat
Apical Sodium-dependent Bile Acid Transporter*
*
This work was supported by National Institutes of Health
Grants DK 02076 and DK 54165.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: Mount Sinai School of
Medicine, Box 1656, One Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-6227; Fax: 212-427-1951; E-mail: Benjamin. Shneider{at}mssm.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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