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Expression of the GTP-binding protein (Galphas) is repressed by the nuclear factor kappaB RelA subunit in human myometrium.
- Source :
-
Endocrinology [Endocrinology] 2005 Nov; Vol. 146 (11), pp. 4994-5002. Date of Electronic Publication: 2005 Aug 04. - Publication Year :
- 2005
-
Abstract
- 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 kappaB (NF-kappaB) family of transcription factors. Recently, we have provided evidence that the RelA NF-kappaB subunit associates with protein kinase A in pregnant myometrial tissue, suggesting links with the Galphas/cAMP/protein kinase A pathway. TNFalpha is a potent activator of NF-kappaB, and levels of this cytokine are increased within the myometrium at term. In the current study, using primary cultures of myometrial cells, TNFalpha was observed to repress expression of Galphas while, at the same time, stimulating NF-kappaB activity. Furthermore, this effect could be replicated by exposure to bacterial lipopolysaccharide and exogenous expression of RelA. Moreover, TNFalpha was seen to repress endogenous Galphas mRNA expression as judged by RT-PCR analyses. Using the chromatin immunoprecipitation assay, we show that RelA did not bind directly to the Galphas promoter. Significantly, expression of a coactivator protein, cAMP response element binding protein binding protein, relieved RelA-induced down-regulation of Galphas expression. Together, these data suggest that, in human myometrium, repression of the Galphas gene by NF-kappaB occurs through a non-DNA binding mechanism involving competition for limiting amounts of cellular coactivator proteins including cAMP response element binding protein binding protein.
- Subjects :
- Cell Line
Cells, Cultured
Cyclic AMP Response Element-Binding Protein pharmacology
Female
GTP-Binding Protein alpha Subunits, Gs genetics
Humans
Lipopolysaccharides pharmacology
Myometrium cytology
NF-kappa B biosynthesis
Pregnancy
Promoter Regions, Genetic drug effects
Transcription Factor RelA antagonists & inhibitors
Transcription Factor RelA metabolism
Tumor Necrosis Factor-alpha pharmacology
GTP-Binding Protein alpha Subunits, Gs antagonists & inhibitors
Myometrium metabolism
Transcription Factor RelA physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0013-7227
- Volume :
- 146
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 16081638
- Full Text :
- https://doi.org/10.1210/en.2005-0533