Volume 271, Number 43,
Issue of October 25, 1996
pp. 26461-26464
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
Sterol-dependent Transcriptional Regulation of Sterol
Regulatory Element-binding Protein-2
(Received for publication, June 28, 1996, and in revised form, August 2, 1996)
Ryuichiro
Sato
,
Jun
Inoue
,
Yoshiki
Kawabe
¶
,
Tatsuhiko
Kodama
¶
,
Tatsuya
Takano
and
Masatomo
Maeda
From the 
Laboratory of Biochemistry, Faculty of
Pharmaceutical Sciences, Osaka University, Suita, Osaka 565, the
¶ Department of Molecular Biology and Medicine, Research Center
for Advanced Science and Technology, University of Tokyo, Meguro, Tokyo
153, and the 
Department of Microbiology and Molecular Pathology,
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko,
Kanagawa 199-01, Japan
We show in this manuscript that expression of the
mRNA for sterol regulatory element-binding protein-2 (SREBP-2) is
regulated by the cellular sterol level in cultured HeLa cells. We have
cloned the 5
-flanking region of the gene encoding human SREBP-2.
Characterization of this region shows the minimum 50-base pair segment,
which contains a 10-base pair sterol regulatory element 1 (SRE-1)
identical to the one in the human LDL receptor promoter, confers sterol
responsiveness when fused to the luciferase reporter gene. Enforced
expression of the truncated SREBP-2 protein (amino acid residues
1-481) also shows that this upstream segment contains the information
required for transcriptional activation. The luciferase assays using
mutant versions of the reporter genes reveal that the
sterol-dependent transcriptional regulation is mediated by
two nearby motifs, the SRE-1 and the NF-Y binding site (the inverted
CCAAT box, ATTGGC); the latter is reported to play a critical role in
sterol-dependent regulation of
3-hydroxy-3-methylglutaryl-coenzyme A synthase and farnesyl diphosphate
synthase genes (Jackson, S. M., Ericsson, J., Osborne, T. F., and
Edwards, P. A. (1995) J. Biol. Chem. 270, 21445-21448). Gel mobility shift assays demonstrate that the
transcription factor NF-Y truly binds to the ATTGGC sequence. These
findings suggest that the activity of SREBP-2 is controlled not only
post-translationally by proteolytic activation of the precursor protein
but also transcriptionally by itself together with NF-Y.
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