Suppression of cell cycle progression by poly(ADP-ribose) polymerase inhibitor PJ34 in neural stem/progenitor cells

Suguru Kurokawa; Akiko Okuda; Yuki Nishizawa; Kyoko Furukawa; Ayumi Sumihiro; Yuki Nakaji; Seigo Tanaka; Masanori Takehashi

doi:10.1016/j.bbrc.2019.01.025

Suppression of cell cycle progression by poly(ADP-ribose) polymerase inhibitor PJ34 in neural stem/progenitor cells

Biochem Biophys Res Commun. 2019 Feb 26;510(1):59-64. doi: 10.1016/j.bbrc.2019.01.025. Epub 2019 Jan 18.

Authors

Suguru Kurokawa¹, Akiko Okuda², Yuki Nishizawa¹, Kyoko Furukawa¹, Ayumi Sumihiro¹, Yuki Nakaji¹, Seigo Tanaka¹, Masanori Takehashi³

Affiliations

¹ Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan.
² 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.
³ Laboratory of Pathophysiology and Pharmacotherapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka, 584-8540, Japan. Electronic address: takeham@osaka-ohtani.ac.jp.

PMID: 30665718
DOI: 10.1016/j.bbrc.2019.01.025

Abstract

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, including p21, 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-regulated cyclin B1 expression in NSPCs, but not in MEFs, which was confirmed by a promoter assay. Down-regulation of FoxM1 and B-MYB revealed that the down-regulation of cyclin B occurs at the transcriptional level. GADD45 was 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.

Keywords: Cyclin B; Neural stem/progenitor cells; PJ34; Poly(ADP-ribose) polymerase; Poly(ADP-ribosyl)ation; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle / drug effects*
Cyclin B / drug effects
Cyclin B / genetics
Fibroblasts / drug effects
Genes, cdc / drug effects
Mice
Neural Stem Cells / cytology*
Neural Stem Cells / drug effects
Neural Stem Cells / metabolism
Phenanthrenes / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
RNA, Messenger / drug effects

Substances

Cyclin B
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Phenanthrenes
Poly(ADP-ribose) Polymerase Inhibitors
RNA, Messenger