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Expression of the GTP-Binding Protein (Gs) Is Repressed by the Nuclear Factor B RelA Subunit in Human Myometrium

School of Surgical and Reproductive Sciences (Obstetrics and Gynecology) (N.R.C., I.S., G.N.E.-F., S.C.R.), Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE2 4HH, United Kingdom; and Academic Unit of Reproductive and Developmental Medicine (N.R.C., D.O.C.A.), Sheffield Teaching Hospitals NHS Trust, Sheffield S10 2SF, United Kingdom

Address all correspondence and requests for reprints to: Dr. Neil Chapman, Academic Unit of Reproductive and Developmental Medicine, Level 4, The Jessup Wing, Central Sheffield Teaching Hospitals Trust, Tree Root Walk, Sheffield, South Yorkshire S10 2SF, United Kingdom. E-mail: n.r.chapman{at}sheffield.ac.uk.

In humans, the factors that govern the switch from myometrial quiescence to coordinated contractions at the initiation of labor are not well defined. The onset of parturition is itself associated with increases in a number of proinflammatory mediators, many of which are regulated by the nuclear factor B (NF-B) family of transcription factors. Recently, we have provided evidence that the RelA NF-B subunit associates with protein kinase A in pregnant myometrial tissue, suggesting links with the Gs/cAMP/protein kinase A 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 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 coactivator protein, cAMP response element binding protein binding protein, 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 coactivator proteins including cAMP response element binding protein binding protein.

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