Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Cell Cycle. 2011 Apr 15;10(8):1208-14. doi: 10.4161/cc.10.8.15328.
In a variety of neurodegenerative disease, despite the frequent correlation of neuronal cell cycle and cell death in the same neuronal populations, the mechanistic pathway linking the two remains undefined. One possible link is the atypical cyclin dependent kinase, Cdk5. Cdk5 exerts a double protective function in neurons, first by suppressing the cell cycle in the nucleus and second by suppressing cell death in the cytoplasm. Cdk5 transport between nucleus and cytoplasm serves to regulate the balance between these two events. Cdk5 nuclear localization relies on its interaction with p27, and its cell cycle suppression activity is achieved by direct binding to E2F1, disrupting the DP1-E2F1 dimer and its DNA binding ability. To bind to E2F1, Cdk5 does not need to be catalytically active but it does require a physical association with both p27 and its cyclin-like activator, p35. Because of this requirement, the proper levels and locations of p27 and p35 are characteristics that endow a neuron a unique form of cell cycle regulation that uses Cdk5 in a non-catalytic role. The findings offer cautionary notes to any strategy aimed at blocking Cdk5 activity as a means of combating neurodegenerative disease. To the extent that these approaches either directly or indirectly influence Cdk5 levels or location, they may produce unexpected and possibly unwanted consequences.
在多种神经退行性疾病中，尽管神经元细胞周期和细胞死亡经常在同一神经元群体中相关，但将两者联系起来的机制途径尚不清楚。一个可能的联系是非典型细胞周期蛋白依赖性激酶 CDK5。CDK5 在神经元中发挥双重保护作用，首先通过抑制核内细胞周期，其次通过抑制细胞质中的细胞死亡。CDK5 在核和细胞质之间的运输有助于调节这两个事件之间的平衡。CDK5 的核定位依赖于其与 p27 的相互作用，其细胞周期抑制活性通过直接结合 E2F1 来实现，破坏 DP1-E2F1 二聚体及其 DNA 结合能力。为了与 E2F1 结合，CDK5 不需要具有催化活性，但它确实需要与 p27 及其细胞周期激活物 p35 具有物理关联。由于这种要求，p27 和 p35 的适当水平和位置是赋予神经元独特的细胞周期调控形式的特征，该形式以非催化作用使用 CDK5。这些发现为旨在阻止 CDK5 活性作为对抗神经退行性疾病的一种手段的任何策略提供了警示。在这些方法直接或间接地影响 CDK5 水平或位置的程度上，它们可能会产生意想不到的、可能是不想要的后果。
