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J. Biol. Chem., Vol. 276, Issue 37, 34419-34427, September 14, 2001

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Functional Interaction between Sterol Regulatory Element-binding Protein-1c, Nuclear Factor Y, and 3,5,3'-Triiodothyronine Nuclear Receptors^*

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

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 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.

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