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Results for “Intercellular Junctions”

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PubMed1990

Inhibition of gap-junctional intercellular communication and enhanced binding of fibronectin-coated latex beads by stimulation of DNA synthesis in quiescent 3T3-L1 cells.

To clarify the modulation of intercellular communication via gap junctions, associated with the growth induction of quiescent 3T3-L1 cells, we investigated the gap-junctional intercellular communication in growth-stimulated cells that were able to bind fibronectin-coated beads. When quiescent 3T3-L1 cells were incubated with fibronectin-coated beads for the first 2 h after the addition of calf serum, 24.0% of the cells bound and phagocytosed beads. Among the cells with bound beads, the percentage of the cells labeled concurrently with bromodeoxyuridine was 63.7% when examined 13 h after the addition of calf serum. Transient reduction of dye-coupling, measured with Lucifer Yellow CH, was observed only in the cells with bound beads 2 h after addition of calf serum, but it was not observed in the cells without bound beads. When the quiescent cells were incubated with fibronectin-coated beads for 2 h from 4-6 h after the addition of calf serum, the percentage of cells with bound beads increased to 53.1%, but the decrease in dye-coupling among the cells with bound beads was slight. These results suggest that the induction of cell growth causes a transient reduction in gap-junctional intercellular communication in 3T3-L1 cells with bound fibronectin-coated beads.

Animals↗

PubMed2005

Nerve growth factor increases connexin43 phosphorylation and gap junctional intercellular communication.

The function of gap junctions is regulated by the phosphorylation state of their connexin subunits. Numerous growth factors are known to regulate connexin phosphorylation; however, the effect of nerve growth factor on gap junction function is not understood. The phosphorylation of connexin subunits is a key event during many aspects of the lifecycle of a connexin, including open/close states, assembly/trafficking, and degradation, and thus affects the functionality of the channel. PC12 cells infected with connexin43 (Cx43) retrovirus were used as a neuronal model to characterize the signal transduction pathways activated by nerve growth factor (NGF) that potentially affect the functional state of Cx43. Immunoblot analysis demonstrated that Cx43 and the mitogen-activated protein kinase (MAPK), ERK-1/2, were phosphorylated in response to TrkA activation via NGF and that phosphorylation could be prevented by treatment with the MEK-1/2 inhibitor U0126. The effects of NGF on gap junction intercellular communication were examined by monitoring fluorescence recovery after photobleaching PC12-Cx43 cells preloaded with calcein. Fluorescence recovery in the photobleached area increased after NGF treatment and decreased when pretreated with the MEK-1/2 inhibitor U0126. These data are the first to show a direct signaling link between neurotrophins and the phosphorylation of connexin proteins through the MAPK pathway resulting in increased gap junctional intercellular communication. Neurotrophic regulation of connexin activity provides a novel mechanism of regulating intercellular communication between neurons during nervous system development and repair.

Animals↗

PubMed2006

Structure and function of the intercellular junctions: barrier of paracellular drug delivery.

The delivery of large hydrophilic molecules (i.e., peptides and proteins) across biological barriers has been hampered by the presence of tight junctions. This delivery process can be improved by enhancing permeation through intercellular junctions of the intestinal mucosa and blood-brain barriers. This is achieved by modulating the intercellular junctions of these biological barriers. To modulate intercellular junctions, it is necessary to understand the structure and function of the proteins that are involved in these junctions. This review focuses on the structure of intercellular junctions and possible mechanisms of intercellular junction formation. Modulation of protein-protein interactions has been shown to increase the porosity of the paracellular pathway. For example, E-cadherin derived peptides have been shown to enhance the permeation of hydrophilic molecules (i.e., mannitol) in cell culture models of biological barriers.

Animals↗

PubMed1987

Restoration of LDL receptor activity in mutant cells by intercellular junctional communication.

