PubMed:7592627 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/7592627","sourcedb":"PubMed","sourceid":"7592627","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/7592627","text":"Two mutations in the promoter region of the human protein C gene both cause type I protein C deficiency by disruption of two HNF-3 binding sites.\nProtein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by the proteolytic inactivation of factors Va and VIIIa. Individuals affected with protein C deficiency are at risk for thrombosis. Genetic analyses of affected individuals, to determine the cause of the protein C deficiency, revealed a large variety of mutations in the protein C gene, including several in the promoter region of this gene. Comparison of the region around two of these mutations, A-32--\u003eG and T-27--\u003eA, with transcription factor consensus sequences suggested the presence of two overlapping and inversely oriented HNF-3 binding sites. Direct evidence for the presence of the two HNF-3 binding sites in the protein C promoter was obtained using electrophoretic mobility shift assays and UV cross-linking experiments. These experiments revealed that HNF-3 can bind specifically to both putative HNF-3 sites in the wild-type protein C promoter. Due to the T-27--\u003eA mutation, one binding site is completely lost, while the other site still binds HNF-3, but with strongly reduced affinity. As a consequence of the A-32--\u003eG mutation, the protein C promoter loses all its HNF-3 binding capacity. Transient transfection experiments demonstrated that the binding of HNF-3 to the protein C promoter is of physiological significance. This followed from experiments in which the introduction of the A-32--\u003eG or T-27--\u003eA mutation resulted in a 4-5-fold reduced promoter activity in HepG2 cells. Furthermore, transactivation of the wild-type protein C promoter construct with HNF-3 showed a 4-5-fold increased promoter activity in HepG2 cells. In HeLa cells, significant wild-type promoter activity was only observed after transactivation with HNF-3. When a promoter construct containing the T--\u003eA mutation at position -27 was used, the transactivation potential of HNF-3 was 2-fold reduced in HepG2 cells, whereas in HeLa cells no transactivation was observed. With the promoter construct containing the A-32--\u003eG mutation, no transactivation by HNF-3 was found either in HepG2 or in HeLa 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