A GCM Motif Protein Is Involved in Placenta-specific Expression of Human Aromatase Gene

Yamada, Kazuyo; Ogawa, Hidenori; Honda, Shin‐ichiro; Harada, Nobuhiro; Okazaki, Tuneko

doi:10.1074/jbc.274.45.32279

Cited by 63 publications

(53 citation statements)

References 45 publications

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“…13 A GCM1-binding motif was also found in the promotor of the human chorionic gonadotropin a-subunit. 26 These findings support a complex and important role for GCM1 in placental maintenance and differentiation. GCM1 is differentially expressed in cytotrophoblasts destined for syncytial fusion in both mice 27 and humans.…”

Section: Discussionsupporting

confidence: 54%

“…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%

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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: Discussionsupporting

confidence: 54%

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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“…One of the native targets for Drosophila Gcm is the repo gene, which contains eleven Gcm-binding sites in its upstream region (Akiyama et al, 1996). Gcm-binding sites were also found in trophoblast-specific element 2 (TSE2), which is a ciselement that functions as a placenta-specific enhancer of the human aromatase gene (Yamada et al, 1999). In the present study, we demonstrated that ectopic expression of mouse Gcm1 in mouse fibroblasts led to the induction of the gene encoding the astrocyte-specific Ca 2+ -binding protein, S100β.…”

Section: Figmentioning

confidence: 99%

The potential to induce glial differentiation is conserved betweenDrosophilaand mammalian glial cells missing genes

et al. 2003

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“…Abnormal development of placenta causes embryonic death in GCMa knockout mice (33). GCMa is also related to the control of placental functions by regulating gene expressions of aromatase, syncytin, and placental growth factor (8,37,40). Thus GCMa is essential for normal placental development and functions, and abnormalities in GCMa expression may be associated with pregnancy complications in humans, as decreased levels of GCMa expression have been reported in pre-eclampsia cases (4,9).…”

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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A GCM Motif Protein Is Involved in Placenta-specific Expression of Human Aromatase Gene

Cited by 63 publications

References 45 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

The potential to induce glial differentiation is conserved betweenDrosophilaand mammalian glial cells missing genes

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

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