Etoposide induces TRP53-dependent apoptosis and TRP53-independent cell cycle arrest in trophoblasts of the developing mouse placenta
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Updated: Jun 26, 2026
Isolation of Primary Mouse Trophoblast Cells and Trophoblast Invasion Assay
Published on: January 8, 2012
Hirofumi Yamauchi1, Kei-Ichi Katayama, Masaki Ueno
1Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. yamauchi-h@umin.net
Abstract:
Abnormal regulation of placental apoptosis and proliferation has been implicated in placental disorders. Recently, several DNA-damaging agents were reported to induce excessive apoptosis and reduce cell proliferation in the placenta; however, the molecular pathways of these toxic effects on the placenta are unclear. The aim of the present study was to determine the involvement of TRP53, a tumor suppressor that mediates cellular responses to DNA damage, in the induction of apoptosis and cell cycle arrest in the developing placenta. For this purpose, we treated pregnant mice on Day 12 of gestation with 10 mg/kg of etoposide and 5-Gy gamma irradiation, potent inducers of DNA damage. We found an increase in the number of trophoblastic apoptoses 8 and 24 h after etoposide injection and 6 and 24 h after irradiation in the placental labyrinth zone. The number of mitoses and DNA syntheses in trophoblasts decreased after treatment. The accumulation and phosphorylation of TRP53 protein were detected 8 and 6 h after etoposide injection and irradiation, respectively. In Trp53-deficient placentas, the induction of etoposide-induced trophoblastic apoptosis is abrogated, while the reduction of proliferation occurred similarly as in wild-type placentas. CDC2A, a regulator of G2/M progression, was inactivated by phosphorylation after etoposide injection and irradiation, suggesting that the cell cycle was arrested at the G2/M border by treatment. Our study demonstrated that etoposide injection induced TRP53-dependent apoptosis and TRP53-independent cell cycle arrest in labyrinthine trophoblasts, providing insights into the molecular pathway of placental disorders.
Insights
DNA damage in placental cells triggers apoptosis and cell cycle arrest. The tumor suppressor TRP53 mediates DNA damage-induced apoptosis, while cell cycle arrest is TRP53-independent in developing placentas.
Area of Science:
- Reproductive biology
- Developmental toxicology
- Molecular genetics
Background:
- Abnormal placental apoptosis and proliferation are linked to placental disorders.
- Molecular pathways of DNA-damaging agent toxicity in the placenta remain unclear.
Purpose of the Study:
- Investigate the role of TRP53 in DNA damage-induced apoptosis and cell cycle arrest in the developing placenta.
- Elucidate molecular mechanisms underlying placental toxicity from DNA-damaging agents.
Main Methods:
- Pregnant mice treated with etoposide or gamma irradiation on Day 12 of gestation.
- Analysis of trophoblastic apoptosis, mitosis, DNA synthesis, and TRP53/CDC2A protein levels.
- Comparison between wild-type and Trp53-deficient placentas.
Main Results:
- Etoposide and gamma irradiation increased trophoblastic apoptosis and decreased proliferation in the placental labyrinth.
- TRP53 protein accumulated and phosphorylated post-treatment.
- TRP53 deficiency abrogated etoposide-induced apoptosis but not proliferation reduction.
- CDC2A inactivation suggested G2/M cell cycle arrest.
Conclusions:
- Etoposide induces TRP53-dependent apoptosis in placental trophoblasts.
- Cell cycle arrest in response to etoposide is TRP53-independent.
- Findings offer insights into the molecular pathways of placental disorders.
