Miller P, Schnur R C, Barbacci E, Moyer M P, Moyer J D
Department of Neurosciences, Pfizer Inc., Groton, CT 06340.
Biochem Biophys Res Commun. 1994 Jun 30;201(3):1313-9. doi: 10.1006/bbrc.1994.1847.
Several benzoquinoid ansamycins, e.g., herbimycin A and geldanamycin, have been widely used as inhibitors of tyrosine kinases. We recently reported that exposure to herbimycin A and several analogs depletes the erbB2 gene product p185 in human breast cancer cells. In order to explore the mechanism of this specific degradation of p185, a biologically active ansamycin incorporating a photoaffinity label was synthesized. This compound, CP202509, specifically bound to a 100 kD protein (p100) in intact SKBr3 cells and in fibroblasts transfected with the c-erbB2 or v-src oncogenes. Binding of other ansamycin analogs to p100, as measured indirectly by their ability to inhibit CP202509 binding, correlated with their ability to lower p185 protein and phosphotyrosine in SKBr3 cells. These results suggest that the ansamycins may deplete tyrosine kinases through binding to this protein.
几种苯醌类安莎霉素，如除莠霉素A和格尔德霉素，已被广泛用作酪氨酸激酶抑制剂。我们最近报道，暴露于除莠霉素A及其几种类似物会使人类乳腺癌细胞中的erbB2基因产物p185耗竭。为了探究p185这种特异性降解的机制，合成了一种带有光亲和标记的生物活性安莎霉素。这种化合物CP202509，在完整的SKBr3细胞以及转染了c-erbB2或v-src癌基因的成纤维细胞中，特异性地与一种100 kD的蛋白质（p100）结合。通过其他安莎霉素类似物抑制CP202509结合的能力间接测定，它们与p100的结合与其降低SKBr3细胞中p185蛋白和磷酸酪氨酸的能力相关。这些结果表明，安莎霉素可能通过与这种蛋白质结合来消耗酪氨酸激酶。
