RRC ID 11780
Author Kanemitsu H, Yamauchi H, Komatsu M, Yamamoto S, Okazaki S, Uchida K, Nakayama H.
Title 6-mercaptopurine (6-MP) induces p53-mediated apoptosis of neural progenitor cells in the developing fetal rodent brain.
Journal Neurotoxicol Teratol
Abstract 6-mercaptopurine (6-MP), a DNA-damaging agent, induces apoptosis of neural progenitor cells, and causes malformation in the fetal brain. The aim of the present study is to clarify the molecular pathway of 6-MP-induced apoptosis of neural progenitor cells in the fetal telencephalon of rats and mice. p53 protein is activated by DNA damage and induces apoptosis through either the intrinsic pathway involving the mitochondria or the extrinsic pathway triggered by death receptors. In this study, the expression of puma and cleaved caspase-9 proteins, which are specific intrinsic pathway factors, increased in the rat telencephalon after 6-MP treatment. 6-MP-induced apoptosis of neural progenitor cells was completely absent in p53-deficient mice. On the other hand, the expression of Fas protein, an extrinsic pathway factor, did not change throughout the experimental period in the rat telencephalon treated with 6-MP. The number of apoptotic neural progenitor cells was similar among Fas-mutated lpr/lpr and wild-type mice, suggesting that the Fas pathway does not play a significant role in 6-MP-induced apoptosis of neural progenitor cells. These results may suggest that the p53-mediated intrinsic pathway is essential for 6-MP-induced apoptosis of neural progenitor cells in the developing telencephalon of rats and mice.
Volume 31(4)
Pages 198-202
Published 2009-7
DOI 10.1016/j.ntt.2009.02.006
PII S0892-0362(09)00032-4
PMID 19281843
MeSH Abnormalities, Drug-Induced / genetics* Abnormalities, Drug-Induced / metabolism Abnormalities, Drug-Induced / physiopathology Animals Apoptosis / drug effects* Apoptosis / physiology Apoptosis Regulatory Proteins Caspase 9 / drug effects Caspase 9 / metabolism Disease Models, Animal Fas Ligand Protein / drug effects Fas Ligand Protein / metabolism Female Male Mercaptopurine / toxicity* Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Nucleic Acid Synthesis Inhibitors / toxicity Pregnancy Prenatal Exposure Delayed Effects / genetics Prenatal Exposure Delayed Effects / metabolism Prenatal Exposure Delayed Effects / physiopathology Stem Cells / drug effects* Stem Cells / metabolism Stem Cells / pathology Telencephalon / abnormalities Telencephalon / cytology Telencephalon / drug effects* Teratogens / toxicity Tumor Suppressor Protein p53 / drug effects* Tumor Suppressor Protein p53 / metabolism Tumor Suppressor Proteins / drug effects Tumor Suppressor Proteins / metabolism
IF 2.902
Times Cited 8
Mice C57BL-p53+/-