TISSUE FACTOR GENE-TRANSCRIPTION IN SERUM-STIMULATED FIBROBLASTS IS MEDIATED BY RECRUITMENT OF C-FOS INTO SPECIFIC AP-1 DNA-BINDING COMPLEXES

Serum stimulation of quiescent mouse fibroblasts results in transcript ional activation of tissue factor (TF), the cellular initiator of the protease cascade leading to blood coagulation. In this study, we demon strate that two AP-1 DNA-binding elements located 200-220 bp upstream of the transcription start site are both necessary and sufficient to c onfer serum inducibility to the TF gene promoter in fibroblasts. Analy sis of AP-1 DNA-binding complexes indicates that the predominant form of AP-1 activity in quiescent cells consists of an unidentified Fos-re lated protein and JunD. While c-Fos is notably absent from these preex isting complexes, serum stimulation results in the rapid entry of c-Fo s into the TF AP-1 DNA-binding complexes. A similar induction of c-Fos DNA-binding activity occurs in cells treated with recombinant growth factors such as platelet-derived growth factor (PDGF) and fibroblast g rowth factor (FGF). Importantly, overexpression of JunD and c-Fos abro gates the requirement for serum in the stimulation of TF promoter acti vity in fibroblasts. Together, these data indicate that the entry of c -Fos into heterodimeric AP-1 DNA-binding complexes with JunD is a key event underlying serum-stimulated transcription of the TF gene in fibr oblasts.