Regulation of the tissue factor gene

The tissue factor (TF) gene is expressed in a cell type‐specific manner in vivo. It is constitutively expressed by several extravascular cell types and indueibly expressed within the vasculature by monocytes and endothelial cells. TF expression initiates thrombotic episodes associated with various diseases, including atherosclerosis, septic shock, and cancer. Regulatory elements within the human TF promoter have been identified by functional analysis of TF promoter‐luciferase gene plasmids transiently transfected into various cell types. Transcription factors that control expression of the TF gene were identified using gel shift mobility assays. Induction of the TF gene in human monocytic cells and endothelial cells exposed lo bacterial lipopolysaccharide or cy‐tokines is mediated by a distal enhancer (‐227 to ‐172 bp) containing two AP‐1 sites and a κB site. Functional interactions between Fos‐Jun heterodiitiers and c‐Rel‐p65 heterodimers are required for transcriptional activation of the TF gene. In contrast, serum and phorbol ester induction of the TF gene in human epithelial cells is controlled by a proximal enhancer (‐111 to +14 bp) containing three overlapping Egr‐l/Spl binding sites. Spl is constitutively expressed whereas Egr‐1 expression is induced by serum or phorbol ester stimulation. Spl also mediates basal promoter activity. Thus, TF gene expression is complex and is regulated by a number of transcription factors that bind to distinct regions of the TF promoter.—Mackman, N. Regulation of the tissue factor gene. FASEB J. 9, 883‐889 (1995)