Estrogen induction and contact phase activation of human factor XII

This paper reviews data reported in the literature and results of our experiments on the transcriptional control of Factor XII by estrogens and on the activation of Factor XII in the plasma. Coagulation Factor XII (Hageman factor, FXII) is a serine protease secreted by the liver and activated by negative charged surfaces to play roles in fibrinolysis, coagulation, and inflammation. Multiple effects on hemostasis involving these processes via Hageman factor have been reported in relation to estrogen therapy. The nucleotide sequence of 3,174 base pair (bp) DNA at the 5' end of the Factor XII gene indicates that the Factor XII promoter is typical of TATA-less, liver-specific, and serine protease-type eukaryotic genes involved in clotting. In addition the Factor XII promoter contains at position -44/-31 a palindrome similar, but not identical, to an estrogen-responsive element (ERE) together with four hemisite EREs between positions -1314 and -608. These promoter regions may underlie the mechanism by which estrogens enhance Factor XII concentrations in plasma. In vivo, a 6-fold stimulation of FXII gene transcription by 17 beta-estradiol was observed in ovariectomized rats. In vitro a 230-bp promoter fragment of Factor XII (-181/+49) confers a strong 17 beta-estradiol responsiveness onto a chlorampenicol acetyltransferase reporter when transiently co-transfected with the human estrogen receptor. The domain structure of Factor XII allows identification of those parts of the protein with particular functions. cDNA constructs, in which sequences coding for selected domains were deleted, were used to produce recombinant deleted Factor XII proteins in a vacinia virus expression system. To identify the domain(s) responsible for contact phase activation, these recombinant proteins were tested for their capacity to bind to negatively charged substrates, to become activated by kallikrein, and to sustain blood clotting and amidolytic activity. In addition to the N-terminal domain, the growth factor and kringle domains and, to a lesser extent, the polyproline region also interact with negatively charged surfaces and presumably thus contribute to activation.