The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome.
The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome.
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发表时间：
2000-07
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通讯作者：
Won G. An;Theodor W. Schulte;Leonard M Neckers
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作者：
Won G. An;Theodor W. Schulte;Leonard M Neckers
包括转录因子和蛋白激酶在内的几种重要信号蛋白的稳定性依赖于热休克蛋白 (Hsp)-90。 p210bcr-abl 是一种在慢性粒细胞性白血病中表达的蛋白质，可受到苯醌安沙霉素除草霉素 A 的功能性抑制。苯醌安沙霉素还可与 Hsp90 结合并抑制 Hsp90 的活性。我们现在证明，在 K562 慢性粒细胞白血病细胞中，p210bcr-abl 与 Hsp90 及其辅助伴侣 p23 复合。短暂暴露于苯醌安沙霉素 Hsp90 抑制剂格尔德霉素 (GA) 会降低 p210bcr-abl 与 Hsp90 和 p23 的关联，并增加其与伴侣 Hsp70 和 p60Hop 的关联。 GA 对与 v-src（另一种 Hsp90 依赖性致癌激酶）相关的分子伴侣具有类似的作用。 p210bcr-abl 和 v-src 的 Hsp90/p23 关联性丧失以及 Hsp70/p60Hop 关联性的获得先于 GA 诱导这些激酶的降解。 GA 诱导的降解是由蛋白酶体介导的，因为蛋白酶体抑制剂会阻断 GA 的作用，导致 p210bcr-abl 和 v-src 在洗涤剂不溶性细胞部分中积累。 p210bcr-abl 和 v-src 比其正常细胞对应物 c-abl 和 c-src 更容易受到 GA 诱导的降解。
Several important signaling proteins including transcription factors and protein kinases depend on heat shock protein (Hsp)-90 for stability. p210bcr-abl, a protein expressed in chronic myelogenous leukemia, is functionally inhibited by the benzoquinone ansamycin herbimycin A. Benzoquinone ansamycins also bind to and inhibit the activity of Hsp90. We now demonstrate that p210bcr-abl is complexed with Hsp90 and its cochaperone p23 in K562 chronic myelogenous leukemia cells. Brief exposure to the benzoquinone ansamycin Hsp90 inhibitor geldanamycin (GA) decreases the association of p210bcr-abl with Hsp90 and p23 and increases its association with the chaperones Hsp70 and p60Hop. GA has a similar effect on chaperone association with v-src, another Hsp90-dependent oncogenic kinase. Loss of Hsp90/p23 association and acquisition of Hsp70/p60Hop association of both p210bcr-abl and v-src precede GA-induced degradation of these kinases. GA-induced degradation is mediated by the proteasome because proteasome inhibitors block the effects of GA, causing both p210bcr-abl and v-src to accumulate in a detergent-insoluble cellular fraction. Both p210bcr-abl and v-src are more susceptible to GA-induced degradation than are their normal cellular counterparts, c-abl and c-src.