The Junctional Proteins Cingulin and Paracingulin Modulate the Expression of Tight Junction Protein Genes through GATA-4

Guillemot, Laurent; Spadaro, Domenica; Citi, Sandra

doi:10.1371/journal.pone.0055873

Cited by 24 publications

(23 citation statements)

References 45 publications

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“…This is consistent with the observation that depletion of CGN, CGNL1, or both has no detectable effect on the organization of cadherin-based junctions (Guillemot et al. , 2008, 2013; Pulimeno et al. , 2011).…”

Section: Resultsmentioning

confidence: 99%

MgcRacGAP interacts with cingulin and paracingulin to regulate Rac1 activation and development of the tight junction barrier during epithelial junction assembly

Guillemot

Guerrera

Spadaro

et al. 2014

MBoC

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Section: Resultsmentioning

confidence: 99%

MgcRacGAP interacts with cingulin and paracingulin to regulate Rac1 activation and development of the tight junction barrier during epithelial junction assembly

Guillemot

Guerrera

Spadaro

et al. 2014

MBoC

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“…Cingulin was previously shown to regulate the expression of claudin-2 in renal epithelial cells through RhoA-and GATA-4-dependent mechanisms. 14,34 However, in CGN −/− mice, in vivo, claudin-5 was unchanged, indicating additional regulatory components. Importantly, the presence or absence of cingulin in vitro and in vivo alters endothelial permeability.…”

Section: Discussionmentioning

confidence: 99%

Evidence That Cingulin Regulates Endothelial Barrier Function In Vitro and In Vivo

Schossleitner

Rauscher

Gröger

et al. 2016

ATVB

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Objective-Cingulin is a cytoplasmic component of tight junctions. Although modulation of cingulin levels in cultured epithelial model systems has no significant effect on barrier function, evidence from cingulin knockout mice suggests that cingulin may be involved in the regulation of the behavior of epithelial or endothelial cells. Here, we investigate the role of cingulin in the barrier function of endothelial cells. Approach and Results-We show that cingulin is expressed in human endothelial cells of the skin, brain, and lung in vivo and in vitro. Endothelial cingulin colocalizes and coimmunoprecipitates with the tight junction proteins zonula occludens-1 and guanine nucleotide exchange factor-H1. Cingulin overexpression in human umbilical vein endothelial cell induces tight junction formation, increases transendothelial electric resistance, and strengthens barrier function for low and high molecular weight tracers. In contrast, cultured endothelial cells lacking cingulin are more permeable for low molecular weight tracers. In cingulin knockout mice, neurons of the area postrema and Purkinje cells show an increased uptake of small molecular weight tracers indicating decreased barrier function at these sites. The expression of cingulin in endothelial cells has been poorly characterized because early studies showed a low abundance of cingulin in endothelial cells when compared with epithelia. 18,19 However, the recently characterized role of GEF-H1 in regulating endothelial permeability 20,21 raises the possibility that cingulin is a key regulator of endothelial barrier function. Conclusions-WeHere, we studied the expression and molecular environment of cingulin in different types of endothelial cells. Furthermore, we characterized the effects of exogenous cingulin expression or deletion of the cingulin head domain on the expression of claudin-5 and endothelial barrier function and analyzed barrier function in cingulin-deficient mice. The results indicate that expression levels of cingulin contribute to regulating endothelial barrier function. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Cingulin Is Localized at Human Endothelial TJ In SituWe analyzed the expression of cingulin in different vascular beds by immunohistochemistry. Endothelial cells of large and small-sized veins and arteries in human skin, lung, and brain tissues stained positive with anticingulin antibodies ( Figure 1A). By immunofluorescence, cingulin labeling was detected in close proximity of VE-cadherin labeling with a Pearson correlation coefficient of 0.11, but was colocalizing with ZO-1 labeling resulting in a Pearson correlation coefficient of 0.31 ( Figure 1B), supporting the notion that cingulin is associated with TJ of endothelial cells. 22 Analysis of mRNA expression levels of cingulin relative to VE-cadherin in different tissues and vessels showed that cingulin expression was detectable in the brain, the vena cava, and the aorta, whereas no expression was detected in muscle an...

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“…Increased expression of the tight junction protein, Cingulin , was also seen in Casr −/− mice compared to their wild-type counterparts [72]. Although the exact mechanism is unknown, Cingulin is associated with the expression of Occludin , Claudin 2 , Claudin 7 , and epithelial specific transcription factors, Gata4 , Gata6 , and Hif-1α [73, 74], a feature also observed in Casr −/− mice [72]. …”

Section: The Role Of the Casr In Secretory Diarrhea And Colitismentioning

confidence: 99%

The role of the calcium-sensing receptor in gastrointestinal inflammation

Owen

Cheng

et al. 2016

Seminars in Cell & Developmental Biology

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The gastrointestinal (GI) tract must balance the extraction of energy and metabolic end-products from ingested nutrition and resident gut microbes and the maintenance of a symbiotic relationship with this microbiota, with the ability to mount functional immune responses to pathogenic organisms to maintain GI health. The gut epithelium is equipped with bacteria-sensing mechanisms that discriminate between pathogenic and commensal microorganisms and regulate host responses between immunity and tolerance. The epithelium also expresses numerous nutrient-sensing receptors, but their importance in the preservation of the gut microbiota and immune homeostasis remains largely unexplored. Observations that a deficiency in the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific receptor knockout mice resulted in diminished intestinal barrier integrity, altered composition of the gut microbiota, modified expression of intestinal pattern recognition receptors, and a skewing of local and systemic innate responses from regulatory to stimulatory, may change the way that this receptor is considered as a potential immunotherapeutic target in gut homeostasis. These findings suggest that pharmacologic CaSR activators and CaSR-based nutrients such as calcium, polyamines, phenylalanine, tryptophan, and oligo-peptides might be useful in conditioning the gut microenvironment, and thus, in the prevention and treatment of disorders such as inflammatory bowel disease (IBD), infectious enterocolitis, and other inflammatory and secretory diarrheal diseases. Here, we review the emerging roles of the CaSR in intestinal homeostasis and its therapeutic potential for gut pathology.

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The Junctional Proteins Cingulin and Paracingulin Modulate the Expression of Tight Junction Protein Genes through GATA-4

Cited by 24 publications

References 45 publications

MgcRacGAP interacts with cingulin and paracingulin to regulate Rac1 activation and development of the tight junction barrier during epithelial junction assembly

MgcRacGAP interacts with cingulin and paracingulin to regulate Rac1 activation and development of the tight junction barrier during epithelial junction assembly

Evidence That Cingulin Regulates Endothelial Barrier Function In Vitro and In Vivo

The role of the calcium-sensing receptor in gastrointestinal inflammation

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