RRC ID 47685
Author Okuda A, Kurokawa S, Takehashi M, Maeda A, Fukuda K, Kubo Y, Nogusa H, Takatani-Nakase T, Okuda S, Ueda K, Tanaka S.
Title Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells.
Journal BMC Neurosci
Abstract BACKGROUND: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.
RESULTS: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.
CONCLUSIONS: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.
Volume 18(1)
Pages 14
Published 2017-1-17
DOI 10.1186/s12868-016-0333-0
PII 10.1186/s12868-016-0333-0
PMID 28095779
PMC PMC5240207
MeSH Animals Apoptosis / drug effects Apoptosis / physiology Blotting, Western Cell Cycle / drug effects Cell Cycle / physiology Cells, Cultured Fibroblasts / drug effects Fibroblasts / metabolism Flow Cytometry Gene Expression Profiling Immunohistochemistry Immunoprecipitation Mice Mice, Inbred ICR Mice, Knockout Neural Stem Cells / drug effects* Neural Stem Cells / metabolism Neurogenesis / drug effects Neurogenesis / physiology Poly (ADP-Ribose) Polymerase-1 / genetics Poly (ADP-Ribose) Polymerase-1 / metabolism Poly(ADP-ribose) Polymerase Inhibitors / pharmacology* Poly(ADP-ribose) Polymerases / genetics Poly(ADP-ribose) Polymerases / metabolism Polymerase Chain Reaction RNA, Messenger / metabolism Signal Transduction / drug effects Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism*
IF 2.811
Times Cited 9
Mice RBRC01348