Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent

Apoptosis. 2007 Oct;12(10):1743-54. doi: 10.1007/s10495-007-0099-z.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / physiology*
  • Caspase 9 / metabolism
  • Cytarabine / pharmacology*
  • Cytochromes c / metabolism
  • DNA Damage
  • Enzyme Activation
  • Female
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Placenta* / drug effects
  • Placenta* / physiology
  • Pregnancy
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Trophoblasts / cytology
  • Trophoblasts / drug effects*
  • Trophoblasts / physiology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • fas Receptor / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • Tumor Suppressor Protein p53
  • fas Receptor
  • Cytarabine
  • Cytochromes c
  • Caspase 9