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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 3

Uterine deletion of Trp53 restricts normal decidual growth.

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Uterine deletion of Trp53 restricts normal decidual growth.
   
(A) Repr...
(A) Representative photographs of day 8 pregnant implantation sites in Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ mice. (B and C) Number and weight of implantation sites in Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ mice on day 8 of pregnancy (mean ± SEM; *P < 0.05). (D and E) Trp53loxP/loxPPgr+/+ blastocysts were transferred into uteri of Trp53loxP/loxPPgr+/+ or Trp53loxP/loxPPgrCre/+ recipients on day 4 of pseudopregnancy. The number and weight of implantation sites were evaluated on day 8, 4 days after embryo transfer (mean ± SEM; *P < 0.05). Numbers in parentheses denote the ratio of implantation sites/total blastocysts transferred. (F) In situ hybridization of Hoxa10 and Bmp2 in Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ uteri on day 8 of pregnancy. Em, embryo; M, mesometrial pole; AM, antimesometrial pole. Scale bar: 200 μm. (G) Northern hybridization of Hoxa10 and Bmp2 in day 8 uteri of Trp53loxP/loxPPgr+/+ and Trp53loxP/loxPPgrCre/+ dams. In each group, 2–3 independent samples were examined (mean ± SEM; *P < 0.05). (H and I) Loss of p53 upregulated pAkt, p110α, and p21 levels in day 8 implantation sites. As assessed by Western blotting (H), quantitatively analyzed band intensities of pAkt were normalized against total Akt, and those of p110α and p21 were normalized against actin (I). In each group, 3 independent samples from different mice were examined (mean ± SEM; *P < 0.05).
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