Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation.
Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation.
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DOI：
10.1371/journal.pone.0008561
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发表时间：
2010-01-01
期刊：
影响因子：
3.7
通讯作者：
Sassone-Corsi P
中科院分区：
文献类型：
--
作者：
Sahar S;Zocchi L;Kinoshita C;Borrelli E;Sassone-Corsi P
昼夜节律支配着大量的生理和代谢功能。为了实现昼夜节律调节的可塑性，构成分子时钟机制的蛋白质经历各种翻译后修饰（PTM），这影响它们的活性和细胞内定位。核心时钟蛋白BMAL 1经历几个PTM。在这里，我们报告Akt-GSK 3 β信号通路调节BMAL 1蛋白的稳定性和活性。GSK 3 β特异性磷酸化丝氨酸17和苏氨酸21上的BMAL 1，并使其泛素化。在不存在GSK 3 β介导的磷酸化的情况下，BMAL 1变得稳定，并且BMAL 1依赖性昼夜节律基因表达受到抑制。已知控制Akt-GSK 3 β通路的多巴胺D2受体介导的信号传导影响纹状体神经元中的BMAL 1稳定性和体内昼夜节律基因表达。这些发现揭示了一个以前未知的生物钟控制机制。GSK 3 β激酶磷酸化BMAL 1，这是一种控制蛋白质稳定性和昼夜节律振荡幅度的事件。BMAL 1磷酸化似乎是维持生物钟稳健性的重要调节步骤。
Circadian rhythms govern a large array of physiological and metabolic functions. To achieve plasticity in circadian regulation, proteins constituting the molecular clock machinery undergo various post-translational modifications (PTMs), which influence their activity and intracellular localization. The core clock protein BMAL1 undergoes several PTMs. Here we report that the Akt-GSK3β signaling pathway regulates BMAL1 protein stability and activity. GSK3β phosphorylates BMAL1 specifically on Ser 17 and Thr 21 and primes it for ubiquitylation. In the absence of GSK3β-mediated phosphorylation, BMAL1 becomes stabilized and BMAL1 dependent circadian gene expression is dampened. Dopamine D2 receptor mediated signaling, known to control the Akt-GSK3β pathway, influences BMAL1 stability and in vivo circadian gene expression in striatal neurons. These findings uncover a previously unknown mechanism of circadian clock control. The GSK3β kinase phosphorylates BMAL1, an event that controls the stability of the protein and the amplitude of circadian oscillation. BMAL1 phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock.
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影响因子：
10.5
作者：
Kondratov, RV;Chernov, MV;Antoch, MP
通讯作者：
Antoch, MP
影响因子：
5.3
作者：
Kwon, Ilmin;Lee, Jiwon;Lee, Kun Ho
通讯作者：
Lee, Kun Ho
DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
Kondratov, Roman V.;Kondratova, Anna A.;Antoch, Marina P.
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Antoch, Marina P.
影响因子：
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通讯作者：
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