Exchange of small molecules between cells through intercellular junctions is a widespread phenomenon implicated in many physiological and developmental processes. This type of intercellular communication can restore the activity of low-density lipoprotein (LDL) receptors in mammalian cells that are deficient in the enzyme UDP-Gal/UDP-GalNAc 4-epimerase. Pure cultures of the 4-epimerase mutant are unable to synthesize normal carbohydrate chains on LDL receptors and many other glycoproteins and therefore do not express LDL receptor activity. When these cells are cocultivated with cells expressing normal 4-epimerase activity, the structure and function of LDL receptors are restored to normal by the transfer of this enzyme's products through intercellular junctions. The formation of functional junctions does not require normal glycosylation of membrane proteins. Because many convenient assays and selections for LDL receptor activity are available, this mutant can provide a powerful new tool for biochemical and genetic studies of intercellular junctional communication.

Animals↗

PubMed1977

Ultrastructure and distribution of intercellular junctions in corneal endothelium.

The intercellular junctions of the corneal endothelium has been studied in rabbit, monkey and human eyes. A union of apposing outer leaflets (tight junction) is usually found near the apical end of the intercellular clefts. However, evidence from lanthanum tracer studies indicates that the tight junctions do not seal the intercellular clefts completely. In addition to tight junctions, the presence of gap junctions or nexuses is demonstrated in all three species studied.

Animals↗

PubMed1993

Intercellular junctions and the application of microscopical techniques: the cardiac gap junction as a case model.

Intercellular junctions are fundamental to the interactions between cells. By means of these junctions, the activities of the individual cells that make up tissues are co-ordinated, enabling each tissue system to function as an integrated whole. In this review, the work of the authors on one specific type of junction--the cardiac gap junction--is presented as a case model to illustrate how the application of a range of microscopical methods, as part of a multidisciplinary approach, can help extend our understanding of cell junctions and their functions. In the heart, gap junctions form the low-resistance pathways for rapid impulse conduction and propagation, enabling synchronous stimulation of myocyte contraction. Gap junctions also form pathways for direct intercellular communication, a function of particular importance for morphogenetic signalling during development. The work discussed demonstrates some of the applications of techniques in electron microscopy, immunocytochemistry and confocal scanning laser microscopy to the understanding of the structural basis of the function of gap junctions in the normal adult heart, the developing heart and the diseased heart. Freeze-fracture electron microscopy of heart tissue prepared by rapid freezing techniques, in which excision-related structural damage to the cells is minimized or avoided, makes it possible to deduce the structure of the functioning gap junction in vivo. Gap junctions in hearts that are beating normally in the living animal until the very instant of freezing consist of connexons (transmembrane channels) organized in a quasi-crystalline arrangement, not a 'random' arrangement as proposed in the original hypothesis on the structural correlates of gap junction function. Alterations in connexon arrangement occur in response to ischaemia and hypoxia, though the relationship of these to gap-junctional permeability is indirect. To obtain probes for mapping the distribution of gap junctions in cardiac tissue, polyclonal antisera to synthetic peptides matching portions of the sequence of connexin43, the major gap-junctional protein reported in the heart, were raised. The specificity of the antisera was confirmed by dot blotting, Western blotting and by immunogold labelling of isolated gap junctions. One antiserum (that raised to residues 131-142) was found to be particularly effective as a cytochemical probe. An immunofluorescence labelling procedure for use with confocal scanning laser microscopy was developed to enable the three-dimensional precision mapping of gap junctions through thick slices of cardiac tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Influence of intercellular junctions on endothelin secretion of human umbilical vein endothelial cells in vitro.

