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A hepatocyte nuclear factor-3 site in the fibrinogen β promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent -148C/T polymorphism

Author: Verschuur, M. · Jong, · Felida, L. · Maat, · Vos, H.L.
Institution: TNO Kwaliteit van Leven
Source:Journal of Biological Chemistry, 17, 280, 16763-16771
Identifier: 238441
doi: doi:10.1074/jbc.M501973200
Keywords: Biology · Biomedical Research · Adenosinetriphosphate · Biological membranes · Calcium · Disease control · Positive ions · Proteins · RNA · Yeast · Cardiovascular disease · Genetic variation · MRNA level · Plasma fibrinogen levels · Cardiovascular system · CCAAT enhancer binding protein · Hepatocyte nuclear factor 3 · Small interfering RNA · Unclassified drug · Beta fibrinogen · DNA binding protein · FOXA1 protein, human · FOXA2 protein, human · FOXA3 protein, human · Hepatocyte nuclear factor 3alpha · Hepatocyte nuclear factor 3beta · Hepatocyte nuclear factor 3gamma · Messenger RNA · Nuclear protein · Primer DNA · Transcription factor · Binding site · Cardiovascular disease · Controlled study · Cytokine production · DNA polymorphism · Fibrinogen blood level · Gel mobility shift assay · Gene expression · Gene sequence · Genetic variability · Hepatoma cell · Human · Human cell · Inflammation · Mutational analysis · Promoter region · Protein protein interaction · Reporter gene · Risk factor · Transcription regulation · Biosynthesis · Cell nucleus · Chemistry · Dose response · Electrophoresis · Gene vector · Genetic polymorphism · Genetics · Metabolism · Molecular genetics · Mutation · Nucleotide sequence · Protein binding · Protein motif · RNA interference · Transactivation · Tumor cell line · Alleles · Amino Acid Motifs · Base Sequence · Binding Sites · Cell Line, Tumor · Cell Nucleus · DNA Mutational Analysis · DNA Primers · DNA-Binding Proteins · Dose-Response Relationship, Drug · Electrophoresis · Fibrinogen · Genes, Reporter · Genetic Vectors · Hepatocyte Nuclear Factor 3-alpha · Hepatocyte Nuclear Factor 3-beta · Hepatocyte Nuclear Factor 3-gamma · Humans · Inflammation · Interleukin-6 · Luciferases · Molecular Sequence Data · Mutation · Nuclear Proteins · Polymorphism, Genetic · Promoter Regions (Genetics) · Protein Binding · Risk Factors · RNA Interference · RNA, Messenger · RNA, Small Interfering · Trans-Activation (Genetics) · Transcription Factors · Variation (Genetics)


An elevated plasma fibrinogen level is an independent risk factor for cardiovascular disease. Therefore, an understanding of the regulation of fibrinogen expression is important. Inflammation and genetic variation of the fibrinogen β gene regulate plasma fibrinogen levels, and there are indications that inflammation and genetic variation interact. The aim of our study was to gain more understanding of the regulation of the inflammatory response of the fibrinogen β gene and to determine the effects of genetic variation. Luciferase reporter gene assays in hepatoma cells, mutation analysis, and electrophoretic mobility shift assays were used to investigate the transcriptional regulation of the fibrinogen β promoter. We identified a hepatocyte nuclear factor-3 (HNF-3) site located just upstream of previously identified interleukin-6 (IL6)-responsive sequences. This HNF-3 site is essential for a full response of the promoter to IL6, which is a new function for HNF-3. The activity of the CCAAT box/enhancer-binding protein site (located 18 nucleotides downstream of the HNF-3 site and important to the IL6 response) depends on the integrity of the HNF-3 site and vice versa, explaining the necessity of HNF-3 in the IL6 response of the fibrinogen β promoter. Furthermore, small interfering RNA to HNF-3 reduces the fibrinogen β mRNA levels. The rare T allele of the -148C/T polymorphism, which is present between the binding sites of HNF-3 and CCAAT box/ enhancer-binding protein, interferes with this mechanism, and this polymorphism is in our assay system the only genetic determinant of IL6-induced promoter activity among six polymorphisms in the fibrinogen β promoter. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. Chemicals / CAS: fibrinogen, 9001-32-5; BBeta fibrinogen; DNA Primers; DNA-Binding Proteins; Fibrinogen, 9001-32-5; FOXA1 protein, human; FOXA2 protein, human; FOXA3 protein, human; Hepatocyte Nuclear Factor 3-alpha; Hepatocyte Nuclear Factor 3-beta, 135845-92-0; Hepatocyte Nuclear Factor 3-gamma, 135845-91-9; Interleukin-6; Luciferases, EC 1.13.12.-; Nuclear Proteins; RNA, Messenger; RNA, Small Interfering; Transcription Factors