DREAM Mediated Regulation of GCM1 in the Human Placental Trophoblast

Baczyk, Dora; Kibschull, Mark; Mellström, Britt; Levytska, Khrystyna; Rivas, Marcos; Drewlo, Sascha; Lye, Stephen J.; Naranjo, José R.; Kingdom, John

doi:10.1371/journal.pone.0051837

Cited by 25 publications

(19 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although a key assumption in studying mRNA expression is that it is informative in the prediction of protein expression, an important limitation of our study was that only DREAM mRNA levels were measured. Nevertheless, some authors have demonstrated that DREAM mRNA and protein levels were correlated in different tissues in human and rats [ 11 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter

Shinzato¹,

Lerário²,

Lin³

et al. 2015

Med Sci Monit Basic Res

View full text Add to dashboard Cite

BackgroundDREAM (Downstream Regulatory Element Antagonistic Modulator) is a neuronal calcium sensor that was suggested to modulate TSH receptor activity and whose overexpression provokes an enlargement of the thyroid gland in transgenic mice. The aim of this study was to investigate somatic mutations and DREAM gene expression in human multinodular goiter (MNG).Material/MethodsDNA and RNA samples were obtained from hyperplastic thyroid glands of 60 patients (54 females) with benign MNG. DREAM mutations were evaluated by PCR and direct automatic sequencing, whereas relative quantification of mRNA was performed by real-time PCR. Over- and under-expression were defined as a 2-fold increase and decrease in comparison to normal thyroid tissue, respectively. RQ M (relative quantification mean); SD (standard deviation).ResultsDREAM expression was detected in all nodules evaluated. DREAM mRNA was overexpressed in 31.7% of MNG (RQ M=6.26; SD=5.08), whereas 53.3% and 15% had either normal (RQ M=1.16; SD=0.46) or underexpression (RQ M=0.30; SD=0.10), respectively. Regarding DREAM mutations analysis, only previously described intronic polymorphisms were observed.ConclusionsWe report DREAM gene expression in the hyperplastic thyroid gland of MNG patients. However, DREAM expression did not vary significantly, and was somewhat underexpressed in most patients, suggesting that DREAM upregulation does not significantly affect nodular development in human goiter.

show abstract

Section: Discussionmentioning

confidence: 99%

Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter

Shinzato¹,

Lerário²,

Lin³

et al. 2015

Med Sci Monit Basic Res

View full text Add to dashboard Cite

show abstract

“…There was no such association between the maternal genotype and the risk of preeclampsia, however. This was presumably related to the selective expression of GCM1 in the placenta being where the modulation of risk emerges [56] and the fact that most of the placenta is of fetal origin [6]. The same group who found the fetal GCM1 association had previously found an association between the risk of maternal preeclampsia and a fetal SNP in the transforming growth factor (TGF)-b3 (TGFB3) gene in the same group of women [57].…”

Section: Human Studiesmentioning

confidence: 99%

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

Petry

Beardsall

2014

Journal of Hypertension

View full text Add to dashboard Cite

The heritability of pregnancy-induced hypertension (encompassing both gestational hypertension and preeclampsia) is around 0.47, suggesting that there is a genetic component to its development. However, the maternal genetic risk variants discovered so far only account for a small proportion of the heritability. Other genetic variants that may affect maternal blood pressure in pregnancy arise from the fetal genome, for example wild-type pregnant mice carrying offspring with Cdkn1c or Stox1 disrupted develop hypertension and proteinuria. In humans, there is a higher risk for preeclampsia in women carrying fetuses with Beckwith-Wiedemann syndrome (including those fetuses with CDKN1C mutations) and a lower risk for women carrying babies with trisomy 21. Other risk may be associated with imprinted fetal growth genes and genes that are highly expressed in the placenta such as GCM1. This article reviews the current state of knowledge linking the fetal genotype with maternal blood pressure in pregnancy.

