TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF THE RECEPTOR FOR UROKINASE-TYPE PLASMINOGEN-ACTIVATOR BY CYTOKINES AND TUMOR PROMOTERS IN THE HUMAN LUNG-CARCINOMA CELL-LINE A549

The receptor for urokinase-type plasminogen activator (uPAR) is an int egral membrane protein that specifically binds urokinase-type plasmino gen activator (uPA) and plays a crucial role in cell surface plasmin g eneration. We have previously found that transforming growth factor-be ta, type 1 (TGF-beta 1), increases uPAR gene transcription in the huma n lung carcinoma cell line A549 and now report that also epidermal gro wth factor (EGF) and the tumour promoter phorbol 12-myristate 13-aceta te (PMA) cause increased uPAR transcription and that PMA and TGF-beta 1 in addition increase the stability of uPAR mRNA, while EGF has no ef fect on this parameter. All three compounds also increase the uPAR pro tein level, as measured by cell-binding experiments with radiolabelled ligand. The increase in uPAR protein level was however considerably l ower with all three compounds than the increase in mRNA level, suggest ing that they also exert a translational or post-translational control . Accompanying the increase in the number of uPAR molecules there was a proportional decrease in their ligand-binding affinity, the mechanis m of which is unknown. Platelet-derived growth factor, basic fibroblas t growth factor and cyclic AMP analogues did not induce any change in the uPAR mRNA level in A549 cells. Previous studies have shown that ex pression of uPA and its type-1 inhibitor is regulated by a variety of cytokines in a cell-specific manner. The present study indicates that cytokines in addition influence cell surface plasminogen activation by regulating uPAR expression.