The endothelium plays a pivotal role in the rheological regulation of blood flow by the secretion of vasoactive factors. The interaction between shear forces and the endothelium is determined by the mechanical properties of the endothelial cell layer which are associated with intercellular junctions. Cell-cell contacts could therefore modulate the secretion of vasocative factors in response to rheological stimuli. We investigated the relationship between intercellular junctions and the secretion of the vasoconstrictor peptide endothelin and the coagulation co-factor von Willebrand factor (vWF). Human umbilical vein endothelial cells (HUVECs) were used as in vitro endothelial model system. Intercellular junctions were reversibly disrupted by calcium chelation or hypertonic stress; alternatively, the formation of intercellular junctions was inhibited by culturing the cells in suspension or by plating them in the presence of an inhibitory anti-VE-cadherin antibody. The opening of intercellular junctions was verified by assessing transmonolayer electrical resistance (TMR) and immunofluorescence morphology. The concentration of endothelin and vWF was measured in the cell culture supernatants using specific ELISAs. The secretion of endothelin was inhibited by EGTA (5 mM) and stimulated by incubation with tumor necrosis factor alpha (TNFalpha, 40 ng/ml). Treatment with hypertonic medium (glycerol, 1,200 mosmol/l) for 10 minutes opened intercellular junctions and markedly reduced the secretion of endothelin. HUVECs in suspension culture did not secrete endothelin and failed to respond to TNFalpha, but readily resumed these functions upon forming a new monolayer on plastic. The reconstitution of intercellular junctions after suspension culture could be inhibited using a specific anti-VE-cadherin antibody. This antibody, but not a non-specific anti-human-IgG antibody reduced endothelin secretion. The secretion of von Willebrand Factor was less dependent on intercellular junctions. The opening of intercellular junctions did not induce cell death, since the cells continued to exclude trypan blue. The results of this study suggest a novel and potentially pathophysiologically/clinically relevant correlation between intercellular junctions and the secretion of endothelin in endothelial cells.

Cadherins↗

PubMed1998

SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype. II. Changes in gap junctional intercellular communication.

Poor gap junctional intercellular communication (GJIC) has been associated with uncontrolled cell growth and neoplasia. We have successfully propagated normal first trimester invasive extravillous trophoblast (EVT) cells, and have produced premalignant EVT lines after SV40 Tag transformation: RSVT-2 is an uncloned line that is long-lived; RSVT2/C is a clonal line that is immortal. Both are hyperproliferative, hyperinvasive and variably refractory to the anti-proliferative and anti-invasive effects of transforming growth factor beta (TGFbeta). Possible changes in gap junctions during the transition of normal invasive EVT cells to the premalignant stage were examined by comparing expression of connexin proteins (by immunolabeling for Cx26, Cx32, Cx40, Cx43), and mRNA (by Northern blot with cDNA probes for Cx26, Cx32, Cx43), and functional GJIC (by dye transfer using the preloading method) in normal parental EVT cells and their SV40 Tag transformants. Results from immunofluorescence and Northern blot analysis revealed that, of the panel of connexins examined, only Cx43 was variably expressed in these cell lines in vitro. Expression of Cx43 protein and mRNA was abundant in normal EVT cell line HTR8, reduced in long-lived RSVT-2 cells and undetectable in immortalized RSVT2/C cells. GJIC, as measured by dye transfer between donor and recipient cells, was also similarly reduced in recipient RSVT-2 cells, and drastically reduced in RSVT2/C cells, irrespective of whether the dye donor was of the same cell type (homocellular coupling) or HTR8 cells (heterocellular coupling). Treatment with TGFbeta reduced Cx43 mRNA expression as well as GJIC in normal EVT cells, but not in the SV40 Tag transformants. Our findings suggest that downregulation of connexins with the resultant impairment in GJIC is an early event in tumor progression, as observed in the premalignant SV40 Tag transformants.

Analysis of Variance↗

PubMed1975

[Highly permeable intercellular junctions in normal and transformed fibroblast cultures].

Intercellular junctions permeable to ions and fluorescein Na were studied with the aid of intracellular microelectrodes in the cultures of normal and transformed mouse-embryo and hamster-embryo fibroblast-like cells. Normal cells were effectively coupled by the highly permeable junctions. In cultures of 7 types of transformed cells, 3 types of coupling were detected: effective, decreased, and fully reduced couplings. The degree of uncoupling was not correlated with morphological patterns of malignization and tumorogeneity of transformed cultures. The decrease of permeability of intercellular junctions to ions and small molecules is concluded not to be necessary for malignization.

