Akashiba H, Matsuki N, Nishiyama N
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Cell Mol Life Sci. 2006 Oct;63(19-20):2397-404. doi: 10.1007/s00018-006-6194-4.
Recent research has demonstrated that cell cycle-associated molecules are activated in multiple forms of cell death in mature neurons, and raised a hypothesis that unscheduled cell cycle activity leads to neuronal cell death. But there is little evidence that changes in endogenous level of these molecules are causally associated with neuronal cell death. Here we transfected small interfering RNA (siRNA) targeting cyclin-dependent kinase (CDK) inhibitor p27, which plays an important role in cell cycle arrest at G1-S phase, into cultured cortical neurons. Transfection of p27 siRNA reduced neuronal viability in a time-dependent manner. p27 siRNA induced phosphorylation of retinoblastoma protein (Rb), a marker of cell cycle progression at late G1 phase. Moreover, phosphorylation of Rb and neuronal cell death provoked by p27 siRNA were abrogated by pharmacological CDK inhibitors, olomoucine and purvalanol A. Our data demonstrate that a decrease in endogenous p27 induces neuronal cell death through elevating cell cycle activity.
最近的研究表明，细胞周期相关分子在成熟神经元的多种细胞死亡形式中被激活，并提出了一个假说，即异常的细胞周期活动会导致神经元细胞死亡。但几乎没有证据表明这些分子的内源性水平变化与神经元细胞死亡存在因果关系。在此，我们将靶向细胞周期蛋白依赖性激酶（CDK）抑制剂p27的小干扰RNA（siRNA）转染到培养的皮质神经元中，p27在G1-S期的细胞周期停滞中起重要作用。p27 siRNA的转染以时间依赖性方式降低了神经元的活力。p27 siRNA诱导了视网膜母细胞瘤蛋白（Rb）的磷酸化，Rb是G1期晚期细胞周期进程的标志物。此外，p27 siRNA引发的Rb磷酸化和神经元细胞死亡被药理学CDK抑制剂olomoucine和purvalanol A所消除。我们的数据表明，内源性p27的减少通过提高细胞周期活性诱导神经元细胞死亡。