show abstract

“…SUMOylation has been implicated in the alteration of placental transcription factors regulating trophoblast differentiation including glial cell missing-1 (GCM1) (Chou et al 2007), downstream regulatory element antagonist modulator (DREAM; also referred to as KChIP-3 or calsenilin) (Palczewska et al 2011), p53 (Chiu et al 2008) and hypoxia inducible factor-1α (HIF-1α) (Bhattacharjee et al 2016) by affecting protein stability, activity and intracellular localization. These transcription factors are of particular interest as they have also been shown to be involved in pre-eclampsia disease progression (Chen et al 2004;Baczyk et al 2013b;Sharp et al 2014). Furthermore, we have recently demonstrated that pre-eclamptic placentas exhibit hyperSUMOylation (Baczyk et al 2013a(Baczyk et al , 2017, further suggesting that the dynamic regulation of SUMOs is critically linked to placental function.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal distribution of small ubiquitin‐like modifiers during human placental development and in response to oxidative and inflammatory stress

Baczyk

Audette

Coyaud

et al. 2018

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points The post‐translational modification of target proteins by SUMOylation occurs in response to stressful stimuli in a variety of organ systems.Small ubiquitin‐like modifier (SUMO) isoforms 1–4 have recently been identified in the human placenta, and are upregulated in the major obstetrical complication of pre‐eclampsia.This is the first study to characterize the spatiotemporal distribution of SUMO isoforms and their targets during placental development across gestation and in response to stress induced by pre‐eclampsia and chorioamnionitis.Keratins were identified as major targets of placental SUMOylation. The interaction with SUMOs and cytoskeletal filaments provides evidence for SUMOylation possibly contributing to underlying dysfunctional trophoblast turnover, which is a hallmark feature of pre‐eclampsia.Further understanding the role of individual SUMO isoforms and SUMOylation underlying placental dysfunction may provide a target for a novel therapeutic candidate as an approach for treating pre‐eclampsia complicated with placental pathology. AbstractSUMOylation is a dynamic, reversible post‐translational modification that regulates cellular protein stability and localization. SUMOylation occurs in response to various stressors, including hypoxia and inflammation, features common in the obstetrical condition of pre‐eclampsia. SUMO isoforms 1–4 have recently been identified in the human placenta, but less is known about their role in response to pre‐eclamptic stress. We hypothesized that SUMOylation components have a unique spatiotemporal distribution during placental development and that their subcellular localization can be further modulated by extra‐cellular stressors. Placental SUMO expression was examined across gestation. First‐trimester human placental explants and JAR cells were subjected to hypoxia or TNF‐α cytokine, and subcellular translocation of SUMOs was monitored. SUMOylation target proteins were elucidated using mass spectrometry and proximity ligation assay. Placental SUMO‐1 and SUMO‐4 were restricted to villous cytotrophoblast cells in first trimester and syncytium by term, while SUMO‐2/3 staining was evenly distributed throughout the trophoblast across gestation. In placental villous explants, oxidative stress induced hyperSUMOylation of SUMO‐1 and SUMO‐4 in the syncytial cytoplasm, whereas SUMO‐2/3 nuclear expression increased. Oxidative stress also upregulated cytoplasmic SUMO‐1 and SUMO‐4 protein expression (P < 0.05), similar to pre‐eclamptic placentas. Keratins were identified as major targets of placental SUMOylation. Oxidative stress increased the cytokeratin‐7 to SUMO‐1 and SUMO‐4 interactions, while inflammatory stress increased its interaction with SUMO‐2/3. Overall, SUMOs display a unique spatiotemporal distribution in normal human placental development. Our data indicate SUMOylation in pre‐eclampsia, which may impair the stability of cytoskeleton filaments and thus promote trophoblast shedding into the maternal circulation in this condition.

show abstract

DREAM Mediated Regulation of GCM1 in the Human Placental Trophoblast

Cited by 25 publications

References 41 publications

Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter

Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

Spatiotemporal distribution of small ubiquitin‐like modifiers during human placental development and in response to oxidative and inflammatory stress

Contact Info

Product

Resources

About