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Vol. 273, Issue 2, 822-828, January 9, 1998
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From the Activation of Ras leads to the constitutive
activation of a downstream phosphorylation cascade comprised of Raf-1,
mitogen-activated protein kinase (MAPK) kinase, and MAPK. We have
developed a yeast-based assay in which the Saccharomyces
cerevisiae mating pheromone-induced MAPK pathway relied on
co-expression of K-Ras and Raf-1. Radicicol, an antifungal antibiotic,
was found to inhibit the K-ras signaling pathway
reconstituted in yeast. In K-ras-transformed, rat
epithelial, and K-ras-activated, human pancreatic carcinoma
cell lines, radicicol inhibited K-Ras-induced hyperphosphorylation of
Erk2. In addition, the level of Raf kinase was significantly
decreased in radicicol-treated cells, whereas the levels of K-Ras
and MAPK remained unchanged. These results suggest that radicicol
disrupts the K-Ras-activated signaling pathway by selectively depleting
Raf kinase and raises the possibility that pharmacological
destabilization of Raf kinase could be a new and powerful approach for
the treatment of K-ras-activated human cancers.
Tokyo Research Laboratories, Kyowa Hakko
Kogyo Co. Ltd., Asahi-machi 3-6-6, Machida-shi, Tokyo 194, Japan,
§ Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo
Co. Ltd., Shimotogari 1188, Nagaizumi-cho, Shuntou-gun, Shizuoka 411, Japan, ¶ Department of Molecular Biology, Faculty of Science,
Nagoya University, Chikusa-ku, Nagoya 464-01, Japan, and
Department of Microbiology and Immunology, University of
Tennessee, Memphis, Tennessee 38163
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