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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Distinct regulation of insulin receptor substrate-1 and -2 by 90-kDa heat-shock protein in adrenal chromaffin cells.
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Distinct regulation of insulin receptor substrate-1 and -2 by 90-kDa heat-shock protein in adrenal chromaffin cells.

机译：肾上腺嗜铬细胞中90 kDa热激蛋白对胰岛素受体底物1和-2的不同调节。

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摘要

Multiple signaling pathways via insulin receptor substrate-1 and -2 play crucial roles in health, diseases, and therapeutics (i.e., longevity, tumorigenesis, and neuroprotection). The 90-kDa heat-shock protein (Hsp90) is an emerging target molecule of therapeutics, Hsp90 inhibitors being promising against various diseases (e.g., cancer, brain and cardiac ischemia, and neurodegenerative diseases). Much remains, however, unknown whether Hsp90 could regulate insulin receptor substrate-1 and -2 signaling pathways. In cultured bovine adrenal chromaffin cells, we observed that 24-h treatment with 1 microM geldanamycin (an inhibitor of Hsp90) decreased insulin receptor substrate-1 level, while increasing insulin receptor substrate-2 level; besides, geldanamycin lowered phosphoinositide 3-kinase, phosphoinositide-dependent kinase-1, Akt, glycogen synthase kinase-3beta, and Raf-1 levels, without changing extracellular signal-regulated kinase and its upstream kinase levels. Chronic (>or=12h) treatment with 0.1-10 microM Hsp90 inhibitor (geldanamycin, 17-allylamino-17-demethoxy-geldanamycin, herbimycin A, and radicicol) decreased insulin receptor substrate-1 level by approximately 66%, while increasing insulin receptor substrate-2 level by approximately 160%. These effects of geldanamycin (IC(50) 155 nM, EC(50) 177 nM) and 17-allylamino-17-demethoxy-geldanamycin (IC(50) 310 nM, EC(50) 260 nM) were time- and concentration-dependent. Geldanamycin-induced decrease of insulin receptor substrate-1 was attenuated by lactacystin, beta-lactone or MG132 (proteasome inhibitor), but not by calpastatin (calpain inhibitor) or leupeptin (lysosome inhibitor); geldanamycin did not affect heteroprotein complex formation between insulin receptor substrate-1 or -2 and Hsp90. Geldanamycin-induced increase of insulin receptor substrate-2 was prevented by cycloheximide or actinomycin D. Geldanamycin lowered insulin receptor substrate-1 mRNA level by approximately 39%, while raising insulin receptor substrate-2 mRNA level by approximately 109% between 3 and 24h, without changing the stability of insulin receptor substrate-1 and -2 mRNAs. Nuclear run-on assay revealed that geldanamycin retarded insulin receptor substrate-1 gene transcription by 42%, while accelerating insulin receptor substrate-2 gene transcription by 41%. Hsp90 inhibitors oppositely altered insulin receptor substrate-1 and -2 levels via proteasomal degradation and gene transcription.
机译：通过胰岛素受体底物1和-2的多种信号通路在健康，疾病和治疗方法（即长寿，肿瘤发生和神经保护）中起着至关重要的作用。 90kDa的热休克蛋白（Hsp90）是一种新兴的治疗靶标分子，Hsp90抑制剂有望抵抗各种疾病（例如癌症，脑和心脏缺血以及神经退行性疾病）。然而，仍然有很多尚不清楚，Hsp90是否可以调节胰岛素受体底物1和-2信号通路。在培养的牛肾上腺嗜铬细胞中，我们观察到用1 microM格尔德霉素（Hsp90的抑制剂）处理24小时可降低胰岛素受体底物1水平，而增加胰岛素受体底物2水平。此外，格尔德霉素还降低了磷酸肌醇3激酶，磷酸肌醇依赖性激酶1，Akt，糖原合酶激酶3β和Raf-1的水平，而没有改变细胞外信号调节激酶及其上游激酶的水平。用0.1-10 microM Hsp90抑制剂（格尔德霉素，17-烯丙基氨基-17-去甲氧基-格尔德霉素，除草霉素A和radicicol）进行慢性（>或= 12h）治疗可使胰岛素受体底物1水平降低约66％，同时增加胰岛素受体底物2水平降低约160％。格尔德霉素（IC（50）155 nM，EC（50）177 nM）和17-烯丙基氨基-17-去甲氧基-格尔德霉素（IC（50）310 nM，EC（50）260 nM）的这些作用是时间和浓度-依赖。格尔德霉素诱导的胰岛素受体底物-1的减少被乳胞素，β-内酯或MG132（蛋白酶体抑制剂）减弱，但未被钙蛋白酶抑制剂（钙蛋白酶抑制剂）或亮肽素（溶酶体抑制剂）抑制。格尔德霉素不影响胰岛素受体底物1或-2与Hsp90之间的异蛋白复合物形成。环己酰亚胺或放线菌素D阻止了格尔德霉素诱导的胰岛素受体底物2的增加。格尔德霉素使胰岛素受体底物2 mRNA的水平降低了约39％，而胰岛素受体底物2 mRNA的水平在3至24小时之间升高了约109％，而不改变胰岛素受体底物1和-2 mRNA的稳定性。核试验显示，格尔德霉素使胰岛素受体底物2基因的转录延迟42％，而使胰岛素受体底物2基因的转录加快41％。 Hsp90抑制剂通过蛋白酶体降解和基因转录相反地改变胰岛素受体底物1和-2的水平。

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