title: p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing.
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.forename: Wenbo
authors.initials: W
authors.lastname: Deng
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Cha
authors.forename: Jia
authors.initials: J
authors.lastname: Yuan
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Haraguchi
authors.forename: Amanda
authors.initials: A
authors.lastname: Bartos
authors.forename: Emma
authors.initials: E
authors.lastname: Leishman
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Heather B
authors.initials: HB
authors.lastname: Bradshaw
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001665:Binding Sites; D016922:Cellular Senescence; D003656:Decidua / Q000502:physiology*; D005260:Female; D006801:Humans; D007249:Inflammation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D018384:Oxidative Stress; D036801:Parturition / Q000502:physiology*; D010544:Peroxidases; D011247:Pregnancy; D047928:Premature Birth; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation; D014599:Uterus / Q000502:physiology; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D000975:Antioxidants; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010544:Peroxidases; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C465398:SESN2 protein, human; D000084622:Sestrins; C495901:TP53 protein, human; C529380:Sesn2 protein, mouse