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.

The Journal of Biological Chemistry
C A SpekPieter H Reitsma

Abstract

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 ...Continue Reading

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Citations

May 12, 2012·Annals of Hematology·Navin PaiShrimati Shetty
Apr 5, 2001·Current Atherosclerosis Reports·D Lillicrap
Oct 12, 2000·Molecular and Cellular Endocrinology·M RastegarG G Rousseau
Aug 4, 1999·Proceedings of the National Academy of Sciences of the United States of America·C E PierreuxF P Lemaigre
Feb 5, 2015·Thrombosis Research·Chun-jie LuanMing-min Gu
Mar 20, 2012·Thrombosis Research·Katherine R ThainKeith R Walley
May 31, 2011·Thrombosis Research·Dezso DavidTeresa Gago
Sep 7, 2011·Cellular Signalling·Kewei Wang, Ai-Xuan Holterman
Apr 9, 1999·Arteriosclerosis, Thrombosis, and Vascular Biology·L Le FlemM Alhenc-Gelas
Mar 9, 2006·Clinical and Vaccine Immunology : CVI·David T BergBrian W Grinnell
May 6, 2019·Cellular and Molecular Life Sciences : CMLS·Sheng-Nan ChangChia-Ti Tsai

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