Document Detail


The microRNA (miR)-199a/214 cluster mediates opposing effects of progesterone and estrogen on uterine contractility during pregnancy and labor.
MedLine Citation:
PMID:  22973051     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Progesterone (P(4)) and estradiol-17β (E(2)) play critical and opposing roles in regulating myometrial quiescence and contractility during pregnancy and labor. Although these contrasting hormonal effects are likely mediated via differential regulation of inflammatory and contractile genes, the underlying mechanisms remain incompletely understood. Recently we discovered that targets of the microRNA (miR)-200 family, transcription factors zinc finger E-box binding homeobox (ZEB)-1 and ZEB2, serve as P(4)/progesterone receptor-mediated regulators of uterine quiescence during pregnancy. In the present study, we found that levels of the clustered miRNAs, miR-199a-3p and miR-214, were significantly decreased in laboring myometrium of pregnant mice and humans and in an inflammatory mouse model of preterm labor, whereas the miR-199a-3p/miR-214 target, cyclooxygenase-2, a critical enzyme in synthesis of proinflammatory prostaglandins, was coordinately increased. Overexpression of miR-199a-3p and miR-214 in cultured human myometrial cells inhibited cyclooxygenase-2 protein and blocked TNF-α-induced myometrial cell contractility, suggesting their physiological relevance. Notably, E(2) treatment of ovariectomized mice suppressed, whereas P(4) enhanced uterine miR-199a-3p/214 expression. Intriguingly, these opposing hormonal effects were mediated by ZEB1, which is induced by P(4), inhibited by E(2) and activates miR199a/214 transcription. Together, these findings identify miR-199a-3p/miR-214 as important regulators of myometrial contractility and provide new insight into strategies to prevent preterm birth.
Authors:
Koriand'r C Williams; Nora E Renthal; Robert D Gerard; Carole R Mendelson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-12
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  26     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-04-17     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1857-67     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Cyclooxygenase 2 / genetics,  metabolism
Estrogens / pharmacology*
Female
Gene Expression Regulation / drug effects
Homeodomain Proteins / metabolism
Humans
Inflammation Mediators / metabolism
Labor, Obstetric / drug effects*,  genetics*
Mice
Mice, Inbred ICR
MicroRNAs / genetics,  metabolism*
Molecular Sequence Data
Multigene Family / genetics
Myometrium / cytology,  drug effects,  metabolism
Pregnancy
Progesterone / pharmacology*
Transcription Factors / metabolism
Uterine Contraction / drug effects*,  genetics*
Grant Support
ID/Acronym/Agency:
5-P01-HD11149/HD/NICHD NIH HHS; GM007062/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Estrogens; 0/Homeodomain Proteins; 0/Inflammation Mediators; 0/MIRN214 microRNA, human; 0/MicroRNAs; 0/Mirn199 microRNA, mouse; 0/Mirn214 microRNA, mouse; 0/Transcription Factors; 0/ZEB1 protein, human; 0/mirn199 microRNA, human; 57-83-0/Progesterone; EC 1.14.99.1/Cyclooxygenase 2
Comments/Corrections
Erratum In:
Mol Endocrinol. 2013 Jan;27(1):188

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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