Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells.
Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells.
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DOI：
10.1186/s12868-016-0333-0
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发表时间：
2017-01-17
期刊：
影响因子：
2.4
通讯作者：
Tanaka S
中科院分区：
文献类型：
--
作者：
Okuda A;Kurokawa S;Takehashi M;Maeda A;Fukuda K;Kubo Y;Nogusa H;Takatani-Nakase T;Okuda S;Ueda K;Tanaka S
多聚ADP核糖聚合酶1（Poly（ADP-ribose）polymerase 1，PARP-1）是一种以NAD+为底物催化蛋白质多聚ADP核糖基化的酶，在DNA修复、复制和转录等核反应中起着重要作用。最近，PARP-1被报道参与体细胞重编程过程。以前，我们揭示了PARP-1在脑缺血细胞模型中诱导神经细胞凋亡的作用，并建议可能使用PARP抑制剂作为一种新的治疗干预。在本研究中，我们检查了PARP抑制剂对小鼠大脑神经干/祖细胞（NSPCs）的影响。 与小鼠胚胎成纤维细胞相比，PARP-1在NSPCs中更丰富，活性更高。用PARP抑制剂处理通过抑制细胞周期进程和诱导细胞凋亡抑制了NSPCs形成神经球。为了确定负责这些影响的基因，我们通过微阵列分析研究了基因表达谱，发现p53信号通路中的几个基因被上调，包括Cdkn 1a，这是细胞周期控制的关键，Fas，Pidd，Pmaip 1和Bbc 3，这是凋亡途径中的主要因素。抑制聚（ADP-核糖基）化增加了p53蛋白的水平，但不是p53 mRNA，并增强了p53在Ser 18的磷酸化。使用特异性抑制剂和shRNA的实验表明，PARP-1而不是PARP-2在p53的调节中起作用。在Trp 53 −/− NSPCs中未观察到PARP抑制剂对NSPCs的影响，表明p53在这些事件中起关键作用。PARP抑制剂促进p53信号通路的发现的基础上，我们提出，聚（ADP-核糖基）化有助于通过抑制p53激活的NSPCs的增殖和自我更新。
Poly(ADP-ribose) polymerase 1 (PARP-1), which catalyzes poly(ADP-ribosyl)ation of proteins by using NAD+ as a substrate, plays a key role in several nuclear events, including DNA repair, replication, and transcription. Recently, PARP-1 was reported to participate in the somatic cell reprogramming process. Previously, we revealed a role for PARP-1 in the induction of neural apoptosis in a cellular model of cerebral ischemia and suggested the possible use of PARP inhibitors as a new therapeutic intervention. In the present study, we examined the effects of PARP inhibitors on neural stem/progenitor cells (NSPCs) of the mouse brain. PARP-1 was more abundant and demonstrated higher activity in NSPCs than in mouse embryonic fibroblasts. Treatment with PARP inhibitors suppressed the formation of neurospheres by NSPCs through the suppression of cell cycle progression and the induction of apoptosis. In order to identify the genes responsible for these effects, we investigated gene expression profiles by microarray analyses and found that several genes in the p53 signaling pathway were upregulated, including Cdkn1a, which is critical for cell cycle control, and Fas, Pidd, Pmaip1, and Bbc3, which are principal factors in the apoptosis pathway. Inhibition of poly(ADP-ribosyl)ation increased the levels of p53 protein, but not p53 mRNA, and enhanced the phosphorylation of p53 at Ser18. Experiments with specific inhibitors and also shRNA demonstrated that PARP-1, but not PARP-2, has a role in the regulation of p53. The effects of PARP inhibitors on NSPCs were not observed in Trp53 −/− NSPCs, suggesting a key role for p53 in these events. On the basis of the finding that PARP inhibitors facilitated the p53 signaling pathway, we propose that poly(ADP-ribosyl)ation contributes to the proliferation and self-renewal of NSPCs through the suppression of p53 activation.