EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease

Zeng, Xue; Hunt, A. C.; Jin, Sheng Chih; Durán, Daniel; Gaillard, Jonathan; Kahle, Kristopher T.

doi:10.1016/j.molmed.2019.01.009

Cited by 44 publications

(28 citation statements)

References 83 publications

(127 reference statements)

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“…RASA1 activates the intrinsic GTPase activity of Ras to promote the hydrolysis of Ras GTP to Ras GDP. RASA1 binds to activated Ras (Ras GTP) via the GTPase activating protein (GAP)-related catalytic domain to block the Ras signaling and inhibit the Ras-MAPK pathway, thereby inhibiting the proliferation but promoting the apoptosis of cells (Zeng 2019 ; Chen et al 2019 ). Hence, we hypothesized that MEG3 activates the Ras-MAPK pathway by negatively regulating the protein levels of RASA1.…”

Section: Discussionmentioning

confidence: 99%

The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion

Zhang

Liu

Gao

2021

Mol Med

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Background Maternally Expressed Gene 3 (MEG3) is expressed at low levels in placental villi during preeclampsia; however, its roles in unexplained recurrent spontaneous abortion (URSA) remain unclear. In this study, we aimed to explore the relationship between MEG3 and URSA. Methods The differentially expressed lncRNAs (MEG3) and its downstream genes (RASA1) were identified using bioinformatics analysis of Genomic Spatial Event (GSE) database. The expression levels of MEG3 in embryonic villis (with gestational ages of 49–63 days) and primary trophoblasts were determined using quantitative RT-PCR assay. A mouse model of Embryo implantation, Cell Counting Kit-8 (CCK-8), flow cytometry, and Transwell migration assays were performed to determine the implantation, proliferative, apoptotic, and invasive capacities of trophoblast. The level of phosphorylated core proteins in the RAS-MAPK pathway were analyzed using Western blot assay. The mechanisms of MEG3 in the regulation of RASA1 were studied by RNA pulldown, RNA immunoprecipitation (RIP), DNA pulldown, and chromatin immunoprecipitation (ChIP) assays. Results MEG3 had a low expression level in embryonic villis of 102 URSA patients compared with those of 102 normal pregnant women. MEG3 could promote proliferation and invasion, inhibit the apoptosis of primary trophoblast of URSA patients (PT-U cells), as well as promote embryo implantation of mouse. Besides, MEG3 also promoted the phosphorylation of rapidly accelerated fibrosarcoma (Raf), mitogen-activated protein kinase kinase (MEK), and extracellular-signal-regulated kinase (ERK) proteins. The results of RNA pull down and RIP assays showed that MEG3 bound with the enhancer of zeste homolog 2 (EZH2). The DNA pulldown assay revealed that MEG3 could bind to the promoter sequence of the RAS P21 Protein Activator 1 (RASA1) gene. Further, the ChIP assay showed that MEG3 promoted the binding of EZH2 to the promoter region of the RASA1 gene. Conclusions The inactivation of MEG3 in embryonic villi association with URSA; MEG3 inhibited the expression of RASA1 by mediating the histone methylation of the promoter of RASA1 gene by EZH2, thereby activating the RAS-MAPK pathway and enhancing the proliferative and invasive capacities of trophoblasts.

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Section: Discussionmentioning

confidence: 99%

The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion

Zhang

Liu

Gao

2021

Mol Med

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“…Arginine vasopressin receptor 1A (AVPR1A) acts as receptor for arginine vasopressin, which belongs to the subfamily of G-protein coupled receptors [23]. EPH Receptor B4 (EPHB4) mediate numerous developmental processes, particularly in the nervous system [24]. ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 1 (ST3GAL1) is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates [25].…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Related to 68Ga-DOTATATE Organ Distribution in Homo Sapiens

Huang

2021

Preprint

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Purpose 68Ga-DOTATATE is a somatostatin analogue that has been used for imaging neuroendocrine tumours. However, there is nonspecific uptake in some organs, and the reasons for that are not clear. The aim of the study is to outline the dynamic distribution pattern of 68Ga-DOTATATE in human body, and identify the genes responsible for 68Ga-DOTATATE uptake by bioinformatics analysis.Methods 68Ga-DOTATATE PET/CT was performed in 32 patients, and dynamic total-body PET scanning was performed with uEXPLORER. The gene expression datasets of human organs were downloaded from the Human Protein Atlas. WGCNA analysis was performed to screen the potential genes related to 68Ga-DOTATATE. BindingDB, SEA and SwissTargetPrediction databases were used to predict the potential binding proteins of DOTATATE based on molecular structure. Results Dynamic total-body PET scanning showed that 68Ga-DOTATATE uptake was not consistent with expression of SSTR2 in human organs. WGCNA analysis revealed 800 genes whose expression level was positively correlated to 68Ga-DOTATATE uptake. According to the molecular structure of DOTATATE, 135 proteins with potential binding ability to DOTATATE were screened by analysis based on drug database. Based on the results of the above two parts, 8 proteins were finally obtained, respectively AVPR1A, EPHA8, EPHB4, OPRL1, SSTR2, SSTR5, ST3GAL1 and NPY1R, which had potential binding possibility with DOTATATE, and their expression was positively correlated with 68Ga-DOTATATE uptake.Conclusion WGCNA analysis was combined with the drug database to obtain new potential binding targets of DOTATATE. The bioinformatics approach developed in this study could potentially be used to discover new potential binding targets for molecular imaging agents.

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“…1,2 Although its pathogenesis is currently unknown, SCFN has been associated to maternal or birth complications, such as perinatal asphyxia, meconium aspiration, hypoxaemia, therapeutic hypothermia, obstetric trauma, preeclampsia and maternal diabetes. 2,3 SCFN is a classical disease of full-term infants; however, atypical cases in premature newborns have been described. Usually develops in the first 6 weeks of life presenting with erythematous to violaceous, indurated nodules or plaques on the cheeks, buttocks, posterior trunk or proximal extremities.…”

Section: Newborn With Purplish Skin Induration Of the Back Answermentioning

confidence: 99%

“…Post‐mortem examination confirmed these findings. Karyotyping and molecular genetic testing for HRAS and RASA1 mutations were negative. Brain AVM is a rare malformation (0.1%) .…”

Section: Answermentioning

confidence: 99%

A refugee newborn with heart failure and initial hydrops: Diagnostic clues of spectral Doppler examinations

2020

J Paediatrics Child Health

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EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease

Cited by 44 publications

References 83 publications

The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion

The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion

Identification of Genes Related to 68Ga-DOTATATE Organ Distribution in Homo Sapiens

A refugee newborn with heart failure and initial hydrops: Diagnostic clues of spectral Doppler examinations

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