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

• Published in: The Journal of biological chemistry 2001-09, Vol.276 (37), p.34419-34427
• Main Authors: Jump, Donald B., Thelen, Annette P., Mater, Michelle K.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; CCAAT-Binding Factor - physiology; CCAAT-Enhancer-Binding Proteins - physiology; DNA-Binding Proteins - physiology; Enhancer Elements, Genetic; Male; Molecular Sequence Data; NF-Y protein; Nuclear Proteins; Promoter Regions, Genetic; Proteins - genetics; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone - physiology; SREBP-1c protein; Sterol Regulatory Element Binding Protein 1; Sterol regulatory element-binding protein 1c; Transcription Factors - physiology; Triiodothyronine - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M105471200

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 T3regulatory 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.