Document Detail


Cell cycle and cell death regulation of neural progenitor cells in the 5-azacytidine (5AzC)-treated developing fetal brain.
MedLine Citation:
PMID:  16427046     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the developing brain, neural progenitor cells are susceptible to many extrinsic stresses, including DNA damage. We treated pregnant rats with 5-azacytidine (5AzC), a DNA demethylating and damaging agent, to investigate the cellular responses of the fetal brain, focusing on the regulation of proliferation and cell death. 5AzC first induced the accumulation of cells in abnormal mitosis, G2-phase accumulation, and then apoptosis of the neural progenitor cells. Most of the apoptotic cells were in G1 phase. Cell cycle transition studies suggested that G2/M progression was blocked, after which the cells moved to G1 phase or underwent apoptosis. p53, a key factor for response to DNA damage, and some of its target genes showed increased expression in Western blot and DNA microarray analyses. In 5AzC-treated fetal brains of p53-deficient mice, apoptosis did not occur, although G2/M accumulation was induced. These results suggest that, in the developing brain, apoptosis is p53-dependent but that another mechanism governs the G2/M checkpoint. The G2/M regulator, Cdc2, was activated by dephosphorylation through G2/M accumulation, suggesting accelerated entry into mitosis leading to accumulation of cells showing abnormal mitosis. Furthermore, some cells may have died due to mitotic catastrophe. Throughout brain development, various cell cycle and cell death regulation mechanisms provide neural progenitor cells with options for defense from DNA damage.
Authors:
Masaki Ueno; Kei-ichi Katayama; Hirofumi Yamauchi; Hiroyuki Nakayama; Kunio Doi
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-01-19
Journal Detail:
Title:  Experimental neurology     Volume:  198     ISSN:  0014-4886     ISO Abbreviation:  Exp. Neurol.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-20     Completed Date:  2006-04-25     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0370712     Medline TA:  Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  154-66     Citation Subset:  IM    
Affiliation:
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. ms-ueno@umin.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Animals
Azacitidine / pharmacology*
Blotting, Western / methods
Brain* / cytology,  drug effects,  embryology
Bromodeoxyuridine / metabolism
Caspase 3
Caspases / metabolism
Cell Cycle / drug effects*
Cell Death / drug effects
DNA Fragmentation / drug effects
Embryo, Mammalian
Enzyme Inhibitors / pharmacology*
Female
Gene Expression Regulation, Developmental / drug effects
Histones / metabolism
Microarray Analysis / methods
Models, Biological
Neurons / cytology*,  drug effects
Pregnancy
RNA, Messenger / metabolism
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction / methods
Stem Cells / cytology*,  drug effects
Time Factors
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Histones; 0/RNA, Messenger; 0/Tumor Suppressor Protein p53; 320-67-2/Azacitidine; 59-14-3/Bromodeoxyuridine; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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