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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5
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Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5

机译：隐色素和蛋白磷酸酶5对哺乳动物昼夜节律的翻译后调控

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摘要

The molecular oscillator that drives circadian rhythmicity in mammals obtains its near 24-h periodicity from posttranslational regulation of clock proteins. Activity of the major clock kinase casein kinase I (CKI) epsilon is regulated by inhibitory autophosphorylation. Here we show that protein phosphatase (PP) 5 regulates the kinase activity of CKI epsilon. We demonstrate that cryptochrome regulates clock protein phosphorylation by modulating the effect of PP5 on CKI epsilon. Like CKI epsilon, PP5 is expressed both in the master circadian clock in the suprachiasmatic nuclei and in peripheral tissues independent of the clock. Expression of a dominant-negative PP5 mutant reduces PER phosphorylation by CKI epsilon in vivo, and down-regulation of PP5 significantly reduces the amplitude of circadian cycling in cultured human fibroblasts. Collectively, these findings indicate that PPS, CKI epsilon, and cryptochrome dynamically regulate the mammalian circadian clock.
机译：在哺乳动物中驱动昼夜节律性的分子振荡器从时钟蛋白的翻译后调节中获得了近24小时的周期性。主要的时钟激酶酪蛋白激酶I（CKI）ε的活性受到抑制性自磷酸化的调节。在这里我们显示蛋白质磷酸酶（PP）5调节CKI epsilon的激酶活性。我们证明隐花色素通过调节PP5对CKI epsilon的作用来调节时钟蛋白的磷酸化。像CKIε一样，PP5在视交叉上核的主生物钟和独立于钟的外周组织中表达。显性阴性PP5突变体的表达减少了CKIε体内的PER磷酸化，而PP5的下调显着降低了培养的人成纤维细胞中昼夜节律循环的幅度。总而言之，这些发现表明，PPS，CKI epsilon和隐色素动态调节哺乳动物的生物钟。

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