Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 3, Pages 803-815Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI40051
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Funding
- NTH Center [AR47363, HD12304, DA006668, DAO1822]
- Japan Society
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD012304, R37HD012304] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P30AR047363] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R37DA006668, R01DA006668] Funding Source: NIH RePORTER
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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/PGF(2 alpha) pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.
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