P53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing
Open accessAbstract
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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A family of molecules that are the mechanistic target of the rapamycin (mTOR) complex has been attributed a major role in the biology of cell metabolism, growth, longevity, and even preterm birth.
“A family of molecules that are the mechanistic target of the rapamycin (mTOR) complex has been attributed a major role in the biology of cell metabolism, growth, longevity, and even preterm birth(230–236).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [234]
Rapamycin can prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.
“Rapamycin can also prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [234]
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Ageing in human parturition: impetus of the gestation clock in the decidua†
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- Authors
- Deng, W., Cha, J., Yuan, J., Haraguchi, H., Bartos, A., Leishman, E., Viollet, B., Bradshaw, H. B., Hirota, Y., & Dey, S. K.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- The University of Tokyo (JP)
- Indiana University Bloomington (US)
- Corresponding author
- Dey, Sudhansu K.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-07-25
- Volume
- 126
- Issue
- 8
- Pages
- 2941-2954
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4966330
- OpenAlex
- W2485481679
- Cited by
- 85
- References
- 62
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 13 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 3
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation (21-FY12-127, 22-FY13-543)
- Vanderbilt University
- Cincinnati Children's Hospital Medical Center
- Vanderbilt University Medical Center
- National Institutes of Health (DA06668)
- Japan Society for the Promotion of Science (15J05982)
- National Institute on Aging (F30AG040858)
- National Institute on Drug Abuse (R01DA006668, R37DA006668)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD068524)
- Topics
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- p53, Sestrin2, AMPK, mTORC1 signaling, parturition timing, preterm birth, metformin, resveratrol, rapamycin, oxidative stress
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sestrins, Animals, Antioxidants, Binding Sites, Decidua, Female, Humans, Inflammation, Mice, Transgenic, Nuclear Proteins, Peroxidases, Pregnancy, Uterus, Signal Transduction, Up-Regulation, Tumor Suppressor Protein p53, Cellular Senescence, Oxidative Stress, Parturition, Multiprotein Complexes, Premature Birth, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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