Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation

Lin, Fang-Yu; Chang, Ching‐Wen; Cheong, Mei‐Leng; Chen, Hsei-Chorn; Lee, Der-Yen; Chang, Geen-Dong; Chen, Hung−Wen

doi:10.1093/nar/gkq838

Cited by 28 publications

(26 citation statements)

References 32 publications

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“…In brief, cells were treated with the indicated concentrations of hCG, followed by coimmunoprecipitation with different combinations of p-Ser269275-GCM1, Ac-K, HA, and GCM1 Abs. The p-Ser269275-GCM1 Ab raised in guinea pigs was described previously (23). In a separate experiment, BeWo31 cells were transfected with p(GBS) 4 E1bLuc in the presence or absence of hCG to study the effect of hCG on GCM1 transcriptional activity.…”

Section: Methodsmentioning

confidence: 99%

“…Activation of cAMP signaling by the cAMP stimulant forskolin (FSK) stimulates GCM1 activity as well the expression of its target genes (21,22). At the molecular level, cAMP activates PKA to phosphorylate Ser269 and Ser275 on GCM1, which recruits dual-specificity phosphatase 23 to dephosphorylate Ser322 (22,23). Dephosphorylation of Ser322 prevents FBW2-mediated GCM1 ubiquitination and facilitates interactions between GCM1 and the CBP coactivator, resulting in GCM1 acetylation and stabilization by CBP (24,25).…”

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confidence: 99%

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A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

Cheong

Wang

Chuang

et al. 2016

Molecular and Cellular Biology

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e Human chorionic gonadotropin (hCG) is composed of a common ␣ subunit and a placenta-specific ␤ subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCG␤ expression, it remains unclear how cAMP stimulates placenta-specific hCG␤ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCG␤ paralogues by chromatin immunoprecipitation-on-chip (ChIPchip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCG␤ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCG␤ promoter and GCM1 but not TFAP2C. Indeed, the hCGcAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCG␤ expression and cell differentiation. Successful pregnancy requires a variety of hormones, growth factors, and cytokines to regulate uterine decidualization, embryo implantation, and pregnancy maintenance. For instance, progesterone and estrogen steroid hormones from the ovary prepare the uterine endometrium for embryo implantation. Human chorionic gonadotropin (hCG) is a critical hormone for pregnancy maintenance in humans. hCG is a glycoprotein hormone comprising ␣ and ␤ subunits. The hCG␣ subunit is shared with other glycoprotein hormones, including thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone (LH), whereas the hCG␤ subunit is specifically expressed in placenta and is unique to hCG. While hCG␣ is encoded by a single gene on chromosome 6, hCG␤ can be encoded by a gene cluster of six (hCG␤1, -2, -3, -5, -7, and -8) paralogues on chromosome 19 (1). Recent studies have suggested that the expression of hCG␤5 and -8 may account for the majority of hCG␤ transcripts given that all hCG␤ paralogues share high sequence homology in their promoter regions (2, 3).hCG expression can be detected in early 6-to 8-cell embryos, and this may serve as an embryonic signal for the rendering of appropriate maternal physiology for pregnancy (1). After implantation, the serum hCG level increases dramatically as pregnancy proceeds, reaching its peak at 9 or 10 weeks of gestation, and then decreases and remains at ϳ20% of the peak value until term (4). One of the crucial hCG functions is to stimulate progesterone synthesis from the corpus luteu...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

Cheong

Wang

Chuang

et al. 2016

Molecular and Cellular Biology

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“…The cells were transfected with 0.5 μg of GCMa expression plasmid using 1 μL of FugeneHD as indicated above. After 24 h, the medium was changed into FCS-free and 275 enhances the interaction between GCMa and dual-specificity phosphatase 23 that dephosphorylates phosphorylated serine 322 (28). Thus posttranslational modifications regulate functions of GCMa in diverse steps.…”

Section: Introductionmentioning

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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“…This may underscore decreased GCM1 and PGF expression in the hypoxic preeclamptic placentas. In contrast, cyclic AMP (cAMP) signaling stimulates GCM1 gene transcription (19) and enhances GCM1 stability by facilitating dualspecificity phosphatase 23-mediated Ser322 dephosphorylation and CREB-binding protein-mediated GCM1 acetylation, providing the underpinnings of the long-known stimulation of trophoblastic fusion by cAMP (8,23).In addition to their critical roles in syncytiotrophoblast differentiation, expression of GCM1 and syncytin-1 in EVTs has been reported (3,25,29). These observations raise questions about the functional role of GCM1 in EVT differentiation and why cell-cell fusion of EVTs is not observed at the maternal-fetal interface.…”

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confidence: 99%

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High-Temperature Requirement Protein A4 (HtrA4) Suppresses the Fusogenic Activity of Syncytin-1 and Promotes Trophoblast Invasion

Wang

Cheong

Lee

et al. 2012

Molecular and Cellular Biology

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dCell-cell fusion and cell invasion are essential for placental development. Human cytotrophoblasts in the chorionic villi may undergo cell-cell fusion to form syncytiotrophoblasts to facilitate nutrient-gas exchange or differentiate into extravillous trophoblasts (EVTs) to facilitate maternal-fetal circulation. The placental transcription factor glial cells missing 1 (GCM1) regulates syncytin-1 and -2 expression to mediate trophoblast fusion. Interestingly, GCM1 and syncytin-1 are also expressed in EVTs with unknown physiological functions. In this study, we performed chromatin immunoprecipitation-on-chip (ChIP-chip) analysis and identified the gene for high-temperature requirement protein A4 (HtrA4) as a GCM1 target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface, and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion. We further demonstrate that HtrA4 interacts with syncytin-1 and suppresses cell-cell fusion. Therefore, HtrA4 may be crucial for EVT differentiation by playing a dual role in prevention of cellcell fusion of EVTs and promotion of their invasion into the uterus. Our study reveals a novel function of GCM1 and HtrA4 in regulation of trophoblast invasion and that abnormal HrtA4 expression may contribute to shallow trophoblast invasion in preeclampsia.H uman placentation proceeds fast after embryo implantation, and different classes of specialized trophoblast cells have evolved to establish blood circulation for nutrient, gas, and waste exchange between mother and fetus. In brief, the mononuclear cytotrophoblasts in chorionic villi proliferate and differentiate through cell-cell fusion into a multinucleated syncytiotrophoblast layer, which is in direct contact with maternal blood to mediate the above-mentioned exchanges and produce hormones and growth factors for pregnancy maintenance. On the other hand, cytotrophoblasts in the chorionic villi that are anchored to uterine decidua proliferate into cell columns from which some cytotrophoblasts migrate and invade deeper layers of decidua. The migratory and invasive cytotrophoblasts, termed interstitial extravillous trophoblasts (EVTs), may further invade the uterine myometrium and replace the endothelial cells of spiral arteries. This phenomenon, called spiral artery remodeling, is essential for sufficient blood flow into intervillous spaces of the placenta, as remodeled arteries become dilated and nonvasoactive. Indeed, insufficient spiral artery remodeling due to shallow trophoblast invasion may result in placental hypoxia and pregnancy complications such as preeclampsia and intrauterine growth retardation with clinical features of gestational hypertension, proteinuria, and failure of optimal fetal growth (6).Glial cells missing 1 (GCM1), also known as GCMa, is a transcription factor critical for placental developmen...

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Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation

Cited by 28 publications

References 32 publications

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

High-Temperature Requirement Protein A4 (HtrA4) Suppresses the Fusogenic Activity of Syncytin-1 and Promotes Trophoblast Invasion

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