UROKINASE-MEDIATED TRANSACTIVATION OF THE PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-2 (PAI-2) GENE PROMOTER IN HT-1080 CELLS UTILIZES AP-1 BINDING-SITES AND POTENTIATES PHORBOL ESTER-MEDIATED INDUCTION OF ENDOGENOUS PAI-2 MESSENGER-RNA

Urokinase-type plasminogen activator (u-PA) bound to its receptor, u-P AR, initiates signal transduction pathways able to induce expression o f the activator protein-1 (AP-1) family member c-fos [1], Since transc ription factors bound to AP-1 recognition sequences within the PAI-2 g ene promoter play a role in basal and phorbol ester-mediated induction of PAI-2 gene expression, we hypothesised that u-PA/u-PAR-mediated mo dulation of AP-1 activity would in turn influence constitutive and ind ucible PAI-2 gene expression. Treatment of HT-1080 or U-937 cells with high molecular weight u-PA (HMW u-PA) resulted in induction of nuclea r proteins binding to a functional AP-1 element in the proximal PAI-2 promoter. This increase in AP-1 activity correlated with a transactiva tion of the PAI-2 gene promoter in transiently transfected HT-1080 cel ls, We also demonstrate the u-PA treatment potentiated phorbol ester ( PMA)-mediated induction of PAI-2 mRNA, indicating that u-PA binding pr oduces a bone fide response in vivo.