Role and regulation of p27 in neuronal apoptosis
Role and regulation of p27 in neuronal apoptosis
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DOI：
10.1111/jnc.13918
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发表时间：
2017-02-01
影响因子：
4.7
通讯作者：
Sharma, Pushkar
中科院分区：
文献类型：
--
作者：
Jaiswal, Surbhi;Sharma, Pushkar
抑制神经元的细胞周期机制以促进其终末分化状态的分化和维持是必要的。细胞周期的重新激活响应神经毒性损伤导致神经元细胞死亡和一些细胞周期相关蛋白质有助于该过程。p27 kip 1（p27）是细胞周期蛋白依赖性激酶的抑制剂，可防止不必要的细胞周期蛋白依赖性激酶活化。在这项研究中，我们已经阐明了一种新的机制，通过这种机制，p27促进神经毒性淀粉样蛋白A β（42）（淀粉样蛋白β（1-42）肽）刺激的神经元凋亡。免疫共沉淀分析显示，p27促进细胞周期蛋白依赖性激酶5（Cdk 5）和细胞周期蛋白D1之间的相互作用，这是由A β诱导的（42）在皮层神经元。因此，Cdk 5与其神经元激活剂p35隔离，导致激酶失活。通过特异性siRNA实现的p27的耗竭通过阻止Cdk 5和细胞周期蛋白D1之间的关联来恢复Cdk 5/p35相互作用，并且还消除了A β 42诱导的皮质神经元凋亡。此外，细胞周期标志物的分析表明，p27可能在A β 42诱导的神经元细胞周期异常进展中发挥作用，这可能导致细胞凋亡。这些发现提供了新的见解p27，否则执行重要的神经元功能，可能会成为有害的神经元在神经毒性条件下。
It is necessary for the cell-cycle machinery of neurons to be suppressed to promote differentiation and maintenance of their terminally differentiated state. Reactivation of the cell cycle in response to neurotoxic insults leads to neuronal cell death and some cell-cycle-related proteins contribute to the process. p27 kip1 (p27), an inhibitor of cyclin-dependent kinases, prevents unwarranted cyclin-dependent kinase activation. In this study, we have elucidated a novel mechanism via which p27 promotes apoptosis of neurons stimulated by neurotoxic amyloid peptide A beta(42) (Amyloid beta(1-42) peptide). Coimmunoprecipitation analysis revealed that p27 promotes interaction between Cyclin-dependent kinase 5 (Cdk5) and cyclin D1, which is induced by A beta(42) in cortical neurons. As aresult, Cdk5 is sequestered from its neuronal activator p35 resulting in kinase deactivation. The depletion of p27, which was achieved by specific siRNA, restored Cdk5/p35 interaction by preventing association between Cdk5 and cyclin D1 and also abrogated A beta 42 induced apoptosis of cortical neurons. Furthermore, analysis of cell cycle markers suggested that p27 may play a role in A beta 42 induced aberrant cell cycle progression of neurons, which may result in apoptosis. These findings provide novel insights into how p27, which otherwise performs important neuronal functions, may become deleterious to neurons under neurotoxic conditions.