RHO protein regulation of contraction in the human uterus

Lartey, J; Bernal, Andrés López

doi:10.1530/rep-09-0160

Cited by 24 publications

(17 citation statements)

References 163 publications

(144 reference statements)

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“…Thus, the differential expression of infection- or inflammation-related genes in our study could be attributed to a combination of infection and labor. For example, inflammatory-related genes and their respective proteins such as NFKB1 [48], CCR1 [49], SOCS3, JAK3 [50], JUNB [51], RHOG [52], TIMP1 [53], IL1beta [54]–[57], ITGAM [58], CD44 [59], [60], TLR5 [61]–[63] and CXCR1 [64], [65] from our Reactome analysis are known to be up-regulated in reproductive tissues and other biologic fluids during term labor or PTL with or without infection. CD63 was increased in our study but fetal blood CD63 was not associated with sPTB [66].…”

Section: Discussionmentioning

confidence: 99%

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

et al. 2014

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Threatened preterm labor (TPTL) is defined as persistent premature uterine contractions between 20 and 37 weeks of gestation and is the most common condition that requires hospitalization during pregnancy. Most of these TPTL women continue their pregnancies to term while only an estimated 5% will deliver a premature baby within ten days. The aim of this work was to study differential whole blood gene expression associated with spontaneous preterm birth (sPTB) within 48 hours of hospital admission. Peripheral blood was collected at point of hospital admission from 154 women with TPTL before any medical treatment. Microarrays were utilized to investigate differential whole blood gene expression between TPTL women who did (n = 48) or did not have a sPTB (n = 106) within 48 hours of admission. Total leukocyte and neutrophil counts were significantly higher (35% and 41% respectively) in women who had sPTB than women who did not deliver within 48 hours (p<0.001). Fetal fibronectin (fFN) test was performed on 62 women. There was no difference in the urine, vaginal and placental microbiology and histopathology reports between the two groups of women. There were 469 significant differentially expressed genes (FDR<0.05); 28 differentially expressed genes were chosen for microarray validation using qRT-PCR and 20 out of 28 genes were successfully validated (p<0.05). An optimal random forest classifier model to predict sPTB was achieved using the top nine differentially expressed genes coupled with peripheral clinical blood data (sensitivity 70.8%, specificity 75.5%). These differentially expressed genes may further elucidate the underlying mechanisms of sPTB and pave the way for future systems biology studies to predict sPTB.

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Section: Discussionmentioning

confidence: 99%

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

et al. 2014

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“…FP receptor-mediated activation of phospholipase C␤ (PLC␤) and production of inositol trisphosphate (IP 3 ) promotes intracellular Ca 2ϩ release, which stimulates Ca 2ϩ -dependent, calmodulin-mediated activation of myosin light chain kinase and subsequent phosphorylation of myosin light chain to promote smooth muscle cell contraction. Activation of the Rho-ROCK pathway through G␣ 12 facilitates inhibitory regulation of the myosin light chain (MLC) phosphatase and the increase in myosin light chain phosphorylation, which maintains the cell in the contracted state (50).…”

Section: Discussionmentioning

confidence: 99%

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Goupil

Tassy

Bourguet

et al. 2010

Journal of Biological Chemistry

113

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The prostaglandin F2␣ (PGF2␣) receptor (FP) is a key regulator of parturition and a target for pharmacological management of preterm labor. However, an incomplete understanding of signaling pathways regulating myometrial contraction hinders the development of improved therapeutics. Here we used a peptidomimetic inhibitor of parturition in mice, PDC113.824, whose structure was based on the NH 2 -terminal region of the second extracellular loop of FP receptor, to gain mechanistic insight underlying FP receptor-mediated cell responses in the context of parturition. We show that PDC113.824 not only delayed normal parturition in mice but also that it inhibited both PGF2␣-and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2␣-mediated, G␣ 12 -dependent activation of the Rho/ROCK signaling pathways, actin remodeling, and contraction of human myometrial cells likely by acting as a non-competitive, allosteric modulator of PGF2␣ binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2␣-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to G␣ q , at the expense of coupling to G␣ 12 . Our findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.

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“…More specifically, LMOD1 and CAMK2G are involved in the maintenance of a contractile phenotype in vascular smooth muscle cells [13,14] but their role in myometrial smooth muscle has not been investigated. The myosin phosphatase regulatory subunit family of proteins (PPP1R12A, B and C) is well conserved [15] and is involved in calcium sensitization mechanisms in human myometrium [16]. AHNAK binds to and stimulates Ltype Ca 2+ channel activity and can be regulated by PKA-mediated phosphorylation [17], and provides a link between Ca 2+ channels and the actin cytoskeleton [18].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of proteins during human myometrial contractions: A phosphoproteomic approach

Hudson

Bernal

2017

Biochemical and Biophysical Research Communications

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms . Other yet unknown phosphorylation or de-phosphorylation events may contribute to myometrial contraction and relaxation. In this study we have performed a global phosphoproteomic analysis of human myometrial tissue using tandem mass tagging to detect changes in the phosphorylation status of individual myometrial proteins during spontaneous and oxytocin-driven phasic contractions. We were able to detect 22 individual phosphopeptides whose relative ratio changed (fold > 2 or < 0.5) in response to spontaneous or oxytocin-stimulated contraction.The most significant changes in phosphorylation were to MYLK on serine 1760, a site associated with reductions in calmodulin binding and subsequent kinase activity.Phosphorylated MYLK (ser1760) increased significantly during spontaneous (9.83 ± 3.27 fold, P < 0.05) and oxytocin -induced (18.56 ± 8.18 fold, P < 0.01) contractions and we were able to validate these data using immunoblotting. Pathway analysis suggested additional proteins involved in calcium signalling, cGMP-PRKG signalling, adrenergic signalling and oxytocin signalling were also phosphorylated during contractions. This study demonstrates that a global phosphoproteomic analysis of myometrial tissue is a sensitive approach to detect changes in the phosphorylation of proteins during myometrial contractions, and provides a platform for further validation of these changes and for identification of their functional significance.

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RHO protein regulation of contraction in the human uterus

Cited by 24 publications

References 163 publications

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Phosphorylation of proteins during human myometrial contractions: A phosphoproteomic approach

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