S. Soga et al., RADICICOL LEADS TO SELECTIVE DEPLETION OF RAF KINASE AND DISRUPTS K-RAS-ACTIVATED ABERRANT SIGNALING PATHWAY, The Journal of biological chemistry, 273(2), 1998, pp. 822-828
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 p
athway relied on co-expression of K-Ras and Raf-1, Radicicol, an antif
ungal antibiotic, was found to inhibit the K-ras signaling pathway rec
onstituted in yeast, In K-ras-transformed, rat epithelial, and K-ras-a
ctivated, human pancreatic carcinoma cell lines, radicicol inhibited K
Ras-induced hyperphosphorylation of Erk2, In addition, the level of R
af kinase was significantly decreased in radicicol-treated cells, wher
eas the levels of K-Ras and MAPK remained unchanged, These results sug
gest that radicicol disrupts the K-Ras-activated signaling pathway by
selectively depleting Raf kinase and raises the possibility that pharm
acological destabilization of Raf kinase could be a new and powerful a
pproach for the treatment of K-ras-activated human cancers.