Effects of Progesterone Treatment on Expression of Genes Involved in Uterine Quiescence

Soloff, Melvyn S.; Jeng, Yow Jiun; Izban, Michael G.; Sinha, Mala; Luxon, Bruce A.; Stamnes, Susan J.; England, Sarah K.

doi:10.1177/1933719111398150

Cited by 60 publications

(34 citation statements)

References 140 publications

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“…In addition to enhancing the activity of the α-subunit, the β2-subunit inactivates the channel currents by N-type inactivation (Wallner et al, 1999; Xia et al, 2003). Consistent with the idea that β2 inhibits uterine contractility during pregnancy, progesterone (which is high until the end of pregnancy) increases the expression of the BK Ca α-subunit but decreases expression of β2 in MSMCs (Soloff et al, 2011). …”

Section: Extrinsic Mechanisms Of Bkca Channel Modulationsupporting

confidence: 62%

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

2014

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The large-conductance voltage- and Ca2+-activated K+ channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.

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Section: Extrinsic Mechanisms Of Bkca Channel Modulationsupporting

confidence: 62%

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

2014

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“…The addition of RU486 to P4/E2-treated cells led to altered expression transcriptional profiles for 666 genes. Our study revealed genes and pathways related to those identified in previous studies that analyzed the global transcriptomic profiles in pregnant and laboring myometrium in humans and other species (32,53,62,69). The in vitro analysis of transcriptional alterations in hUtSMCs in response to two of the main steroid regulators provides important insights into the role played by a key individual cell type, the smooth muscle cell, in all physiological and pathophysiological states where these two hormones fluctuate.…”

Section: Discussionmentioning

confidence: 84%

“…In uterine smooth muscle cells myocyte enhancer factor 2 is also bound in this complex (57). Previous studies have also reported the upregulation of several transcription factors associated with the transition from pregnant not-in-labor to laboring myometrium in rat, mouse and human (8,16,25,28,32,53,62,69).…”

Section: Discussionmentioning

confidence: 94%

“…No transcriptomic study has yet been carried out to investigate the combined effects of 17␤-estradiol (E2) and P4, and the impact of the progesterone inhibitor (RU486) on cultured uterine smooth muscle cells in relation to myometrial contractility, though an in vitro study has recently been published on the gene expression profile of immortalized human myometrial cells primarily in response to P4 (69). Global transcriptomic profiling of cultured human uterine smooth muscle cells (hUtSMCs) following combined P4 and E2 steroid hormone treatments, including combined hormone treatment in the presence of the P4 antagonist RU486 to functionally withdraw P4 as occurs at human labor, is presented here.…”

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confidence: 99%

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Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells

Chandran

Cairns

O’Brien

et al. 2016

Physiological Genomics

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Chandran S, Cairns MT, O'Brien M, O'Connell E, Mashayekhi K, Smith TJ. Effects of combined progesterone and 17␤-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells. Physiol Genomics 48: 50 -61, 2016. First published November 3, 2015 doi:10.1152/physiolgenomics.00021.2015.-A transcriptomic analysis of cultured human uterine smooth muscle cells (hUtSMCs) was performed to examine gene expression profiles in smooth muscle in an environment containing the two major steroid hormones that regulate the human myometrium in physiological states associated with estrous, pregnancy, labor, and pathophysiological states such as leiomyoma and endometrial cancer. hUtSMCs were treated with progesterone (P4) and 17␤-estradiol (E2) individually and in combination, in the presence and absence of RU486 (mifepristone). Transcription of many genes was modulated in the presence of P4 or E2 alone, but almost six times more genes were transcriptionally modulated in the presence of the P4/E2 hormone combination. In total 796 annotated genes were significantly differentially expressed in the presence of both P4 and E2 relative to their expression in untreated cells. Functional withdrawal of P4 by addition of RU486 effectively reversed almost all transcriptional changes caused by P4/E2 treatment. Gene ontology analysis of differentially expressed genes revealed a strong association between P4/E2 treatment and downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response, and differentiation. Upregulated processes included cell survival, gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling, and cell growth.progesterone; 17␤-estradiol; uterine smooth muscle cells; microarray; transcriptomics THE TWO STEROID HORMONES, estrogen and progesterone (P4), play vital roles in maintaining pregnancy and initiating labor (51) and more generally in myometrial physiology and contractility. P4 maintains uterine quiescence during pregnancy, while estrogen induces uterine contraction at labor (49 -51). These hormones fluctuate relative to each other throughout life from puberty, through the fertile years, to the postfertile years and also within these life stages during specific physiological states such as estrous, pregnancy, labor, and menopause. Furthermore, both hormones have profound effects on pathophysiological conditions such as leiomyoma, endometriosis, and endometrial cancer.In maternal physiology these hormones induce changes that prepare the mother for pregnancy and aid in conceptus development (11). In most species, a sharp decline in circulating P4 and an increase in estrogen are observed toward parturition (11,38). However, in humans, no marked difference in the levels of circulating P4 or estrogen is noted before or at term (51). Hence, in humans, withdrawal of P4 and responsiveness of the myometrium to circulating estrogen during labor is believed to occur at a functional level, with changes in ho...

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“…Reduction of cell excitability lowers the contraction frequency and leads to uterine quiescence after mid-pregnancy. 35 …”

Section: Proteome-driven Studies On Functional Remodelingmentioning

confidence: 97%

Proteomic Analyses Reveal the Role of Progesterone and Inducible Nitric Oxide Synthase in Uterine Remodeling during Pregnancy

Wang¹,

Chen

et al. 2012

Journal of Experimental & Clinical Medicine

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Effects of Progesterone Treatment on Expression of Genes Involved in Uterine Quiescence

Cited by 60 publications

References 140 publications

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells

Proteomic Analyses Reveal the Role of Progesterone and Inducible Nitric Oxide Synthase in Uterine Remodeling during Pregnancy

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