Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells

BMC Neuroscience

Research Article

Shujiro Okuda¹  Kunihiro Ueda²  Seigo Tanaka³  Yukari Kubo³  Katsuya Fukuda³  Hyuma Nogusa³  Masanori Takehashi³  Suguru Kurokawa³  Aika Maeda³  Tomoka Takatani-Nakase⁴  Akiko Okuda⁵ 

[1] Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkochodori, Chuo-ku, 951-8514, Niigata, Japan;Kobe Tokiwa University, 2-6-2 Otanicho, Nagata-ku, 653-0838, Kobe, Hyogo, Japan;Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, 584-8540, Tondabayashi, Osaka, Japan;Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, 584-8540, Tondabayashi, Osaka, Japan;Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien-kyubancho, 663-8179, Nishinomiya, Hyogo, Japan;Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, 584-8540, Tondabayashi, Osaka, Japan;Niigata University Graduate School of Health Sciences, 2-746 Asahimachidori, Chuo-ku, 951-8518, Niigata, Japan;

关键词: Poly(ADP-ribosyl)ation;    Poly(ADP-ribose) polymerase;    Neural stem/progenitor cells;    p53;    Cell cycle;    Apoptosis;   

DOI  :  10.1186/s12868-016-0333-0

 received in 2016-07-01, accepted in 2016-12-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPoly(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.ResultsPARP-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.ConclusionsOn 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.

【 授权许可】

CC BY   
© The Author(s) 2017