Functional interaction between sterol regulatory element-binding protein-1c, nuclear factor Y, and 3,5,3'-triiodothyronine nuclear receptors.
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 (T(3)) receptors, and co-activators using the S14 gene promoter as a model. T(3), 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 T(3)- and SREBP-1c-mediated induction of S14 promoter activity in rat primary hepatocytes. T(3) and glucose/insulin induce S14 gene transcription through separate enhancers. Enhancer substitution studies reveal a preferential interaction between SREBP-1c.NF-Y and the T(3) 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 T(3) 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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Departments of Physiology, Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA. Jump@msu.edu
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D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000502:physiology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology
D023081:CCAAT-Binding Factor; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011988:Receptors, Thyroid Hormone; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; C051065:THRSP protein, human; C501478:Thrsp protein, rat; D014157:Transcription Factors; C402244:nuclear factor Y; D014284:Triiodothyronine