Okadaic acid induction of the urokinase‐type plasminogen activator gene occurs independently of cAMP‐dependent protein kinase and protein kinase C and is sensitive to protein synthesis inhibition.

Urokinase‐type plasminogen activator (uPA) gene expression in LLC‐PK1 cells is induced by activation of cAMP‐dependent protein kinase (cAMP‐PK) or protein kinase C (PK‐C). To determine whether protein phosphatases can also modulate uPA gene expression, we tested okadaic acid, a potent specific inhibitor of protein phosphatases 1 and 2A, in the presence and absence of cAMP‐PK and PK‐C activators. Okadaic acid by itself induced uPA mRNA accumulation. This induction was strongly attenuated by the inhibition of protein synthesis. In contrast, the inhibition of protein synthesis enhanced induction by 8‐bromo‐cAMP and only delayed induction by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). In addition, down‐regulation of PK‐C by chronic treatment with TPA did not abrogate the okadaic acid‐dependent induction. These results provide evidence for a novel signal transduction pathway leading to gene regulation that involves protein phosphorylation but is independent of both cAMP‐PK and PK‐C.