Animals↗

PubMed1983

Fluid-overload pulmonary oedema in mice: the intercellular junctions of bronchiolar epithelium and arterial endothelium.

It has been reported previously that fluid leaks through the intercellular junctions of arterial endothelium and bronchiolar epithelium in fluid-overload pulmonary oedema in mice. In this study, freeze fracture technique was used to see morphological changes in the intercellular junctions at these sites. In arterial endothelium, the intercellular junction consists of a combination of gap junctions and tight junctions. In this experiment, only the tight junctions were disrupted. In bronchiolar epithelium, the tight junction was disrupted. The other sites in the vascular system and respiratory surface did not show any changes in the morphology of intercellular junctions. Thus, this study confirms the previous study and provides some structural correlation for the changes of permeability in fluid-overload pulmonary oedema.

Animals↗

PubMed1990

Lack of correlation between intercellular junctional communication, p21rasEJ expression, and spontaneous metastatic properties of rat mammary cells after transfection with c-H-rasEJ or neo genes.

The loss of intercellular junctional communication between rat 13762NF mammary carcinoma cells and their spontaneous metastatic potentials from the mammary fat pad show a high degree of correlation. We examined a stable, benign, completely junctionally coupled cell clone (MTC.4) of this system after calcium phosphate-mediated transfection with c-H-rasEJ/pSV2neo and control pSV2neo-containing plasmids. There was a good correlation between the copy numbers of c-H-rasEJ incorporated into MTC.4 cells and their contents of p21rasEJ; however, there was not always a correspondence between spontaneous metastatic potential and copy number of c-H-rasEJ or amount of p21rasEJ. After c-H-rasEJ/pSV2neo transfection, some MTC.4 cells lost intercellular junctional communication and became spontaneously metastatic, although some nonmetastatic transfectants also had low percentages of junctionally coupled cells. One of the control pSV2neo transfectants also became metastatic and lost intercellular junctional coupling, and calcium phosphate treatment itself resulted in increased growth rates at mammary fat pad sites and a marginal increase in incidence of spontaneous metastases, both of which preceded loss of intercellular junctional coupling in some cells. Examination of 12 subclones derived from two cloned transfectants, however, revealed a poor correlation between spontaneous metastatic potential and intercellular junctional coupling. The results suggest that loss of junctional communication between cells is often but not always associated with the progression of cells from benign to metastatic states.

Animals↗

PubMedDate not supplied

Intercellular junctions in oral epithelial cells: ultrastructural and immunological aspects.

The activation of the molecular cascade leading to Ca++ -induced differentiation in cultured epithelial cells might be provided by the establishment of intercellular junctions between cells. In the present paper, we tested the hypothesis that Ca++ concentration would determine morphological and biochemical changes in intercellular junctions of cultured human gingival cells. Triplicate samples of monolayer cultures of human oral gingival cells were grown with two different Ca++ concentrations (0.3 and 1.8 mM), and examined by transmission (TEM) and scanning (SEM) electron microscopy at different time periods. To determine the role of the E-cadherin/beta-catenin complex in intercellular junction formation, oral epithelial cell cultures were grown in 0.3 mM Ca++ in presence of a blocking antibody anti human E-cadherin, stained with antibodies anti human beta-catenin, and examined by confocal laser scanning microscopy (CLSM). By TEM and SEM, cells grown at physiologic Ca++ concentrations (i.e., 1.8 mM) showed a subjective increase of the size of microvilli and of the number of intercellular junctions, which was more evident after 3 days in culture. Desmosome-like junctions were observed in cells grown in 1.8 mM Ca++, not in cells grown in 0.3 mM. By CLSM, development of intercellular adhesion was marked by membranous localization of E-cadherin and beta-catenin within the first hours in both culture types. When cell-cell adhesion was prevented, cells showed round shape and no membranous localization of beta-catenin. Restoring cell adhesion brought about polygonal cell shape and membranous localization of beta-catenin. We can conclude that increased Ca++ concentration may determine biochemical and morphological changes at membranous level in human oral epithelial cells. These changes may facilitate the development of intercellular junctions.

