Regulation of GTP-binding Protein (Gαs) Expression in Human Myometrial Cells

Abstract

Background:The GTP-binding protein G␣ s facilitates myometrial quiescence during pregnancy. Results: TNF overcomes trichostatin A (TSA)-induced myometrial relaxation. This is due to changes in levels of CBP and acetylated H4K8 within the G␣ s promoter. Conclusion: Promoter acetylation is important in governing expression of G␣ s . Significance: TSA-induced myometrial relaxation can be overcome by TNF through repression of G␣ s promoter activity.

The effect of trichostatin-A and tumor necrosis factor on expression of splice variants of the MaxiK and L-type channels in human myometrium

“…In our previous studies, we have reported differential effects of both TNF and TSA on signaling pathways in primary myometrial myocytes (Chapman et al, 2005 ; Webster et al, 2013 ). In the present study we sought to determine if such compounds could also influence expression of the MaxiK mRNA.…”

“…We and others have previously demonstrated that external agents such as TNF (potent pro-inflammatory cytokine) can induce myometrial contractility while other compounds, namely trichostatin-A (TSA), can promote myometrial relaxation in isolated human smooth muscle strips (Lu et al, 1999 ; Moynihan et al, 2008 ; Webster et al, 2013 ). While the exact means by which this process occurred could not be elucidated, that study also demonstrated that TSA caused an up-regulation of the GTP-binding protein, Gαs, while TNF had the reciprocal function and repressed the Gαs promoter.…”

“…While the exact means by which this process occurred could not be elucidated, that study also demonstrated that TSA caused an up-regulation of the GTP-binding protein, Gαs, while TNF had the reciprocal function and repressed the Gαs promoter. The repression was due to recruitment of an enzyme, histone deacetylase-1 (HDAC-1) to the regulatory region of the Gαs gene (Webster et al, 2013 ). Together, these data illustrated that while TSA can induce a relaxed myometrial phenotype required to stop muscle contraction, it could not overcome the uterine inflammation induced by those pro-inflammatory mediators, including TNF, known to be present in the uterus during labor.…”

“…It is likely, however, that both agents would also influence both ion channel expression and subsequent RNA splicing, which, in turn, would also modulate myometrial contractility. Given the effects we have previously reported for both TNF and TSA on primary human myometrium and myometrial myocytes (Webster et al, 2013 ), in this study we wished to examine the expression, localization, and splicing pattern of both the MaxiK channel and the LTCC in primary human myometrial cells and define whether these parameters were influenced by TNF and TSA.…”

Inhibition of Inflammatory Changes in Human Myometrial Cells by Cell Penetrating Peptide and Small Molecule Inhibitors of NFκB

“…The genes examined in this study are listed in Table 2. The approach to gene selection for this panel was multifactorial: a number of genes encoding for proteins associated with the physiological events of uterine contraction, cervical dilation and membrane rupture that occur during human labor, termed labor associated genes, were selected (41); also, for comparison, a collection of genes encoding for G-proteins involved in maintaining uterine quiescence (42). A number of pro inflammatory genes, including genes encoding for proteins in the NFκB pathway (16), and genes involved in the production of prostaglandins (18) were chosen to aid understanding of the potential mechanism of action of inhibitors used in this study.…”