| Title: | Radicicol leads to selective depletion of Raf kinase and disrupts K-Ras-activated aberrant signaling pathway |
| Author(s): | Soga S; Kozawa T; Narumi H; Akinaga S; Irie K; Matsumoto K; Sharma SV; Nakano H; Mizukami T; Hara M; |
| Address: | "Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Asahi-machi 3-6-6, Machida-shi, Tokyo 194, Japan" |
| ISSN/ISBN: | 0021-9258 (Print) 0021-9258 (Linking) |
| Abstract: | "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" |
| Keywords: | "Animals Cell Line Enzyme Inhibitors/*pharmacology *Genes, ras Humans Lactones/*pharmacology Macrolides Pancreatic Neoplasms/metabolism Proto-Oncogene Proteins c-raf/*antagonists & inhibitors Rats Recombinant Proteins/antagonists & inhibitors/metabolism Sa;" |
| Notes: | "MedlineSoga, S Kozawa, T Narumi, H Akinaga, S Irie, K Matsumoto, K Sharma, S V Nakano, H Mizukami, T Hara, M eng 1998/02/14 J Biol Chem. 1998 Jan 9; 273(2):822-8. doi: 10.1074/jbc.273.2.822" |
