REGULATION OF TISSUE FACTOR GENE-EXPRESSION IN EPITHELIAL-CELLS - INDUCTION BY SERUM AND PHORBOL 12-MYRISTATE 13-ACETATE

Cell-specific expression of tissue factor (TF) in vivo is consistent w ith its primary role in hemostasis. In addition, TF expression is indu ced in cultured cells by a variety of agents, including serum and grow th factors, which define the TF gene as a ''primary response'' gene. I n this study we examined the signaling pathways and cis-acting regulat ory elements required for induction of TF gene expression in HeLa cell s in response to serum and the tumor promoter, phorbol 12-myristate 13 -acetate (PMA). TF activity and mRNA were induced greater than sixfold in quiescent HeLa cells by serum and PMA. TF mRNA induction by both a gonists required intracellular Ca2+ mobilization, whereas inhibition o f protein kinase C abolished induction of the TF gene by PMA but had n o effect on induction by serum. Functional studies demonstrated that a region of the human TF promoter between -96 and +121 bp contained reg ulatory elements required for serum and PMA induction. These data indi cate that different signaling pathways regulate TF gene expression in response to serum and PMA, although the same cis-acting DNA elements m ay mediate induction.