Cadherins↗

PubMed1997

A characterization of permolybdate and its effect on cellular tyrosine phosphorylation, gap junctional intercellular communication and phosphorylation status of the gap junction protein, connexin43.

Biological and analytical characterizations of permolybdate (a mixture of H2O2 and molybdate) were done. Molybdate (10 mM) and molybdenum(V) chloride (3 mM) did not affect gap junctional intercellular communication (GJIC), phosphorylation status of connexin43 (Cx43) or cellular tyrosine phosphorylation in early passage hamster embryonic cells (mainly fibroblast-like). High concentrations of H2O2 (3-10 mM) affected some of the parameters. Acidified permolybdate was clearly more stable than the unadjusted permolybdate. The maximum biological potency of acidified permolybdate was found at a molar ratio of 2:1 (H2O2:molybdate). The mixtures of molybdenum(V) chloride and H2O2 gave a maximum effect at 4:1 molar ratio (H2O2:molybdenum(V)). This can be explained by decomposition of H2O2 and by the generation of less biologically active compounds. Spectrophotometric analyses of the mixtures corroborated the biological results. The Mo(V) electron spin resonance spectrum disappeared upon addition of H2O2 to Mo(V) solutions, and no spectrum appeared when H2O2 was mixed with Mo(VI). Thus, permolybdate is probably diperoxomolybdate, a Mo(VI) compound. Regardless of the parent metal salt, the H2O2/metal salt mixtures showed concentration-dependent biphasic responses with an initial decrease in GJIC followed by an increase. A dissociation between alteration in Cx43 phosphorylation status and GJIC was obtained under certain conditions. The biological activities of permolybdate were only partially mimicked by phenylarsine oxide, an alternative protein tyrosine phosphatase inhibitor.

Animals↗

PubMed1994

Increased gap junctional intercellular communication capacity and connexin 43 and 26 expression in rat bladder carcinogenesis.

Many reports have suggested that gap junctional intercellular communication or gap junction proteins (connexins) could have tumor suppression characteristics. We investigated gap junctional intercellular communication capacity and connexin 26, 32 and 43 mRNA expression in four rat bladder cell lines and the results were compared to their tumorigenicity. We also examined connexin expression in rat bladder carcinomas induced by 3,2'-dimethyl-4-aminobiphenyl or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and in normal bladders. There was clear tendency that cell lines with greater communication had stronger tumorigenicity and more expression of connexin 26 or 43. We could not detect connexin 32 in these cell lines. In normal bladder tissue, connexin 43 expression was barely detectable and there was no detectable connexin 26. However, in rat bladder carcinomas, especially the EHBN-induced carcinomas, abundant expression of both connexins was observed. These results indicate that increased gap junctional intercellular communication capacity or increased connexin(s) expression may give a growth advantage in rat bladder carcinogenesis.

Aminobiphenyl Compounds↗

PubMed1989

Potential role of the human Ha-ras oncogene in the inhibition of gap junctional intercellular communication.

The modulation of gap junctional intercellular communication (GJIC) plays an important role during tumor promotion. Several tumor-promoting agents are known to inhibit this form of cellular coupling. In addition, tumor cells and cells expressing certain oncogenic products have been shown to exhibit inhibited or reduced GJIC. The Ha-ras oncogene is expressed in a wide variety of human tumors from different tissues. Its p21 product is a membrane-bound polypeptide, the function of which is not fully characterized. We tested the effects of the expression of the human c-Ha-ras-1 oncogene, derived from the EJ/T4 bladder carcinoma cell line, on the ability of the Chinese hamster V79 cells to conduct gap junctional communication. The junctional competence was studied by two different methods, the scrape-loading/dye transfer technique and the metabolic cooperation assay. The results indicate a strong correlation between the expression of p21 ras protein and the inhibition of gap junctional function. Assuming that reversible inhibition of intercellular communication plays a role during tumor promotion and stable inhibition during the tumor progression phase of carcinogenesis, our data suggest that, while chemical tumor promoters and the ras oncogenes might work by different biochemical mechanisms, they both affect a critical cellular function; namely, GJIC.

