Cdh1/Hct1-APC is essential for the survival of postmitotic neurons
Cdh1/Hct1-APC is essential for the survival of postmitotic neurons
复制标题
DOI：
10.1523/jneurosci.1143-05.2005
复制
发表时间：
2005-09-07
影响因子：
5.3
通讯作者：
Moreno, S
中科院分区：
文献类型：
--
作者：
Almeida, A;Bolaños, JP;Moreno, S
有丝分裂和G（1）结束时的细胞分裂由Cdh 1/Hct 1控制，Cdh 1/Hct 1是E3-泛素连接酶后期促进复合物（APC）的激活剂，促进有丝分裂周期蛋白和其他底物的泛素化和降解。Cdh 1-APC在有丝分裂后的神经元中是活跃的，在那里它调节发育中的大脑中的轴突生长和图案化。然而，它仍然是未知的Cdh 1-APC是否参与阻止终末分化的神经元细胞周期的进展。为了解决这个问题，我们使用小发夹RNA策略来耗尽有丝分裂后神经元中的Cdh 1。我们观察到Cdh 1沉默迅速引发神经元凋亡。为了研究潜在的机制，我们专注于细胞周期蛋白B1，一个主要的Cdh 1-APC基板。我们的研究结果表明，Cdh 1是必需的，以防止细胞周期蛋白B1在终末分化的神经元中的积累。此外，通过保持细胞周期蛋白B1低，Cdh 1防止这些神经元进入异常的S期，导致细胞凋亡。这些结果为发生在患有神经退行性疾病（如阿尔茨海默病）的患者大脑中的细胞周期蛋白B1再激活机制提供了解释。
Cell division at the end of mitosis and G(1) is controlled by Cdh1/Hct1, an activator of the E3-ubiquitin ligase anaphase-promoting complex (APC) that promotes the ubiquitylation and degradation of mitotic cyclins and other substrates. Cdh1-APC is active in postmitotic neurons, where it regulates axonal growth and patterning in the developing brain. However, it remains unknown whether Cdh1-APC is involved in preventing cell-cycle progression in terminally differentiated neurons. To address this issue, we used the small hairpin RNA strategy to deplete Cdh1 in postmitotic neurons. We observed that Cdh1 silencing rapidly triggered apoptotic neuronal death. To investigate the underlying mechanism, we focused on cyclin B1, a major Cdh1-APC substrate. Our results demonstrate that Cdh1 is required to prevent the accumulation of cyclin B1 in terminally differentiated neurons. Moreover, by keeping cyclin B1 low, Cdh1 prevented these neurons from entering an aberrant S phase that led to apoptotic cell death. These results provide an explanation for the mechanism of cyclin B1 reactivation that occurs in the brain of patients suffering from neurodegenerative diseases, such as Alzheimer's disease.