Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals affected by protein C deficiency are at risk for venous thrombosis. One such affected individual was shown earlier to carry a -14 T --> C mutation in the promoter region of the protein C gene. It is shown here that the region around this mutation corresponds to a binding site for the transcription factor hepatocyte nuclear factor (HNF)-6 and that this site completely overlaps an HNF-1 binding site. HNF-6 and HNF-1 bound in a mutually exclusive manner. The -14 T --> C mutation reduced HNF-6 binding. In transient transfection experiments, HNF-6 transactivated the wild-type protein C promoter and introduction of the mutation abolished transactivation by HNF-6. Similar experiments showed that wild-type protein C promoter activity was reduced by cotransfection of an HNF-1 expression vector. This inhibiting effect of HNF-1 was reversed to a stimulatory effect when promoter sequences either upstream or downstream of the HNF-6/HNF-1 site were deleted. It is concluded that HNF-6 is a major determinant of protein C gene activity. Moreover, this is the first report describing the putative involvement of HNF-6 and of an HNF-6 binding site in human pathology.
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PMID:Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein C gene promoter. 955 65

Recent studies on the regulation of protein C gene transcription revealed the presence of three transcription-factor binding sites in the close proximity to the transcription start site. The proximal 40 bp upstream of the transcription-initiation site contain two, partly overlapping, binding sites for the liver-enriched hepatocyte nuclear factor (HNF)-3 and one binding site to which HNF-1 and HNF-6 bind in a mutually exclusive manner. In order to examine the functionality of the tight alignment of transcription-factor binding sites around the transcription-initiation site, we performed insertional mutagenesis experiments. Sequences were inserted at position -21, separating both HNF-3 binding sites from the HNF-1-HNF-6 binding site, and position -5, separating the HNF-3-HNF-1-HNF-6 complex from the transcription start site. All insertions were made in the context of the protein C gene -386/+107 promoter region and tested for activity by transient transfection experiments. Insertions at position -21 resulted in a combined distance- and DNA-turn-dependent increase in protein C gene expression. Insertions of variable length at position -5 decreased protein C gene expression in a DNA-turn-dependent manner. However, this turn-dependent decrease was accompanied by a distance-dependent increase in promoter activity. This is the first report in which changing the spacing between adjacent transcription-factor binding sites results in enhanced transcription, indicating the submaximal alignment of promoter elements in the wild-type protein C gene promoter region.
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PMID:Unique distance- and DNA-turn-dependent interactions in the human protein C gene promoter confer submaximal transcriptional activity. 1033 97

The level and tissue specificity of eukaryotic gene transcription is determined by the binding of specific transcription factors to DNA sequence elements located around the transcription start site. The availability and activity of specific transcription factors depends on a variety of developmental and environmental cues and, therefore, varies from cell type to cell type. For instance, liver tissue, the principal site of expression of the coagulation inhibitor protein C, expresses a heterogeneous group of transcription factors called hepatocyte nuclear factors (HNFs). Some of these HNFs are essential players in protein-C gene expression. This review discusses the significance of HNF-1 and HNF-6 in regulating the transcription of the protein-C gene and gives directions for future research.
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PMID:Type-I protein-C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein-C gene promoter. 1057 22