Suppression of cell cycle progression by poly(ADP-ribose) polymerase inhibitor PJ34 in neural stem/progenitor cells.
Suppression of cell cycle progression by poly(ADP-ribose) polymerase inhibitor PJ34 in neural stem/progenitor cells.
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DOI：
10.1016/j.bbrc.2019.01.025
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发表时间：
2019-02
影响因子：
3.1
通讯作者：
Suguru Kurokawa;A. Okuda;Y. Nishizawa;K. Furukawa;Ayumi Sumihiro;Y. Nakaji;Seigo Tanaka;M. Takehashi
中科院分区：
文献类型：
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作者：
Suguru Kurokawa;A. Okuda;Y. Nishizawa;K. Furukawa;Ayumi Sumihiro;Y. Nakaji;Seigo Tanaka;M. Takehashi
神经干/祖细胞 (NSPC) 比小鼠胚胎成纤维细胞 (MEF) 表达更高水平的聚（ADP-核糖）聚合酶 1 (PARP1)。 PARP 的抑制会诱导 p53 信号通路中多个基因的表达，包括 p21，它对于 G1/S 期的细胞周期控制至关重要，可触发细胞凋亡，并抑制 NSPC 的细胞周期进程。然而，当 p21 上调时，细胞周期不会停滞在任何特定阶段。在本研究中，分析了用 PARP 抑制剂 PJ34（N-[6-氧代-5,6-二氢-菲啶-2-基]-N,N-二甲基乙酰胺）处理后细胞周期 G1/S 和 G2/M 期特异基因的表达。 PJ34 处理显着下调 NSPC 中的细胞周期蛋白 B1 表达，但在 MEF 中则不然，这一点已通过启动子测定得到证实。 FoxM1和B-MYB的下调表明cyclin的下调发生在转录水平。GADD45在NSPCs中也特异上调。总之，PJ34 处理 NSPC 时 p53 的激活诱导了细胞周期相关基因表达的变化。荧光激活细胞分选分析表明，PJ34 处理抑制 NSPC 中 G2/M 至 G1 的进展，但在 MEF 中则不然。这些数据表明 PJ34 治疗可抑制 mRNA 水平的细胞周期蛋白表达并抑制 NSPC 中的细胞周期进程。
Neural stem/progenitor cells (NSPCs) express higher levels of poly(ADP-ribose) polymerase 1 (PARP1) than mouse embryonic fibroblasts (MEFs). Inhibition of PARP induces the expression of several genes in the p53 signaling pathway, includingp21, which is critical for cell cycle control at the G1/S phase, triggers apoptosis, and suppresses cell cycle progression in NSPCs. However, upon the up-regulation of p21, the cell cycle does not arrest at any specific phase. In the present study, the expression of genes specific to the G1/S and G2/M phases of the cell cycle were analyzed following treatment with PJ34 (N-[6-oxo-5,6-dihydro-phenanthridin-2-yl]-N,N-dimethylacetamide), an inhibitor of PARP. PJ34 treatment dramatically down-regulatedcyclin B1expression in NSPCs, but not in MEFs, which was confirmed by a promoter assay. Down-regulation ofFoxM1andB-MYBrevealed that the down-regulation ofcyclin Boccurs at the transcriptional level.GADD45was also specifically up-regulated in NSPCs. Taken together, the activation of p53 by PJ34 treatment in NSPCs induced changes in the expression of genes involved in the cell cycle. Fluorescence-activated cell sorting analysis revealed that PJ34 treatment suppressed G2/M to G1 progression in NSPCs, but not in MEFs. These data indicate that PJ34 treatment inhibits cyclin expression at the mRNA level and suppresses cell cycle progression in NSPCs.