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p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing
Wenbo Deng, … , Yasushi Hirota, Sudhansu K. Dey
Wenbo Deng, … , Yasushi Hirota, Sudhansu K. Dey
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):2941-2954. https://doi.org/10.1172/JCI87715.
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Research Article Reproductive biology

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

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Abstract

Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB.

Authors

Wenbo Deng, Jeeyeon Cha, Jia Yuan, Hirofumi Haraguchi, Amanda Bartos, Emma Leishman, Benoit Viollet, Heather B. Bradshaw, Yasushi Hirota, Sudhansu K. Dey

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Figure 1

Met and Rsv attenuate preterm birth and dystocia.

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Met and Rsv attenuate preterm birth and dystocia.
(A and B) Treatment sc...
(A and B) Treatment schedules for Met and Rsv treatment. (C and D) Percent preterm birth and live pups under Met or Rsv treatment in p53fl/fl and p53d/d females. ‡Three of six p53d/d females that had preterm birth also showed dystocia. §One of ten p53d/d females showed both preterm birth and dystocia. *P < 0.05, χ2 test. (E and F) Percent preterm birth and live pups under Met or Rsv in combination with P4 4 hours before an LPS (10 μg) injection in p53fl/fl and p53d/d mice. ‡One of two p53d/d females that had preterm birth also showed dystocia. §One of four p53d/d females showing preterm birth also had dystocia. *P < 0.05, χ2 test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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