Ethylnitrosourea induces neural progenitor cell apoptosis after S-phase accumulation in a p53-dependent manner.
Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53.
Katayama
Kei-ichi
K
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. katayama-vet@umin.ac.jp
Ueno
Masaki
M
Yamauchi
Hirofumi
H
Nagata
Takayuki
T
Nakayama
Hiroyuki
H
Doi
Kunio
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D005038:Ethylnitrosourea