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A more recent version of this article appeared on September 7, 2001
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M105471200v1
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Papers In Press, published online ahead of print July 11, 2001
J. Biol. Chem, 10.1074/jbc.M105471200
Submitted on June 13, 2001
Revised on July 10, 2001
Accepted on July 11, 2001

Functional interaction between SREBP-1c, NF-Y and T3 nuclear receptors

Donald B. Jump, Annette P. Thelen, and Michelle K. Mater

Physiology, Michigan State University, East Lansing, MI 48824

Corresponding Author: jump{at}msu.edu

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, NF-Y, 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 -139/-131 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 response region (TRR, -2.8/-2.5 kb) binding TR/RXR heterodimers. Elevating hepatocellular levels of specific co-activators (CBP, p/CAF or GCN5) induced S14 promoter activity 2 to 3-fold, while SREBP-1c induced promoter activity 10-fold. The combination of these treatments induced S14 promoter activity (20 to 35-fold). However, this additive effect was lost when the TRR was deleted. Based on these results, we suggest that the SREBP-1c/NF-Y complex may facilitate the interaction between co-activators recruited to distal hormone-regulated enhancers and the basal transcription machinery binding proximal elements in the S14 promoter.


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