Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent.
Placental apoptosis plays important roles in both normal morphogenesis and pathogenesis. We previously reported that administration of cytosine arabinoside (Ara-C), a DNA-damaging agent, to pregnant rats induced apoptosis of trophoblasts in the placental labyrinth zone. Our aim here was to clarify the molecular pathway of DNA damage induced-trophoblastic apoptosis. We found the accumulation and phosphorylation of p53 protein, a tumor suppressor that mediates apoptosis under various cellular stresses, in Ara-C-treated rat placentas. Expression of the mRNAs of downstream targets of p53 was upregulated, suggesting that p53 exerts its function as a transcription factor. We also observed release of mitochondrial cytochrome c and activation of caspase-9, hallmarks of the intrinsic apoptotic pathway. Phosphorylation of Chk1 and H2A.X, target substrates of DNA damage transducers, was detected immediately after Ara-C treatment, suggesting activation of DNA damage cascades to phosphorylate p53. Ara-C-induced trophoblastic apoptosis was almost completely abrogated in placentas of Trp53 (coding p53)-deficient mice, whereas the levels of physiological apoptosis in trophoblasts were similar among wild-type and Trp53-deficient mice. These results indicate that p53 is essential for DNA damage-induced trophoblastic apoptosis and suggest that the mechanisms that regulate the damage-induced apoptosis differ from those that regulate physiological apoptosis.
Yamauchi
Hirofumi
H
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. yamauchi-h@umin.net
Katayama
Kei-ichi
K
Ueno
Masaki
M
He
Xi Jun
XJ
Mikami
Takashi
T
Uetsuka
Koji
K
Doi
Kunio
K
Nakayama
Hiroyuki
H
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D005260:Female; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D003561:Cytarabine; D045304:Cytochromes c; D053453:Caspase 9