Stimulation of GCMa Transcriptional Activity by Cyclic AMP/Protein Kinase A Signaling Is Attributed to CBP-Mediated Acetylation of GCMa

Chang, Ching‐Wen; Chuang, Hsiao-Ching; Yu, Chenchou; Yao, Tso‐Pang; Chen, Hung−Wen

doi:10.1128/mcb.25.19.8401-8414.2005

Cited by 84 publications

(117 citation statements)

References 50 publications

(72 reference statements)

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“…This is in agreement with findings in human trophoblast cells showing that acetylation increases the stability of GCM1 and the binding of GCM1 to the promoter of the syncytin (ERVWE1 -Human Gene Nomenclature Committee) gene, which encodes a placental fusogenic membrane protein (Chang et al, 2005;Chuang et al, 2006).…”

Section: Research Articlesupporting

confidence: 80%

“…The transcriptional activity of Gcm1 is increased by CBP (Crebbp -Mouse Genome Informatics)-dependent acetylation (Chang et al, 2005). Since p45NF-E2 interacts with CBP, which regulates 2241 RESEARCH ARTICLE p45NF-E2 and syncytiotrophoblast formation acetylation in mouse erythroleukemia (MEL) cells (Kiekhaefer et al, 2004), we explored whether p45NF-E2 regulates Gcm1 via acetylation.…”

Section: P45nf-e2 Regulates Acetylation Of Gcm1mentioning

confidence: 99%

“…Previous data established that the transcriptional activity of human GCM1 is enhanced by acetylation of lysine residues (Chang et al, 2005). To determine whether post-translational…”

Section: P45nf-e2 Modulates Syncytiotrophoblast Formation Via Acetylamentioning

confidence: 99%

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p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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SUMMARYAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

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Section: Research Articlesupporting

confidence: 80%

Section: P45nf-e2 Regulates Acetylation Of Gcm1mentioning

confidence: 99%

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p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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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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“…The placental glial cell missing Drosophila homolog a (GCMa) 2 transcription factor regulates expression of syncytin, which is a fusogenic protein mediating cell-cell fusion of mononucleated cytotrophoblasts to form syncytiotrophoblasts (1).…”

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confidence: 99%

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

Chou

Chang

Liu

et al. 2007

Journal of Biological Chemistry

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Glial cell missing Drosophila homolog a (GCMa) is an essential transcription factor for placental development, which controls the differentiation of the syncytiotrophoblast layer. Although the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery, specifically interacts with the N-terminal domain of GCMa and promotes GCMa sumoylation on lysine 156. Moreover, GCMa-mediated transcriptional activation was repressed by sumoylation but was enhanced in the presence of the SUMO-specific protease, SENP1. The repressive effect of sumoylation on GCMa transcriptional activity was attributed to decreased DNA binding activity of GCMa. Furthermore, structural analysis revealed a steric clash between the SUMO1 moiety of sumoylated GCMa and the DNA-binding surfaces of GCMa, which may destabilize the interaction between GCMa and its cognate DNA sequence. Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation.

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Stimulation of GCMa Transcriptional Activity by Cyclic AMP/Protein Kinase A Signaling Is Attributed to CBP-Mediated Acetylation of GCMa

Cited by 84 publications

References 50 publications

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

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

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

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