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Submitted on May 3, 2005
Accepted on July 18, 2005
s) is repressed by the nuclear factor kappaB (NF-
B) RelA subunit in human myometrium
School of Surgical and Reproductive Sciences, (Obstetrics and Gynaecology), 3rd Floor, William Leech Building, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, United Kingdom; Academic Unit of Reproductive and Developmental Medicine, Level 4, The Jessop Wing, Sheffield Teaching Hospitals NHS Trust, Tree Root Walk, Sheffield, S10 2SF, United Kingdom
* To whom correspondence should be addressed. E-mail: n.r.chapman{at}ncl.ac.uk.
In humans, the factors that govern the switch from myometrial quiescence to co-ordinated contractions at the initiation of labor are not well defined. The onset of parturition is itself associated with increases in a number of pro-inflammatory mediators, many of which are regulated by the nuclear factor kappaB (NF-
B) family of transcription factors. Recently, we have provided evidence that the RelA NF-B subunit associates with PKA in pregnant myometrial tissue suggesting links with the G
s/cAMP/PKA pathway. TNF is a potent activator of NF-B and levels of this cytokine are increased within the myometrium at term. In the current study, using primary cultures of myometrial cells, TNF was observed to repress expression of Gs while at the same time stimulating NF-B activity. Furthermore, this effect could be replicated by exposure to bacterial lipopolysaccharide (LPS) and exogenous expression of RelA. Moreover, TNF was seen to repress endogenous Gs mRNA expression as judged by RT-PCR analyses. Using the chromatin immunoprecipitation assay, we show that RelA did not bind directly to the Gs promoter. Significantly, expression of a co-activator protein, CBP, relieved RelA-induced down-regulation of Gs expression. Together these data suggest that in human myometrium, repression of the Gs gene by NF-B occurs through a non-DNA binding mechanism involving competition for limiting amounts of cellular co-activator proteins including CBP.
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