HSP90 Affects the Stability of BMAL1 and Circadian Gene Expression
HSP90 Affects the Stability of BMAL1 and Circadian Gene Expression
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DOI：
10.1177/0748730414523559
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Reinke, Hans
中科院分区：
文献类型：
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作者：
Schneider, Rebecca;Linka, Rene M.;Reinke, Hans
哺乳动物的生物钟包含一个相互连接的转录和翻译反馈环系统。正确的振荡器功能需要核心时钟蛋白的精确定时合成和降解。热休克蛋白 90 (HSP90) 是一种三磷酸腺苷 (ATP) 依赖性分子伴侣，通过控制其各种客户蛋白的活性和稳定性，在许多细胞调节途径中具有重要功能。尽管越来越多的证据表明热休克反应与昼夜节律系统之间的相互作用，但 HSP90 在哺乳动物核心时钟中的作用尚不清楚。这项研究的结果表明，抑制 HSP90 的 ATP 依赖性伴侣活性会损害培养的小鼠成纤维细胞的昼夜节律，从而主要影响振荡的幅度和相位。 HSP90 的抑制缩短了 BMAL1 的半衰期，从而导致细胞蛋白水平降低和节律性 BMAL1-CLOCK 靶基因的表达减弱。此外，HSP90亚型HSP90AA1和HSP90AB1，而不是HSP90B1-GRP94或TRAP1，负责维持BMAL1蛋白的适当细胞水平。总之，这些发现为哺乳动物生物钟正臂的转录激活过程需要细胞质 HSP90 的模型提供了证据。
The mammalian circadian clock comprises a system of interconnected transcriptional and translational feedback loops. Proper oscillator function requires the precisely timed synthesis and degradation of core clock proteins. Heat shock protein 90 (HSP90), an adenosine triphosphate (ATP)-dependent molecular chaperone, has important functions in many cellular regulatory pathways by controlling the activity and stability of its various client proteins. Despite accumulating evidence for interplay between the heat shock response and the circadian system, the role of HSP90 in the mammalian core clock is not known. The results of this study suggest that inhibition of the ATP-dependent chaperone activity of HSP90 impairs circadian rhythmicity of cultured mouse fibroblasts whereby amplitude and phase of the oscillations are predominantly affected. Inhibition of HSP90 shortened the half-life of BMAL1, which resulted in reduced cellular protein levels and blunted expression of rhythmic BMAL1-CLOCK target genes. Furthermore, the HSP90 isoforms HSP90AA1 and HSP90AB1, and not HSP90B1-GRP94 or TRAP1, are responsible for maintaining proper cellular levels of BMAL1 protein. In summary, these findings provide evidence for a model in which cytoplasmic HSP90 is required for transcriptional activation processes by the positive arm of the mammalian circadian clock.