From the Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
J Biol Chem. 2013 Dec 27;288(52):36878-89. doi: 10.1074/jbc.M113.494856. Epub 2013 Nov 14.
Circadian rhythm is a biological rhythm governing physiology and behavior with a period of ∼24 h. At the molecular level, circadian output is controlled by a molecular clock composed of positive and negative feedback loops in transcriptional and post-translational processes. CLOCK is a transcription factor known as a central component of the molecular clock feedback loops generating circadian oscillation. Although CLOCK is known to undergo multiple post-translational modifications, the knowledge of their entities remains limited. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine-threonine kinase that is involved in various neuronal processes. Here, we report that Cdk5 is a novel regulator of CLOCK protein. Cdk5 phosphorylates CLOCK at the Thr-451 and Thr-461 residues in association with transcriptional activation of CLOCK. The Cdk5-dependent regulation of CLOCK function is mediated by alterations of its stability and subcellular distribution. These results suggest that Cdk5 is a novel regulatory component of the core molecular clock machinery.
昼夜节律是一种控制生理和行为的生物节律，其周期约为 24 小时。在分子水平上，昼夜节律由转录和翻译后过程中的正反馈和负反馈环组成的分子钟控制。CLOCK 是一种转录因子，被认为是分子钟反馈环的核心组成部分，可产生昼夜节律振荡。尽管已知 CLOCK 会经历多种翻译后修饰，但对其修饰物的认识仍然有限。细胞周期蛋白依赖性激酶 5（Cdk5）是一种脯氨酸导向的丝氨酸/苏氨酸激酶，参与多种神经元过程。在这里，我们报告 Cdk5 是 CLOCK 蛋白的一种新型调节因子。Cdk5 可在 Thr-451 和 Thr-461 残基处磷酸化 CLOCK，同时 CLOCK 的转录激活。Cdk5 对 CLOCK 功能的调节是通过改变其稳定性和亚细胞分布来介导的。这些结果表明 Cdk5 是核心分子钟机制的新型调节成分。
