Tissue factor is the glycoprotein component of the cell surface receptor for Factor VII/VIIa. Tissue factor is a critical molecule in the coagulation pathway since this complex initiates both the extrinsic pathway of coagulation by activation of Factor X to Xa and the intrinsic pathway through the activation of Factor IX to IXa. Although tissue factor mRNA and protein are synthesized in many tissues, the expression of this gene is tightly regulated in cells of the vasculature. Synthesis of tissue factor mRNA is inducible in both endothelial cells and peripheral blood monocytes by a variety of agonists including lipopolysaccharide (LPS). The ability of both monocytes and endothelial cells to induce tissue factor synthesis is most likely an adaptive response; however, abnormal tissue factor gene expression may correlate with disease. On the one hand, the inappropriate induction of tissue factor synthesis may produce a hypercoagulable state resulting in thrombosis and fibrin deposition. On the other hand, the inability to appropriately induce tissue factor synthesis in response to stimulation by biologically meaningful agonists may result in bleeding disorders and abnormal inflammatory responses. The molecular tools required to evaluate tissue factor gene expression are available. The applicant will use these reagents to study the molecular events that modulate tissue factor synthesis in several monocyte cell lines. The regulated expression of tissue factor most likely results from the interplay of nuclear factors with regulatory sequences located near the gene. The experiments described in this application propose to identify these cis-acting sequences and the nuclear trans-acting factors that interact with these elements to repress tissue factor synthesis in uninduced cells and activate synthesis in cells induced with LPS. In addition, other experiments will examine the biology of tissue factor synthesis in these cells by evaluating the roles of transcriptional and post-transcriptional events on mRNA synthesis and accumulation. This analysis should provide insight into the molecular events that regulate tissue factor gene expression. Intervention strategies for the prevention and treatment of thrombotic disease may evolve as we begin to understand the molecular controls of tissue factor synthesis in the vascular compartment.
| Groupp, E R; Donovan-Peluso, M (1996) Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter. J Biol Chem 271:12423-30 |
| Donovan-Peluso, M; George, L D; Hassett, A C (1994) Lipopolysaccharide induction of tissue factor expression in THP-1 monocytic cells. Protein-DNA interactions with the promoter. J Biol Chem 269:1361-9 |
