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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 |
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| Authors: | Shazia Amar Albert Glozman Denise Chung Victor Adler Zeev Ronai Fred K. Friedman Richard Robinson Paul Brandt-Rauf Z. Yamaizumi Matthew R. Pincus |
| Affiliation: | (1) Department of Pathology and Laboratory Medicine, Veterans Affairs Medical Center, 800 Poly Place, Brooklyn, NY 11209, USA, US;(2) Department of Pathology, SUNY Health Science Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA, US;(3) Department of Chemistry, Long Island University, Brooklyn, NY, USA, IS;(4) Department of Biology, Long Island University, Brooklyn, NY, USA, IS;(5) Molecular Carcinogenesis Division, American Health Foundation, 1 Dana Road, Valhalla, NY 10595, USA, US;(6) Laboratory of Molecular Carcinogenesis, Room 4E24, Building 37, National Institutes of Health, Bethesda, MD 20892, USA, US;(7) Division of Environmental Sciences, Columbia College of Physicians and Surgeons, 60 Haven Avenue, New York, NY 10032, USA, US;(8) National Cancer Center Research Institute, Tokyo, Japan, JP |
| Abstract: | 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, jun kinase (JNK). We now present evidence that suggests that oncogenic but not normal activated p21 depends strongly on early activation of JNK/jun. This early activation most likely involves direct interaction between oncogenic p21 and JNK/jun because p21 peptides that blocked the binding of p21 to JNK and jun strongly inhibited oncogenic p21-induced oocyte maturation while they did not inhibit insulin-activated normal cellular p21-induced maturation. Very similar results were also obtained 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-induced oocyte maturation while they inhibited insulin-activated normal p21-induced oocyte maturation. These results suggest that the peptides and JNK inhibitor may be useful agents in selectively blocking the effects of oncogenic but not normal p21 in cells. Received: 8 January 1997 / Accepted: 4 April 1997 |
| Keywords: | Selective inhibition Oncogenic ras-p21 jun-N-kinase jun proteins |
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