Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions

Knerr, Ina; Schubert, Steffen; Wich, Christina; Amann, Kerstin; Aigner, Thomas; Vogler, Tina; Jung, Ronny; Dötsch, Jörg; Rascher, Wolfgang; Hashemolhosseini, Said

doi:10.1016/j.febslet.2005.06.029

Cited by 124 publications

(119 citation statements)

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“…At the transcriptional level, GCM1 was shown to be regulated by a functional cAMP-responsive element and a histone deacetylase 3-binding motif in the promoter region upstream of the start codon. 21,23,24 GCM1 was shown to regulate the expression of different proteins, such as the placental growth factor, 25 a human aromatase, 26 and the fusion protein, Syncytin1. 13 A GCM1-binding motif was also found in the promotor of the human chorionic gonadotropin a-subunit.…”

Section: Discussionmentioning

confidence: 99%

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

et al. 2009

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Mammalian placentation is a highly regulated process and is dependent on the proper development of specific trophoblast cell lineages. The two major types of trophoblast, villous and extravillous, show mitotic arrest during differentiation. In mice, the transcription factor, glial cell missing-1 (Gcm1), blocks mitosis and is required for syncytiotrophoblast formation and morphogenesis of the labyrinth, the murine equivalent of the villous placenta. The human homolog GCM1 has an analogous expression pattern, but its function is presently unknown. We studied GCM1 function in the human-derived BeWo choriocarcinoma cell line and in first trimester human placental villous and extravillous explants. The GCM1 expression was either inhibited by siRNA and antisense oligonucleotides methods or upregulated by forskolin treatment. Inhibition of GCM1 resulted in an increased rate of proliferation, but prevented de novo syncytiotrophoblast formation in syncytially denuded floating villous explants. GCM1 inhibition prevented extravillous differentiation along the invasive pathway in extravillous explants on matrigel. By contrast, forskolin-induced expression of GCM1 reduced the rate of proliferation and increased the rate of syncytialization in the floating villous explant model. Our studies show that GCM1 has a distinct role in the maintenance, development and turnover of the human trophoblast. Alterations in GCM1 expression or regulation may explain several aspects of two divergent severe placental insufficiency syndromes, namely preeclampsia and intrauterine growth restriction, which cause extreme preterm birth. Successful mammalian pregnancy demands two key steps in placental development, both of which are regulated by differentiation of the epithelial trophoblast lineage. 1 First, maternal blood flow to the implantation site must increase exponentially to serve the demands of the rapidly growing fetus. This is achieved through the invasion of extravillous cytotrophoblasts (EV-CTs) from the base of the placenta into the maternal uterine stroma, where they surround and dilate the distal portions of the utero-placental arteries. 2 Second, the increased delivery of maternal blood to the placenta must be matched by an exchanger organ to transfer nutrients, remove waste products and respiratory gases between the mother and the developing fetus. This requirement is achieved through the expansion and differentiation of the chorionic villous trees of the placenta. These villi are covered by a villous trophoblast compartment comprising of villous cytotrophoblasts (V-CTs) beneath a continuous multinucleated layer of syncytiotrophoblast (SCT), which is in direct contact with maternal blood. 3 In the human placenta, EV-CTs of the proximal portion of the anchoring villus cell column are proliferative, but more distal cells differentiate, as they invade and disperse into the uterine stroma. Here these cells surround and replace the smooth muscle cells of maternal uterine arteries, converting them into high-flow dilated sinusoids. The ar...

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Section: Discussionmentioning

confidence: 99%

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

et al. 2009

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“…The crucial role of the placental cAMP/PKA cascade in up-regulated fusogenic gene expression and differentiation-associated hCG production is well established (Keryer et al, 1998;Knerr et al, 2005; A c c e p t e d M a n u s c r i p t 11 also evaluated. Results showed that incubation of BeWo cells with forskolin for 24h in the presence of SB202190 or U0126 significantly attenuated hCG secretion by 40-55% (Fig.6a).…”

Section: Contribution Of Mapk Cascades In Bewo Hormonogenesismentioning

confidence: 99%

“…Indeed, in placental trophoblasts, PKA has been shown to be an important mediator of fusogenic gene expression as well as hCG induction (Keryer et al, 1998;Knerr et al, 2005;Knöfler et al, 1999). In BeWo trophoblasts, the signalling molecules activated in response to adenylyl cyclase activation were investigated.…”

Section: Signalling Pathways Activated By Forskolinmentioning

confidence: 99%

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Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line

Delidaki

Hein

et al. 2011

Molecular and Cellular Endocrinology

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. Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line. Molecular and Cellular Endocrinology, Elsevier, 2010, 332 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 32A c c e p t e d M a n u s c r i p t respectively) the transcription factors old astrocyte specifically-induced substance (OASIS) and glial cells missing a (GCMa) (by 3 and 6 fold, respectively) and the syncytin-2 receptor, major facilitator superfamily domain containing 2 (MFSD2) (by 2 fold). Up-regulation of AKAP79 and AKAP250, (by 2.5 and 4 fold, respectively) was also identified in forskolin-treated BeWo cells. Forskolin effects on all these genes were suppressed by chemical inhibition of p38MAPK whereas only specific genes were sensitive to ERK1/2 inhibition. This data provide novel insights into the signalling molecules and mechanisms regulating fusogenic gene expression by the adenylyl cyclase pathway.

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“…These data suggest that in JEG-3 cells the PMA-induced PKC-and MEK/ ERK-dependent pathway stimulates hCG production but much less so than the FSK-induced cAMPdependent pathway. The cAMP-dependent pathway has been shown to increase the expression level and transcriptional activity of GCMa in trophoblast cells (6,7,27), leading to trophoblast differentiation. In contrast, the PKC-and MEK/ERK-dependent pathway enhances GCMa degradation as well as transcriptional activity.…”

Section: The Pma-induced Pkc-and Mek/erk-dependent Pathway May Enhancmentioning

confidence: 99%

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

et al. 2012

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Glial cells missing Drosophila homolog a (GCMa) is a member of the GCM transcription factor family and plays critical roles in trophoblast differentiation and placental functions. It is well established that the cyclic AMP (cAMP)-dependent pathway induces the expression and transcriptional activity of GCMa by regulating post-translational modifications of GCMa, which results in enhancement of trophoblast differentiation. We previously observed that phorbol 12-myristate 13-acetate (PMA) stimulates phosphorylation of GCMa on serines 328, 378 and 383 through the protein kinase C (PKC)-and mitogen-activated protein kinase kinase (MEK)/extracellular signalregulated kinase (ERK)-dependent pathway, which decreases the protein stability of GCMa. Here we report that PMA increases the ubiquitination level of GCMa, dependent on the phosphorylation of GCMa on serines 328, 378 and 383. We found that this phosphorylation also stimulates the transcriptional activity of GCMa. Our data indicate that the PMA-induced PKC-and MEK/ERKdependent pathway enhances the degradation as well as the transcriptional activity of GCMa. We also examined the impact of this signaling pathway on trophoblasts and the results suggest that the PKC-and MEK/ERK-dependent pathway is involved in the regulation of trophoblast differentiation.

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Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions

Cited by 124 publications

References 40 publications

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

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