The unfolded protein response element protects against endoplasmic reticulum stress and delivers protection towards potentially harmful challenges. The components of this multi-branch molecular machinery, namely the protein kinase RNA-like ER kinase, the activating transcription factor 6, and the inositol-requiring enzyme-1α; expand the endoplasmic reticulum capacity to support cellular function under stress conditions. In the present study, we employed bovine pulmonary aortic endothelial cells and mice to investigate the possibility that the Hsp90 inhibitors Tanespimycin (17-AAG) and Luminespib (AUY-922) exert the capacity to trigger the unfolded protein response. The induction of the unfolded protein response regulators immunoglobulin heavy-chain-binding protein, endoplasmic reticulum oxidoreductin-1alpha; and protein disulfide isomerase was also examined. It appears that both inhibitors capacitate the induction of the unfolded protein response element in vitro, since lung cells exposed to 1, 2 and 10 μM of 17-AAG or AUY-922 for 4, 6, 8, 16 and 48 h demonstrated increased levels of those proteins. Similar events occurred in the lungs of mice treated with AUY-922. Thus, our study demonstrates that Hsp90 inhibition triggers the activities of the unfolded protein response, and suggests that this molecular machinery contributes in the protective action of Hsp90 inhibitors in the lung microvasculature.

中文翻译：

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Hsp90抑制剂诱导牛和小鼠肺细胞中未折叠的蛋白质反应。

展开的蛋白质反应元件可抵抗内质网应激，并提供针对潜在有害挑战的保护。这种多分支分子机制的组成部分是蛋白质激酶RNA样ER激酶，激活转录因子6和需要肌醇的酶1α。扩大内质网的容量以支持应激条件下的细胞功能。在本研究中，我们使用牛肺动脉主动脉内皮细胞和小鼠研究Hsp90抑制剂Tanespimycin（17-AAG）和Luminespib（AUY-922）发挥触发未折叠蛋白反应能力的可能性。展开的蛋白应答调节剂免疫球蛋白重链结合蛋白，内质网氧化还原蛋白1α的诱导；还检查了蛋白质二硫键异构酶。似乎这两种抑制剂在体外都能诱导未折叠的蛋白质反应元件，因为暴露于1、2和10μM的17-AAG或AUY-922的肺细胞4、6、8、16和48 h表现出升高的水平这些蛋白质。在用AUY-922处理的小鼠的肺部发生了类似的事件。因此，我们的研究表明Hsp90抑制触发了展开的蛋白质反应的活动，并表明这种分子机制有助于Hsp90抑制剂在肺微脉管系统中的保护作用。在用AUY-922处理的小鼠的肺部发生了类似的事件。因此，我们的研究表明Hsp90抑制触发了展开的蛋白质反应的活动，并表明这种分子机制有助于Hsp90抑制剂在肺微脉管系统中的保护作用。在用AUY-922处理的小鼠的肺中发生了类似的事件。因此，我们的研究表明Hsp90抑制触发了展开的蛋白质反应的活动，并表明这种分子机制有助于Hsp90抑制剂在肺微脉管系统中的保护作用。