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J Biol Chem, Vol. 273, Issue 51, 34105-34114, December 18, 1998
From the Departments of Obstetrics & Gynecology and Pharmacology & Toxicology and Medical Research Council of Canada Group in Fetal and
Neonatal Health and Development, University of Western Ontario, London
Regional Cancer Centre, London, Ontario, Canada N6A 4L6
Hepatocytes are the major source of sex
hormone-binding globulin (SHBG), a glycoprotein that transports sex
steroids in the blood and regulates their access to target tissues. The
human SHBG proximal promoter was analyzed by
DNase I footprinting, and the functional significance of 6 footprinted
regions (FP1-FP6) within the proximal promoter was studied in human
HepG2 hepatoblastoma cells. Two footprinted regions (FP1 and FP3)
contain binding sites for the chicken ovalbumin upstream
promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4
(HNF-4). In experiments where SHBG promoter-luciferase
reporter gene constructs were co-transfected into HepG2 cells with
COUP-TF and/or HNF-4 expression vectors, HNF-4 markedly increased
transcription, whereas COUP-TF suppressed this probably by displacing
HNF-4 from their common FP1-binding site. This COUP-TF/HNF-4-binding
site within FP1 includes a TTTAA sequence, located at nucleotides
Hepatocyte Nuclear Factor-4 Controls Transcription from a
TATA-less Human Sex Hormone-binding Globulin Gene Promoter
30/26 upstream of the transcription start site, which fails to
interact with human TFIID, TATA-binding protein in vitro.
When this sequence was replaced with an idealized HNF-4-binding site,
the transcriptional activity of the promoter increased in HepG2 cells.
Taken together, these data imply that an interplay between COUP-TF and
HNF-4 at a site within FP1 regulates human SHBG expression
and that HNF-4 controls transcription from this TATA-less promoter by
somehow substituting for TATA-binding protein in the recruitment of a
transcription preinitiation complex.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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