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J. Biol. Chem., Vol. 276, Issue 21, 18153-18160, May 25, 2001
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From the Department of Biochemistry, Bioproducts Research Center
and Yonsei Proteome Research Center, Yonsei University, 134 Shinchon-dong, Sudaemoon-ku, Seoul 120-749, Korea
The 7-dehydrocholesterol reductase (Dhcr7) is the
terminal enzyme in the pathway of cholesterol biosynthesis. We have
previously reported that sterol depletion in vivo caused a
significant induction of both liver mRNA and enzyme activity of
Dhcr7 (Bae, S.-H., Lee, J. N., Fitzky, B. U., Seong, J., and
Paik, Y.-K. (1999) J. Biol. Chem. 274, 14624-14631).
In this paper, we also observed liver cell-specific sterol-mediated
Dhcr7 gene induction in vitro by sterol depletion in rat
hepatoma cells, suggesting the presence of sterol-mediated regulatory
elements in the Dhcr7 gene. To understand the mechanisms responsible
for regulating Dhcr7 expression, we have isolated the 5'-flanking
region of the gene encoding rat Dhcr7 and have characterized the
potential regulatory elements of the gene that are responsible for
sterol-mediated regulation. The Dhcr7 promoter contains binding sites
for Sp1 (at 
177, 172, 125, and 20), NF-Y (at 88 and 51),
and SREBP-1 or ADD1 (at 33). Deletion analysis of the Dhcr7 gene
promoter (1053/+31), employing a nested series of Dhcr7-luciferase
constructs, demonstrated that the 179 upstream region of the gene is
necessary and sufficient for optimal efficient sterol-regulated
transcription. DNase I footprinting and electrophoretic mobility shift
assay showed that the SRE1/E box (33/22) involved in sterol
response of many sterol-related enzyme genes was protected specifically
by the overexpressed recombinant ADD1. Mutational analysis for the
functional relationship between the identified cis-elements
in this region indicate that one of the binding sites for Sp1 (GC box
at 125) and NF-Y (CCAAT box at 88) plays a cooperative role in the
sterol-mediated activation, in which the latter site also acts as a
co-regulator for SREBP-activated Dhcr7 promoter activity. We believe
that Dhcr7 is the first enzyme characterized with a sterol-regulatory
function in the post-lanosterol pathway. This may be important for
understanding the coordinated control of cholesterol biosynthesis as
well as the molecular mechanism of Smith-Lemli-Opitz syndrome-related
protein in mammals.
To whom correspondence should be addressed: Yonsei University,
Dept. of Biochemistry, 134 Shinchon-dong, Sudaemoon-ku, Seoul, 120-749, Korea. Tel.: 82-2-2123-4242; Fax: 82-2-393-6589 or 362-9897; E-mail:
paikyk@yonsei.ac.kr.
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