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

AI Article Synopsis

  • Inflammation and oxidative stress are linked to preterm birth (PTB), but the exact mechanisms remain unclear; this study investigates the role of mTORC1 signaling in a specific mouse model with a p53 gene deletion that exhibits characteristics of early pregnancy complications.
  • Treatment with mTORC1 inhibitor rapamycin, as well as the drugs metformin and resveratrol, showed promise in reducing PTB incidence by activating protective AMPK signaling and inhibiting harmful mTORC1 activity in the mouse model.
  • Findings suggest that p53 regulates the relationship between AMPK and mTORC1 signaling, impacting labor timing, and highlight the potential use of metformin and resveratrol as therapeutic options for preventing PTB in

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966330PMC
http://dx.doi.org/10.1172/JCI87715DOI Listing

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