Departments of Molecular Biology and Genetics, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey.
Eur J Neurosci. 2013 May;37(10):1610-9. doi: 10.1111/ejn.12185. Epub 2013 Mar 15.
Neurons are differentiated postmitotic cells residing in G0 phase of the cell cycle and are unable to proceed through G1 phase, in which cyclinD1 needs to be up-regulated for initiation. Yet, a growing body of evidence has shown that cell cycle re-activation via cyclinD1 up-regulation drives neurons into apoptosis. By contrast, there is also evidence demonstrating cell cycle proteins playing roles in neuronal differentiation. cyclinD1 has been shown to be differently regulated by protein kinase C alpha (PKC-α) in various mitotic cells. Based on these different effects, we investigated the role of PKC-α on cyclinD1 regulation in hippocampal neurons. Neurons were treated with PKC activator, PMA, and analysed for subcellular distributions of PKC-α and cyclinD1. Remarkably, PMA treatment increased nuclear PKC-α and cyclinD1, but not PKC-ε in hippocampal neurons. Increases in nuclear PKC-α and cyclinD1 were accompanied by microtubule re-organisation via increases in tau and retinoblastoma protein phosphorylation levels. Increased p60-katanin and p53 changed the neuronal morphology into neurons with shorter, but increased number of side branches. Since up-regulation of cell cycle is associated with apoptosis in neurons, we also analysed changes in Bax, Bcl-2 early and PARP (poly(ADP-ribose)polymerase), caspase3 late apoptotic markers. However, we did not observe any indication of apoptosis. These data suggest that in addition to their previously known roles in mitotic cells on cell cycle regulation, PKC-α and cyclinD1 seem to be important for differentiation, and nuclear PKC-α and cyclinD1 interfere with differentiation by promoting microtubule re-organisation through PKC signaling without triggering apoptosis.
神经元是处于细胞周期 G0 期的有丝分裂后细胞，无法进入 G1 期，而 cyclinD1 需要上调才能起始。然而，越来越多的证据表明，通过 cyclinD1 上调使细胞周期重新激活会导致神经元凋亡。相比之下，也有证据表明细胞周期蛋白在神经元分化中发挥作用。在各种有丝分裂细胞中，蛋白激酶 Cα（PKC-α）已被证明对 cyclinD1 的调节具有不同的作用。基于这些不同的作用，我们研究了 PKC-α 在海马神经元中对 cyclinD1 调节的作用。用 PKC 激活剂 PMA 处理神经元，并分析 PKC-α 和 cyclinD1 的亚细胞分布。值得注意的是，PMA 处理增加了海马神经元中的核 PKC-α 和 cyclinD1，但不增加 PKC-ε。核 PKC-α 和 cyclinD1 的增加伴随着微管的重新组织，通过增加 tau 和视网膜母细胞瘤蛋白的磷酸化水平。增加的 p60-卡坦in 和 p53 将神经元形态改变为具有较短但增加的侧分支的神经元。由于细胞周期的上调与神经元中的凋亡有关，我们还分析了 Bax、Bcl-2 早期和 PARP（多聚（ADP-核糖）聚合酶）、caspase3 晚期凋亡标志物的变化。然而，我们没有观察到任何凋亡的迹象。这些数据表明，除了它们在有丝分裂细胞中对细胞周期调节的先前已知作用外，PKC-α 和 cyclinD1 似乎对分化很重要，核 PKC-α 和 cyclinD1 通过促进微管组织通过 PKC 信号而不触发凋亡来干扰分化。
