CD9 regulates transcription factor GCM1 and ERVWE1 expression through the cAMP/protein kinase A signaling pathway

Muroi, Yoshikage; Sakurai, ﻿Toshihiro; Hanashi, Akira; Kubota, Kentaro; Nagaoka, Kentaro; Imakawa, Kazuhiko

doi:10.1530/rep-09-0082

Cited by 28 publications

(13 citation statements)

References 33 publications

(35 reference statements)

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“…Cyclic AMP treatment has long been known to promote fusion of both primary human cytotrophoblasts [30] and BeWo cells [24], [25], and to upregulate several proteins involved in fusion, including syncytin-1 [31], syncytin-2 [32], MFSD2A [33] and CD9 [34]. In the present study, treatment of BeWo cells with the cell-permeable cAMP analogue dbcAMP led to an upregulation of RhoE, concomitant with an increase in cell fusion.…”

Section: Discussionsupporting

confidence: 50%

RhoE Is Regulated by Cyclic AMP and Promotes Fusion of Human BeWo Choriocarcinoma Cells

et al. 2012

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Fusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. In this study we examined the role of the Rho GTPase family member RhoE in trophoblast differentiation and fusion using the BeWo choriocarcinoma cell line, a model of villous cytotrophoblast fusion. Treatment of BeWo cells with the cell permeable cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP) resulted in a strong upregulation of RhoE at 24h, coinciding with the onset of fusion. Using the protein kinase A (PKA)-specific cAMP analogue N6-phenyl-cAMP, and a specific inhibitor of PKA (14–22 amide, PKI), we found that upregulation of RhoE by cAMP was mediated through activation of PKA signalling. Silencing of RhoE expression by RNA interference resulted in a significant decrease in dbcAMP-induced fusion. However, expression of differentiation markers human chorionic gonadotrophin and placental alkaline phosphatase was unaffected by RhoE silencing. Finally, we found that RhoE upregulation by dbcAMP was significantly reduced under hypoxic conditions in which cell fusion is impaired. These results show that induction of RhoE by cAMP is mediated through PKA and promotes BeWo cell fusion but has no effect on functional differentiation, supporting evidence that these two processes may be controlled by separate or diverging pathways.

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Section: Discussionsupporting

confidence: 50%

RhoE Is Regulated by Cyclic AMP and Promotes Fusion of Human BeWo Choriocarcinoma Cells

et al. 2012

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“…Splicing efficiency has not been studied at all in cancer-specific aberrant expression of other HERV families. Third, the trophoblastic expression of ERVWE1 is controlled from a juxtaposed trophoblast-specific enhancer localized in MaLR LTR [9] and requires stimulation by certain tissue-specific transcription factors, such as GCM1 [10, 39], whose activity could be studied in germ line tumors. In neither type of tumors described in this study, we observed GCM1 expression comparable with placenta or BeWo cells, which points to the critical importance of promoter demethylation as a prerequisite for ERVWE1 transcriptional de-repression.…”

Section: Discussionmentioning

confidence: 99%

“…[39]) and inducible expression of HERV-K rec gene in mice led to a disturbance of germ cell development reminiscent of early seminoma [40]. Genome-wide comparison of HERV expression in testicular cancer and normal testicular tissue has been done using copy-specific microarray and several HERV copies of families E, H, K, and W were found to be differentially expressed in testicular tumors.…”

Section: Discussionmentioning

confidence: 99%

DNA hypomethylation and aberrant expression of the human endogenous retrovirus ERVWE1/syncytin-1 in seminomas

et al. 2017

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Background Syncytin-1 and 2, human fusogenic glycoproteins encoded by the env genes of the endogenous retroviral loci ERVWE1 and ERVFRDE1, respectively, contribute to the differentiation of multinucleated syncytiotrophoblast in chorionic villi. In non-trophoblastic cells, however, the expression of syncytins has to be suppressed to avoid potential pathogenic effects. Previously, we have shown that the transcriptional suppression of ERVWE1 promoter is controlled epigenetically by DNA methylation and chromatin modifications. In this study, we describe the aberrant expression of syncytin-1 in biopsies of testicular germ cell tumors.ResultsWe found efficient expression and splicing of syncytin-1 in seminomas and mixed germ cell tumors with seminoma component. Although another fusogenic gene, syncytin-2 was also derepressed in seminomas, its expression was significantly lower than that of syncytin-1. Neither the transcription factor GCM1 nor the increased copy number of ERVWE1 were sufficient for this aberrant expression of syncytin-1 in seminomas. In accordance with our recent finding of the highly increased expression of TET1 dioxygenase in most seminomas, the ERVWE1 promoter was significantly hypomethylated in comparison with the matched controls. In contrast, 5-hydroxymethylcytosine levels were not detectable at the ERVWE1 promoter. We further describe that another endogenous retroviral element adjacent to ERVWE1 remains transcriptionally suppressed and two additional HERV-W family members are only slightly upregulated in seminomas.ConclusionsWe conclude that DNA demethylation of the ERVWE1 promoter in seminomas is a prerequisite for syncytin-1 derepression. We propose the spliced syncytin-1 expression as a marker of seminoma and suggest that aberrant expression of endogenous retroviruses might be a correlate of the hypomethylated genome of seminomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0342-9) contains supplementary material, which is available to authorized users.

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“…A multispanning membrane protein, CD9, was identified as a regulator for GCM1 gene (Muroi et al . ). This protein is involved in the invasive regulation of cancer cells, and in cell fusion between sperm and egg as well as myoblasts (Tachibana & Hemler ; Le Naour et al .…”

Section: Placenta Ervsmentioning

confidence: 97%

“…CD9 is another upstream factor controlling GCM1 and syncytin genes (Muroi et al . ). Just as in humans, GCM1 controls the expression of mouse syncytin A and syncytin B genes (Schubert et al .…”

Section: Hypothesis Of Gene Evolution Through Baton Passmentioning

confidence: 97%

Baton pass hypothesis: successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution

2015

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It is well accepted that numerous RNAs derived from endogenous retroviruses (ERVs) are expressed in mammalian reproductive structures, particularly in the uterus, trophoblast, and placenta. Syncytin 1 and syncytin 2 in humans and syncytin A and syncytin B in mice are membrane proteins originating from Env genes of ERVs. These ERVs are involved in the fusion of trophoblast cells, resulting in multinucleated syncytiotrophoblast formation. Evidence accumulated indicates that syncytin-like fusogenic proteins are expressed in the placenta of rabbits, dogs/cats, ruminant ungulates, tenrecs, and opossums. The syncytin genes so far characterized are known to be endogenized to the host genome only within the past 12-80 million years, more recently than the appearance of mammalian placentas, estimated to be 160-180 million years ago. We speculate that ERVs including syncytin-like gene variants integrated into mammalian genomes in a locus-specific manner have replaced the genes previously responsible for cell fusion. We therefore propose the 'baton pass' hypothesis, in which multiple successive ERV variants 'take over' cell-fusion roles, resulting in increased trophoblast cell fusion, morphological variations in placental structures, and enhanced reproductive success in placental mammals.

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CD9 regulates transcription factor GCM1 and ERVWE1 expression through the cAMP/protein kinase A signaling pathway

Cited by 28 publications

References 33 publications

RhoE Is Regulated by Cyclic AMP and Promotes Fusion of Human BeWo Choriocarcinoma Cells

RhoE Is Regulated by Cyclic AMP and Promotes Fusion of Human BeWo Choriocarcinoma Cells

DNA hypomethylation and aberrant expression of the human endogenous retrovirus ERVWE1/syncytin-1 in seminomas

Baton pass hypothesis: successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution

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