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Regulation of the human oxytocin receptor by nuclear factor-kappa B and CCAAT/enhancer-binding protein-beta
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Terzidou, Vasso, Lee, Yooni, Lindstrom, Tamsin, Johnson, Mark, Thornton, Steven and Bennett, Phillip R. (2013) Regulation of the human oxytocin receptor by nuclear factor-kappa B and CCAAT/enhancer-binding protein-beta. Journal of Clinical Endocrinology & Metabolism , Volume 91 (Number 6). pp. 2317-2326. doi:10.1210/jc.2005-2649 ISSN 0021-972x.
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Official URL: http://dx.doi.org/10.1210/jc.2005-2649
Abstract
Context: Increased myometrial sensitivity to oxytocin at term is mediated through increased oxytocin receptor (OTR) expression. OTR promoter contains putative transcription factor-binding sites for activating protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP), and nuclear factor-kappa B (NF-kappa B), which may be activated by IL-1 beta, whose concentrations increase with labor.
Objective: The objective of this study was to examine the effect of IL-1 beta on OTR expression and the roles of AP-1, C/EBP, and NF-kappa B in OTR promoter function.
Results: IL-1 beta induces an increase in OTR mRNA concentrations and OTR ligand binding in myometrial cells, which is maximal at 4 h and decreased after 20 h. IL-1 beta activates the transcription factors AP-1 C/EBP beta, and NF-kappa B. Using computer-based analysis and EMSA studies, we have identified three AP-1, nine C/EBP, and three NF-kappa B DNA-binding sites in the OTR promoter. In transient transfection studies, OTR promoter activity was increased by C/EBP beta and NF-kappa B, but not by AP-1. C/EBP beta and NF-kappa B together had a synergistic action in the induction of OTR promoter activity. Site-directed mutagenesis of each individual C/EBP and NF-kappa B site had no effect on the ability of C/EBP beta, NF-kappa B, or their combination to activate OTR promoter. However, mutation of both NF-kappa B sites inhibited promoter activation by NF-kappa B alone, but not that by the combination of C/EBP beta and NF-kappa B. Deletion studies showed that a region between -851 and -656 of the OTR confers responsiveness to the combination of C/EBP beta and NF-kappa B.
Conclusion: IL-1 beta has a biphasic effect on OTR expression in myometrial cells, and C/EBP and NF-kappa B play synergistic roles in OTR promoter activation.
Item Type: | Journal Article | ||||||||
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Subjects: | R Medicine > RC Internal medicine | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Journal of Clinical Endocrinology & Metabolism | ||||||||
Publisher: | Endocrine Society | ||||||||
ISSN: | 0021-972x | ||||||||
Official Date: | 20 July 2013 | ||||||||
Dates: |
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Volume: | Volume 91 | ||||||||
Number: | Number 6 | ||||||||
Number of Pages: | 10 | ||||||||
Page Range: | pp. 2317-2326 | ||||||||
DOI: | 10.1210/jc.2005-2649 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access |
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