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

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 mut...

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Veröffentlicht in:The Journal of biological chemistry 1998-04, Vol.273 (17), p.10168-10173
Hauptverfasser: Spek, C. Arnold, Lannoy, Vincent J., Lemaigre, Frédéric P., Rousseau, Guy G., Bertina, Rogier M., Reitsma, Pieter H.
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Sprache:eng
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Zusammenfassung: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.273.17.10168