Animals↗

PubMed1977

Intercellular junctions in the central nervous system of insects.

The intercellular junctional complexes in the central nervous system (CNS) from a variety of insect species have been examined by thin-sectioning and freeze-fracturing techniques. Of particular concern has been the fine-structural basis of the blood-brain barrier observed to be present in the outer perineurial layer around the avascular insect CNS. The basis of this has been found in the form of tight junctions (zonulae occludentes) present both in sections and in replicas of the perineurium. In the latter, they appear as one or two simple linear ridges, lying parallel to the outer surface, which occasionally display overlapping. The complex geometry of the interdigitating perineurial cells apparently permits such a relatively simple series of ridges to function as a barrier, since tracers are found not to penetrate beyond this level into the underlying nervous tissue. Such evidence is supported by microprobe X-ray analysis of lanthanum-incubated tissues, the perineurium compared with the glia-ensheathed axons showing the presence and absence of lanthanum, respectively. Possible physiological mechanisms that could operate 'in vitro' to maintain the blood-brain barrier are also considered. Other intercellular junctions such as desmosomes, septate junctions and gap junctions are found in the perineurial layer too, the last exhibiting EF particle plaques and PF pits. Glia-glia junctions also occur in some insect species; they include desmosomes, inverted gap junctions and occasional tight junctions. Septate, gap and tight junctions are also found on the membranes of tracheoles penetrating the CNS. Short, ridge-like elaborations and other particle arrays are found on the PF on the axon surfaces and the significance of these structures is discussed.

Animals↗

PubMed1985

Intercellular junctions between human odontoblasts. A freeze-fracture study after demineralization.

Intercellular junctions in the odontoblastic layer have been studied with a freeze-fracture technique. Children's tooth germs were fixed, sliced and demineralized. Samples of the pulpodentinal border were routinely prepared for freeze-fracture. Three kinds of intercellular junctions were detected between human odontoblast cell bodies: gap junctions, desmosomes and tight junctions. Numerous gap junctions are responsible for intercellular communication at different levels of the cell bodies. Focal tight junctions, parallel to the axis of the cell, and desmosomes are sites of cell-to-cell adhesion between lateral plasma membranes. At the distal end of the cell bodies, junctional complexes consist of zonular tight junctions and gap junctions. These zonular tight junctions, never before described between odontoblasts, contribute to the pseudo-epithelial organization of the odontoblastic layer. They constitute a predentin-pulp barrier, the permeability of which must be studied to establish their role in relation to dentin formation.

Adolescent↗

PubMedDate not supplied

The role of gap junctional intercellular communication in neoplasia.

Gap junctions are comprised of proteinaceous, plasma membrane channels that link the interiors of adjacent cells and permit cells to directly exchange small (< 1,000 Daltons) molecules and ions. This exchange, termed gap junctional intercellular communication (GJIC), appears to be involved in growth regulation. Growth controlling factors may pass between cells through the junctions. The loss of gap junctions or impairment of their permeability has been observed in many neoplastic cells and cells treated with growth promoting carcinogens and other agents. The loss of GJIC appears to be an important event in the conversion of a normal cell into a neoplastic one. On the other hand, the restoration of GJIC in neoplastic cells by transfection with gap junction protein (connexin) cyclic deoxyribonucleic acids (cDNAs) or by stimulating endogenous connexin gene expression has led to the reversal of the neoplastic phenotype. The biology of gap junctions and their role in growth regulation and neoplasia are reviewed.

Animals↗