细胞周期蛋白依赖性激酶PFTK1在少突胶质前体细胞分化中的潜在作用

A novel role of cyclin-dependent kinase PFTK1 in the differentiation of oligodendrocyte precursor cells

背景:少突胶质细胞主要来自少突胶质前体细胞,该分化过程被多种因子严格调控。一些细胞周期蛋白依赖性激酶可以调控少突胶质前体细胞分化的早期阶段,对少突胶质细胞形成具有重要意义。目的:分析细胞周期蛋白依赖性激酶PFTK1在少突胶质前体细胞分化中的潜在作用及相应机制。方法:利用siRNA技术和Western印迹实验来检测OLN-93细胞分化的相关分子标志物及相应信号通路的活化情况。结果与结论:撤去血清后,少突胶质前体细胞系OLN-93细胞可进行自发分化。形态观察表明,用siRNA技术沉默PFTK1基因表达后,OLN-93细胞的分化得以明显加快。Western印迹实验显示PFTK1基因沉默后,OLN-93分化的相关分子标志物环核苷酸磷酸二酯酶和髓鞘少突胶质细胞糖蛋白的诱导出现显著增加。对PFTK1相关信号通路的研究则发现,PFRK1基因的沉默表达可诱发PI3K/AKT信号通路的活化。而对PI3K/AKT信号通路的特异性抑制可抵消PFTK1沉默对OLN-93细胞分化的促进效果。实验结果首次发现细胞周期蛋白依赖性激酶PFTK1可通过PI3K/AKT信号通路抑制少突胶质前体细胞的分化,为脱髓鞘引起的神经退化性疾病的治疗提供了重要的理论参考。

BACKGROUND： Oligodendrocytes are mainly differentiated from oligodendrocyte precursor cells and the differentiation is tightly regulated by various factors. Some cyclin-dependent kinases play pivotal roles in oligodendrocyte precursor cell differentiation due to their regulation on the early stage of differentiation. OBJECTIVE： To investigate the potential role of a newly identified cyclin-dependent kinase-like protein, PFTK1 in differentiation and also study the related mechanisms. METHODS： siRNA technology and western blot assay were used to examine the differentiation markers of OLN-93 and the activation condition of corresponding signal pathways. RESULTS AND CONCLUSION： With serum-deprivation, OLN-93 underwent differentiation simultaneously. When PFTK1 was silenced by siRNA technology, OLN-93 differentiation was significantly improved, as judged by morphological observations. Accordingly, western blot results showed a marked increase of differentiation markers cyclic nucleotide phosphodiesterase and myelin oligodendrocyte glycoprotein in PFTKl-silenced cells. From the study on PFTKl-related signaling pathways, we found that PFTK1 silencing induced the activation of PI3K/AKT pathway but not MAPWERK pathway. Furthermore, the inhibition of AKT by its specific inhibitor abrogated PFTK1 silencing-promoted OLN-93 differentiation. Taken together, our data demonstrate that PFTK1 negatively regulates OLN-93 differentiation through PI3KJAKT pathway, providing a clue for developing new therapeutic approaches to treat degenerative neurological diseases related to demyelination.