Tissue factor is the membrane protein which serves as an essential cofactor for factor VII in the initiation of blood coagulation. The procoagulant activity of tissue factor, and hence its ability to initiate coagulation, is greatly influenced by the lipids with which it is associated, and varies among cell types. Genetic expression, cell surface transition from cryptic to active state, specific activity available following transition, and suppression of activity are all relevant aspects of tissue factor regulation which remain to be described. The long-term goal of this research is to elucidate the mechanisms by which tissue factor is expressed, limited in its expression, and inhibited once coagulation has been initiated. The research is approached with model systems (using purified coagulation factors and inhibitors and tissue factor reconstituted into vesicles of controlled composition) and with cells in culture in which tissue factor is dynamically regulated. The model systems will be used to specifically address the physical association of the tissue factor protein with various lipids (e.g. phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, cholesterol) and the resultant specific procoagulant activity. Lipid-binding proteins which are known to affect tissue factor expression (e.g. apolipoprotein A-II and the acute-phase reactant C-reactive protein) will be further studied to elucidate the mechanism(s) of their effects. Tissue factor is present in a variety of cultured cells and the specific activity per cell diminishes as the cultures approach confluency. A monoclonal antibody against tissue factor will be used to determine if the decreased specific activity is due to diminished tissue factor antigen. The mechanism(s) by which cultured cells regulate their specific tissue factor activity will be investigated. These studies are prerequisite to a full understanding of tissue factor regulation and future efforts to intervene at various levels of its expression.
| Cohen, S M; Cano, M; Earl, R A et al. (1991) A proposed role for silicates and protein in the proliferative effects of saccharin on the male rat urothelium. Carcinogenesis 12:1551-5 |
