| Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice. | |
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MedLine Citation:
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PMID: 20124728 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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(2alpha) pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition. |
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Authors:
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Yasushi Hirota; Takiko Daikoku; Susanne Tranguch; Huirong Xie; Heather B Bradshaw; Sudhansu K Dey |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 120 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-03-15 Completed Date: 2010-03-31 Revised Date: 2012-02-07 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 803-15 Citation Subset: AIM; IM |
Affiliation:
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The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Ohio, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cyclooxygenase 2 / metabolism Cyclooxygenase 2 Inhibitors / pharmacology Decidua / metabolism*, pathology Dinoprost / genetics, metabolism Embryo Implantation / drug effects, genetics Female Fertilization / drug effects, genetics Hydroxyprostaglandin Dehydrogenases / genetics, metabolism Mice Mice, Transgenic Ovulation / drug effects, genetics, metabolism Pregnancy Premature Birth / genetics, metabolism*, pathology Proto-Oncogene Proteins c-akt / genetics, metabolism Pyrazoles / pharmacology Sulfonamides / pharmacology Tumor Suppressor Protein p53* |
| Grant Support | |
ID/Acronym/Agency:
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AR47363/AR/NIAMS NIH HHS; DA006668/DA/NIDA NIH HHS; DA01822/DA/NIDA NIH HHS; HD12304/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyclooxygenase 2 Inhibitors; 0/Pyrazoles; 0/Sulfonamides; 0/Tumor Suppressor Protein p53; 169590-42-5/celecoxib; 551-11-1/Dinoprost; EC 1.1.1.-/Hydroxyprostaglandin Dehydrogenases; EC 1.1.1.188/prostaglandin-F synthase; EC 1.14.99.-/Ptgs2 protein, mouse; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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