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Regulation of GTP-binding protein (Gαs) expression in human myometrial cells: A role for tumour necrosis factor in modulating Gαs promoter acetylation by transcriptional complexes

Lookup NU author(s): Professor Nick Europe-Finner

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Abstract

The onset of parturition is associated with a number of pro-inflammatory mediators which are themselves regulated by the Nuclear Factor kappa B (NF-κB) family of transcription factors. In this context we previously reported that the RelA NF-κB subunit represses transcription and mRNA expression of the pro-quiescent Gαs gene in human myometrial cells following stimulation with the pro-inflammatory cytokine TNF. In this present study we initially defined the functional consequence of this on myometrial contractility. Here we show that, contrary to our initial expectations, TNF did not induce myometrial contractility but did inhibit the relaxation produced by the HDAC inhibitor, TSA; an effect which was, in turn, abolished by the NF-κB inhibitor, QNZ. This result suggested a role for TNF in regulating Gαs expression via activating NF-κB and modifying histone acetylation associated with the promoter region of the gene. In this context we show that the -837 to -618 region of the endogenous Gαs promoter is occupied by CREB, Egr-1 and Sp1 transcription factors and that CBP transcriptional complexes form within this region where it induces histone acetylation resulting in increased Gαs expression. TNF, acting via NF-κB, did not change the levels of CREB, Sp1 or Egr-1 binding to the Gαs promoter but it induced a significant reduction in the level of CBP. This was associated with increased levels of HDAC-1 and, surprisingly, an increase in H4K8 acetylation. The latter is discussed herein.


Publication metadata

Author(s): Webster SJ, Waite S, Cookson VJ, Warren A, Khan R, Gandhi SV, Europe-Finner GN, Chapman NR

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2013

Volume: 288

Issue: 9

Pages: 6704-6716

Print publication date: 07/01/2013

ISSN (print): 0021-9258

Publisher: The American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M112.440602

DOI: 10.1074/jbc.M112.440602


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