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Regulation of von Willebrand factor gene expression by the E4BP4 transcriptional repressor


, : Regulation of von Willebrand factor gene expression by the E4BP4 transcriptional repressor. Blood 96(11 Part 1): 634a, November 16

von Willebrand factor (VWF) is a large adhesive glycoprotein that is synthesized in endothelial cells and megakaryocytes. Studies of the mechanisms regulating expression of the VWF gene have demonstrated that, in addition to the involvement of cell-type specific transcriptional activators such as GATA and ETS, expression is modulated by the binding of several repressor proteins including an NF1-like factor and Oct-1. In this study we describe investigations of an additional repressor element in the 5' non-coding region of the VWF gene. Initial transient transfection studies were performed in bovine aortic endothelial cells (BAECs) and the DAMI megakaryocytic cell line using luciferase reporter genes. Deletion of GATA binding sites at nucleotides (nts) -91/-72 and +215/+230 from a regulatory element encompassing nts -91 to +230 of the VWF promoter resulted in an 80% reduction in luciferase expression in both cell types. However, further deletion of nts +70/+169 from this sequence resulted in a 2 to 5-fold increase in transactivation. Furthermore, when the region of the VWF 5' non-coding sequence between nts +31/+169 was cloned upstream of an SV40-driven luciferase construct, luciferase expression was reduced by 50-80% in DAMI cells, HepG2 hepatoma cells and Baby Hamster Kidney cells. Additional deletion studies localized the transcriptional repressor function to between nts +83/+124 and an analysis of this sequence has shown a 10 nt element between +96/+106 on the non-coding strand that demonstrates a 9 out of 10 nucleotide identity with the binding site for the bZIP repressor protein E4BP4. The nt +96/+106 element from the VWF gene, a mutated version of this sequence, an element containing nts +63/+101 from the VWF sequence and the consensus E4BP4 sequence were cloned upstream of the SV40-luciferase construct. Following co-transfection with an E4BP4 expression plasmid into HepG2 and COS-7 cells both the VWF +96/+106 element and the E4BP4 binding element repressed luciferase expression by 3-fold. Neither of the other two elements showed any effect on luciferase expression. Finally, using EMSA studies we have shown that the +96/+106 VWF element binds DAMI cell and HepG2 nuclear proteins in a manner that can be specifically competed by the E4BP4 binding sequence. This finding was further supported by the inhibition of nuclear protein binding to both the VWF +96/+106 element and the E4BP4 sequence by pre-incubation of the nuclear extracts with anti-E4BP4 antibody. In conclusion, these studies demonstrate a further repressor element in the VWF 5'non-coding region that binds to the ubiquitous bZIP protein E4BP4.

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