Glutathione-S-transferase as a selective inhibitor of oncogenic ras-p21-induced mitogenic signaling through blockade of activation of jun by jun-N-terminal kinase

We have identified the intracellular detoxification enzyme, glutathione-S-t ransferase (GST), as a potent inhibitor of the activation of jun by its kin ase, jun-N-terminal kinase (JNK), in vitro. All three major isozymes (alpha , mu, and pi) bind to JNK-jun complexes and inhibit activation of jun by JN K. We now find that GST inhibits JNK-induced oocyte maturation in vivo and strongly inhibits oocyte maturation induced by oncogenic ras-p21 protein, b ut not by insulin-activated normal cellular p21 protein. These results corr elate with the finding that oncogenic, but not insulin-activated normal, p2 1 induces high levels of activated JNK. GST also strongly blocks induction of oocyte maturation by protein kinase C (PKC) which is a critical downstre am target of oncogenic but not normal ras-p21. Thus, we have established a new function for GST as a potent physiological inhibitor of the ras-JNK-jun pathway.