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J. Biol. Chem., Vol. 276, Issue 37, 34419-34427, September 14, 2001
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From the Departments of Physiology, Biochemistry and Molecular
Biology, Michigan State University, East Lansing, Michigan 48824
Sterol regulatory element binding
protein-1c (SREBP-1c) is a key hepatic transcription factor
involved in lipogenic gene expression. In an effort to understand the
role SREBP-1c plays in lipogenic gene transcription, we have examined
the functional interaction between SREBP-1c, nuclear factor Y,
3,5,3'-triiodothyronine (T3) receptors, and
co-activators using the S14 gene promoter as a model. T3,
glucose, and insulin rapidly induce S14 gene transcription in rat liver
and in primary hepatocytes. Linker scanning analyses of the S14
promoter showed that an SRE at
Functional Interaction between Sterol
Regulatory Element-binding Protein-1c, Nuclear Factor Y, and
3,5,3'-Triiodothyronine Nuclear Receptors*
,
139/131 base pairs (bp) binding
SREBP-1c and a Y-box at 104/99 bp binding NF-Y are
indispensable for both T3- and SREBP-1c-mediated induction of S14 promoter activity in rat primary hepatocytes.
T3 and glucose/insulin induce S14 gene transcription
through separate enhancers. Enhancer substitution studies reveal a
preferential interaction between SREBP-1c·NF-Y and the T3
regulatory region (2.8/2.5 kb) binding thyroid hormone
receptor/RXR heterodimers. Elevating hepatocellular levels of specific
co-activators (CBP, p/CAF, or GCN5) induced S14 promoter activity
2-3-fold, while SREBP-1c induced promoter activity 10-fold. The
combination of these treatments induced S14 promoter activity
(20-35-fold). However, this additive effect was lost when the
T3 regulatory region was deleted. Based on these results,
we suggest that the SREBP-1c·NF-Y complex facilitates the
interaction between co-activators that are recruited to distal hormone-regulated enhancers and the general transcription machinery that binds the S14 proximal promoter.
*
This work was supported by National Institutes of Health
Grant DK43220 and United States Department of Agriculture Grant
98-35200-6064.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: Physiology Dept., 115 Giltner Hall, Michigan State University, East Lansing, MI 48824. Tel.:
517-355-6475 (ext. 1246); E-mail: Jump@msu.edu.
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