Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol

• Published in: Oncogene Vol. 16; no. 20; pp. 2639 - 2645
• Main Authors: SHARMA, S. V, AGATSUMA, T, NAKANO, H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 21.05.1998; Nature Publishing Group
• Subjects: 3T3 Cells; Animals; Antifungal Agents - metabolism; Antifungal Agents - pharmacology; Benzoquinones; Biological and medical sciences; Cell Line, Transformed; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - drug effects; Fibroblasts; Fundamental and applied biological sciences. Psychology; Heat shock proteins; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Lactams, Macrocyclic; Lactones - pharmacology; Macrolides; MAP kinase; Mice; Molecular and cellular biology; Molecular Chaperones - drug effects; Molecular weight; Proteins; Quinones - pharmacology; Raf protein; Ras protein; Signal transduction; Vertebrata; Antibiotic; Mammalia; Cell line; Mouse; Chaperone; Rodentia; Heat shock protein; Molecular interaction; Mechanism of action; Cell transformation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201790

Radicicol, a macrocyclic anti-fungal antibiotic, has the ability to suppress transformation by diverse oncogenes such as Src, Ras and Mos. Despite this useful property, the mechanism by which radicicol exerts its anti-transformation effects is currently unknown. To understand the transformation-suppressing effects of radicicol, a biotinylated derivative of radicicol was chemically synthesized and used as a probe in a Western-blot format to visualize cellular proteins that interact with radicicol. In transformed and untransformed mouse fibroblasts, the most prominent cellular protein that bound to radicicol had a molecular weight of approximately 90 kDa. Further analysis revealed that this protein was the mouse homologue of the 90 kDa heat shock protein (HSP90). This was confirmed by demonstrating the ability of radicicol to specifically bind purified human HSP90. Specificity of binding was demonstrated by the inhibition of binding of biotinylated radicicol by the native drug. Taken together with other studies the present observations suggest that the anti-transformation effects of radicicol may be mediated, at least in part, by the association of radicicol with HSP90 and the consequent dissociation of the Raf/HSP90 complex leading to the attenuation of the Ras/MAP kinase signal transduction pathway.