Role of ERK1/2 in uterine contractility and preterm labor in rats

Li, Yunping; Je, Hyun‐Dong; Malek, Sabah; Morgan, Kathleen G.

doi:10.1152/ajpregu.00042.2004

Cited by 40 publications

(46 citation statements)

References 45 publications

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“…the elevated levels of myometrial ERK phosphorylation in late gestation, and the delayed labor caused by inhibition of the ERK pathway in RU486-treated rats (Li et al 2004), we hypothesize that this is an important signaling pathway that is activated as part of the parturition process. Increased ERK phosphorylation may remodel the myometrium into a contractile phenotype by modulating gene expression via activation of transcription factors (Yoon & Seger 2006) and/ or by altering the contractile apparatus via phosphorylation of cytoskeletal proteins including hCaD, paxillin, and FAK (Yoon & Seger 2006).…”

Section: Discussionmentioning

confidence: 92%

“…In pregnant rats, the abundance of activated ERK in myometrial cells increases with gestation (Oldenhof et al 2002, Serrano-Sanchez et al 2008 and labor onset (Li et al 2003). In animals induced to deliver preterm (PT) by administration of the progesterone receptor antagonist RU486, concurrent inhibition of ERK signaling delayed preterm labor and decreased myometrial contractility (Li et al 2004). These data emphasize the potential importance of this pathway in the regulation of myometrial smooth muscle contractility.…”

Section: Introductionmentioning

confidence: 96%

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Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERa and ERb (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E 2 ) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERa and GPR30 mRNAs were expressed in the human pregnant myometrium while ERb mRNA was virtually undetectable. While mRNA encoding ERa was the predominant ER transcript in the pregnant myometrium, ERa protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERa protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERa protein by proteasomal processing in the pregnant myometrium. E 2 stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERa. Inhibition of ERK signaling abrogated the ability of E 2 to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERa via activation of the ERK/mitogen-activated protein kinase pathway.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 96%

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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“…Animals were maintained in a virus-and parasite-free barrier facility and exposed to a 12-h light/dark cycle. To evaluate the effect of Erk inhibition on growth plate maturation and apoptosis, wild-type mice were treated twice daily from 18 to 21 days with 100 mg/kg U0126 or vehicle (12) and killed on day 21 or 31.…”

Section: Methodsmentioning

confidence: 99%

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Miedlich

Zalutskaya

Zhu

et al. 2010

Journal of Biological Chemistry

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Growth plate abnormalities, associated with impaired hypertrophic chondrocyte apoptosis, are observed in humans and animals with abnormalities of vitamin D action and renal phosphate reabsorption. Low circulating phosphate levels impair hypertrophic chondrocyte apoptosis, whereas treatment of these cells with phosphate activates the mitochondrial apoptotic pathway. Because phosphate-mediated apoptosis of chondrocytes is differentiation-dependent, studies were performed to identify factors that contribute to hypertrophic chondrocyte apoptosis. An increase in the percentage of cells with low mitochondrial membrane potential, evaluated by JC-1 fluorescence, was observed during hypertrophic differentiation of primary murine chondrocytes in culture. This percentage was further increased by treatment of hypertrophic, but not proliferative, chondrocytes with phosphate. Phosphate-mediated apoptosis was observed as early as 30 min post-treatment and was dependent upon Erk1/2 phosphorylation. Inhibition of Erk1/2 phosphorylation in vivo confirmed an important role for this signaling pathway in regulating hypertrophic chondrocyte apoptosis in growing mice. Murine embryonic metatarsals cultured under phosphate-restricted conditions demonstrated a 2.5-fold increase in parathyroid hormone-related protein mRNA expression accompanied by a marked attenuation in phospho-Erk immunoreactivity in hypertrophic chondrocytes. Thus, these investigations point to an important role for phosphate in regulating mitochondrial membrane potential in hypertrophic chondrocytes and growth plate maturation by the parathyroid hormone-related protein signaling pathway.Maturation of the growth of long bones is dependent upon the differentiation of proliferative chondrocytes into prehypertrophic and subsequently hypertrophic chondrocytes. Terminal differentiation of hypertrophic chondrocytes is characterized by the expression of signaling molecules that promote vascular invasion, apoptosis, and replacement of hypertrophic chondrocytes by osteoblasts that lay down the primary spongiosa of bone. Aberrant regulation of this developmental process results in growth plate disorders. Although calcium has been shown to play an important role in regulating chondrocyte maturation (1), apoptosis of terminally differentiated hypertrophic chondrocytes is dependent upon normal levels of circulating phosphate (2).Rickets is a growth plate anomaly observed in growing animals and humans with abnormalities of vitamin D action and renal phosphate reabsorption (3-6). In vivo investigations in genetically modified and dietary-manipulated mouse models demonstrate that hypophosphatemia is the underlying metabolic abnormality that impairs growth plate maturation in these disorders: low circulating phosphate levels result in impaired apoptosis of terminally differentiated hypertrophic chondrocytes in the growth plate, leading to rickets (2). The observation that inhibition of phosphate transport prevents phosphate-mediated apoptosis in hypertrophic chondrocytes (7-9) further ...

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“…More recent studies have suggested that mitogen-activated protein (MAP) kinases may also impact on contractile responses in airways [64,[77][78][79] and other types of smooth muscle [80,81]. In particular, MLC20 are the proposed substrate of extracellular signal-regulated kinase (ERK)1 and 2 [82][83][84].…”

Section: Adrenoceptors In the Lungmentioning

confidence: 99%

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

Eur Respir J

132

118

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b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

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Role of ERK1/2 in uterine contractility and preterm labor in rats

Cited by 40 publications

References 45 publications

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

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Role of ERK1/2 in uterine contractility and preterm labor in rats

Cited by 40 publications

References 45 publications

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 Phosphorylation

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

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Beyond the dogma: novel β₂-adrenoceptor signalling in the airways