title: Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells.
abstract: 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.
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.|Niigata University Graduate School of Health Sciences, 2-746 Asahimachidori, Chuo-ku, Niigata, 951-8518, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Okuda
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Kurokawa
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Takehashi
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
authors.forename: Hyuma
authors.initials: H
authors.lastname: Nogusa
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.|Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien-kyubancho, Nishinomiya, Hyogo, 663-8179, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takatani-Nakase
authors.affiliation: Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkochodori, Chuo-ku, Niigata, 951-8514, Japan.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Kobe Tokiwa University, 2-6-2 Otanicho, Nagata-ku, Kobe, Hyogo, 653-0838, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan. tanakase@osaka-ohtani.ac.jp.
authors.forename: Seigo
authors.identifier: 0000-0002-4304-202X
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse
keywords: Apoptosis; Cell cycle; Neural stem/progenitor cells; Poly(ADP-ribose) polymerase; Poly(ADP-ribosyl)ation; p53