Guanine Nucleotide-Binding Protein Gαi2: A New Partner of Claudin-5 that Regulates Tight Junction Integrity in Human Brain Endothelial Cells

Luissint, Anny‐Claude; Federici, Christian; Guilhot, François; Chrétien, Fabrice; Camoin, Luc; Glacial, Fabienne; Ganeshamoorthy, Kayathiri; Couraud, Pierre‐Olivier

doi:10.1038/jcbfm.2011.202

Cited by 62 publications

(69 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…25 In vitro BTB model was established successfully so as to clarify the function and molecular mechanism of miR-181a in BTB. We found that the expression of miR-181a in GECs was upregulated compared with that in ECs, which suggested that miR-181a might involve in the regulation of BTB function.…”

Section: Discussionmentioning

confidence: 99%

MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

Yao

Wang

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that impairs the delivery of therapeutic drugs. However, the methods and molecular mechanisms underlying the BTB opening remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of various biologic processes and therapeutic targets. In this study, we have identified microRNA-181a (miR-181a) as a critical miRNA in opening BTB. MicroRNA-181a expression was upregulated in glioma endothelial cells (GECs), which were obtained by coculturing endothelial cells (ECs) with glioma cells. Overexpression of miR-181a resulted in an impaired and permeability increased BTB, and meanwhile reduced the expression of zonula occluden (ZO)-1, occludin, and claudin-5. Kruppel-like factor 6 (KLF6), a transcription factor of the zinc-finger family, was downregulated in GECs. Mechanistic investigations defined it as a direct and functional downstream target of miR-181a, which was involved in the regulation of BTB permeability and the expression of ZO-1, occludin, and claudin-5. Furthermore, luciferase assays and chromatin immunoprecipitation assays showed that KLF6 upregulated the promoter activities and interacted with the promoters of ZO-1, occludin, and claudin-5 in GECs. Collectively, we showed the possibility that overexpression of miR-181a contributes to the increased permeability of BTB by targeting KLF6, thereby revealing potential therapeutic targets for the treatment of brain gliomas.

show abstract

Section: Discussionmentioning

confidence: 99%

MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

Yao

Wang

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…6 Along the same line, here we intended to assess the putative contribution of the Par/aPKC PCP complex to this process.…”

Section: Resultsmentioning

confidence: 99%

“…6 Results are expressed as permeability coefficients (Pe) in 10 À 3 cm per minute or as the percentage of control permeability (corresponding to either untreated cells or control-conditioned medium or control siRNA-treated cells, as indicated).…”

Section: Permeability Assaysmentioning

confidence: 99%

“…Proteins of the whole-cell lysate were heated at 951C for 5 minutes and processed for immunoblotting as previously described. 6 xCELLigence Assays…”

Section: Image Analysismentioning

confidence: 99%

“…5 In addition, cytosolic proteins, such as the ZO family (ZO À 1, À 2, À 3) directly bind the intracellular domains of these transmembrane proteins and act as molecular links to the cytoskeleton and signal transducers. We recently identified Gai2 as a new cldn-5 partner that regulates TJ integrity in the hCMEC/D3 human brain endothelial cell line, an extensively used in vitro model of the human BBB, 6 initially produced and characterized by us. 7,8 Development and maintenance of the BBB needs a dynamic dialog between endothelial and perivascular cells of the so-called neurovascular unit: indeed, neural precursor cells were shown to secrete factors that have a central role in BBB formation and integrity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Artus

Glacial

Ganeshamoorthy

et al. 2013

J Cereb Blood Flow Metab

Self Cite

View full text Add to dashboard Cite

Wnt morphogens released by neural precursor cells were recently reported to control blood-brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/b-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct b-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical b-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/b-catenin canonical pathway, is a key regulator of the BBB.

show abstract

Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

Liu

Fang-shu

et al. 2019

FEBS Letters

View full text Add to dashboard Cite

Cerebral malaria (CM) is a severe complication with brain vascular hyperpermeability. Claudin‐5 is the major component of tight junctions. To investigate the expression of claudin‐5 in CM, we established a murine experimental cerebral malaria (ECM) model and an in vitro model by treating murine brain endothelial cells (bEnd3) with plasma from ECM mice. Expression of claudin‐5 and the ETS transcription factor Erg was reduced in the brain endothelium of ECM mice. In bEnd3 cells exposed to ECM plasma, decreased expression of claudin‐5 and Erg, and increased permeability were observed. Silencing of Erg significantly reduced Cldn5 expression. ChIP assays indicated that Erg binds to the −813 ETS motif of the murine Cldn5 gene promoter, and the binding is decreased by treatment with ECM plasma.

show abstract

Guanine Nucleotide-Binding Protein Gαi2: A New Partner of Claudin-5 that Regulates Tight Junction Integrity in Human Brain Endothelial Cells

Cited by 62 publications

References 44 publications

MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

Contact Info

Product

Resources

About