THE SELECTIVE PROTEIN-KINASE-C INHIBITOR, RO-31-8220, INHIBITS MITOGEN-ACTIVATED PROTEIN-KINASE PHOSPHATASE-1 (MKP-1) EXPRESSION, INDUCES C-JUN EXPRESSION, AND ACTIVATES JUN N-TERMINAL KINASE

The role of protein kinase C (PKC) in inflammation, mitogenesis, and d ifferentiation has been deduced in part through the use of a variety o f PKC inhibitors. Two widely used inhibitors are the structurally rela ted compounds GF109203X and Ro-31-8220, both of which potently inhibit PKC activity and are believed to be highly selective. While using GF1 09203X and Ro-31-8220 to address the role of PKC in immediate early ge ne expression, we observed striking differential effects by each of th ese two compounds. Growth factors induce the expression of the immedia te early gene products MAP kinase phosphatase-1 (MKP-1), c-Fos and c-J un. Ro-31-8220 inhibits growth factor-stimulated expression of MKP-1 a nd c-Fos but strongly stimulated c-Jun expression, even in the absence of growth factors, GF109203X displays none of these properties. These data suggest that Ro-31-8220 may have other pharmacological actions i n addition to PKC inhibition, Indeed, Ro-31-8220 strongly stimulates t he stress-activated protein kinase, JNK1. Furthermore, Ro-31-8220 appa rently activates JNK in a PKC-independent manner. Neither the down-reg ulation of PKC by phorbol esters nor the inhibition of PKC by GF109203 X affected the ability of Ro-31-8220 to activate JNK1, These data sugg est that, in addition to potently inhibiting PKC, Ro-31-8220 exhibits novel pharmacological properties which are independent of its ability to inhibit PKC.