Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol
Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol
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DOI：
10.1038/sj.onc.1201790
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发表时间：
1998-05-21
期刊：
影响因子：
8
通讯作者：
Nakano, H
中科院分区：
文献类型：
--
作者：
Sharma, SV;Agatsuma, T;Nakano, H
Radicicol是一种大环抗真菌抗生素，具有抑制多种癌基因（如Src、Ras和Mos）转化的能力。为了了解根尖醇的转化抑制作用，我们化学合成了一种根尖醇的生物素化衍生物，并将其作为Western-blot探针，在转化和未转化的小鼠成纤维细胞中观察与根尖醇相互作用的细胞蛋白。与radicicol结合的最突出的细胞蛋白分子量约为90 kDa，进一步分析表明该蛋白是90 kDa热休克蛋白（HSP90）的小鼠同源物。这是通过证明根尖醇能够特异性结合纯化的人HSP90来证实的，结合的特异性是通过抑制生物素化根尖醇的结合来证明的。结合其他研究，目前的观察结果表明，根尖醇的抗转化作用可能是介导的，至少部分是介导的。通过自由基与HSP90的结合以及Raf/HSP90复合物的解离导致Ras/MAP激酶信号转导通路的衰减。
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.