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Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice
Yasushi Hirota, … , Heather B. Bradshaw, Sudhansu K. Dey
Yasushi Hirota, … , Heather B. Bradshaw, Sudhansu K. Dey
Published February 1, 2010
Citation Information: J Clin Invest. 2010;120(3):803-815. https://doi.org/10.1172/JCI40051.
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Research Article Reproductive biology

Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice

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Abstract

Many signaling pathways that contribute to tumorigenesis are also functional in pregnancy, although they are dysregulated in the former and tightly regulated in the latter. Transformation-related protein 53 (Trp53), which encodes p53, is a tumor suppressor gene whose mutation is strongly associated with cancer. However, its role in normal physiological processes, including female reproduction, is poorly understood. Mice that have a constitutive deletion of Trp53 exhibit widespread development of carcinogenesis at early reproductive ages, compromised spermatogenesis, and fetal exencephaly, rendering them less amenable to studying the role of p53 in reproduction. To overcome this obstacle, we generated mice that harbor a conditional deletion of uterine Trp53 and examined pregnancy outcome in females with this genotype. These mice had normal ovulation, fertilization, and implantation; however, postimplantation uterine decidual cells showed terminal differentiation and senescence-associated growth restriction with increased levels of phosphorylated Akt and p21, factors that are both known to participate in these processes in other systems. Strikingly, uterine deletion of Trp53 increased the incidence of preterm birth, a condition that was corrected by oral administration of the selective COX2 inhibitor celecoxib. We further generated evidence to suggest that deletion of uterine Trp53 induces preterm birth through a COX2/PGF synthase/PGF2α pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.

Authors

Yasushi Hirota, Takiko Daikoku, Susanne Tranguch, Huirong Xie, Heather B. Bradshaw, Sudhansu K. Dey

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Figure 1

Efficient deletion of uterine Trp53.

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Efficient deletion of uterine Trp53.
   
(A and B) Trp53 mRNA was undete...
(A and B) Trp53 mRNA was undetectable in 2-month-old Trp53loxP/loxPPgrCre/+ uteri analyzed by RT-PCR (A) and Northern hybridization (B). Actb and Rpl7 were used as internal controls. (C) p53 protein levels were very low to undetectable in irradiation-induced 2-month-old Trp53loxP/loxPPgrCre/+ uteri assessed by Western blotting. Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ dams were killed 6 hours after 9.5 Gy whole-body γ irradiation. Protein extracts from mouse lymphoma cell line WR19L were used as a positive control. (D) Immunostaining of p53 in Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ decidua on day 8 of pregnancy. Immunoreactive p53 was undetectable in Trp53loxP/loxPPgrCre/+ decidua. Fast Green solution was used to counterstain the cytoplasm. Dark green-black staining shows nuclear p53 localization. Scale bar: 200 μm.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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