SELECTIVE-INHIBITION OF ONCOGENIC RAS-P21 IN-VIVO BY AGENTS THAT BLOCK ITS INTERACTION WITH JUN-N-KINASE (JNK) AND JUN PROTEINS - IMPLICATIONS FOR THE DESIGN OF SELECTIVE CHEMOTHERAPEUTIC-AGENTS

We have obtained evidence that oncogenic and activated normal ras-p21 proteins utilize overlapping but distinct signal transduction pathways . Recently, we found that ras-p21 binds to both jun and its kinase, ju n kinase (JNK). We now present evidence that suggests that oncogenic b ut not normal activated p21 depends strongly on early activation of JN K/jun. This early activation most likely involves direct interaction b etween oncogenic p21 and JNK/jun because p21 peptides that blocked the binding of p21 to JNK and jun strongly inhibited oncogenic p21-induce d oocyte maturation while they did not inhibit insulin-activated norma l cellular p21-induced maturation. Very similar results were also obta ined for a newly characterized specific inhibitor of JNK which blocked oncogenic but not normal activated p21-induced oocyte maturation. We also found that both jun and JNK strongly enhanced oncogenic p21-induc ed oocyte maturation while they inhibited insulin-activated normal p21 -induced oocyte maturation. These results suggest that the peptides an d JNK inhibitor may be useful agents in selectively blocking the effec ts of oncogenic but not normal p21 in cells.