Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced rat fetal brain lesions.
1-beta-D-Arabinofuranosylcytosine (Ara-C), a cytidine analogue cytotoxic to proliferating cells, has a teratogenic effect in the brain of experimental animals and causes neural cell apoptosis in vitro and in vivo. In the present study, pregnant rats were injected with Ara-C on Day 13 of gestation and the fetal brain was collected from 1 to 48 h after treatment. Histopathological examinations revealed marked induction of apoptotic cell death and decrease of mitosis in neuroepithelial cells in the brain of Ara-C-treated fetus, and these changes were most prominent from 9 to 12 h. Expression of p53 protein, which mediates apoptosis and cell cycle arrest after DNA damage, was elevated remarkably and peaked at 3 h. p21, a cyclin-dependent kinase inhibitor responsible for p53-mediated cell cycle arrest, showed intense overexpression in protein and mRNA levels following the increase of p53 protein. The mRNA expressions of other p53 transcriptional target genes, bax, cyclinG1, and fas, also significantly increased and peaked at around 9 h. In conclusion, prenatal treatment of Ara-C is thought to induce apoptosis and inhibition of cell proliferation mediated by p53 and its target genes in the fetal brain.
Yamauchi
Hirofumi
H
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, 113-8657 Tokyo, Japan. yamauchi-h@umin.ac.jp
Katayama
Kei-Ichi
K
Ueno
Masaki
M
Uetsuka
Koji
K
Nakayama
Hiroyuki
H
Doi
Kunio
K
D000818:Animals; D015152:Blotting, Northern; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000633:toxicity*; D004622:Embryo, Mammalian; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C534704:Ccng1 protein, rat; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D003561:Cytarabine; D020741:rho GTP-Binding Proteins