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PubMed2001

[Effect of transfected Cx43 gene on the gap junction intercellular communication and the human glioma cells proliferation].

OBJECTIVE: To investigate the role of connexin 43 (Cx43) gene in the gap junction intercellular communication (GJIC) and the development of glioma so as to demonstrate the feasibility of using Cx43cDNA as the target of gene therapy for gliomas. METHODS: TJ905 human glioblastoma cell line without Cx43 gene expression was transfected with Cx43cDNA mediated by lipofectamine. Northern blot, in situ hybridization and immunocytochemistry were used for examination of Cx43mRNA and its protein examination; MTT assay and silver colloid stain were used to detect cell proliferation. TUNEL method was used to determine the cell apoptosis. Scrape loading dye transfer (SLDT) was used to monitor GJIC. RESULTS: The TJ905 transfectants resulted in dramatic upregulation of Cx43mRNA and its protein, with the GJIC of transfected glioma cells restored. Clones with high Cx43 expression also showed reduced proliferation in vitro. However, the cell apoptosis did not increase following the transfection with Cx43 gene. CONCLUSION: These results indicate that Cx gene and gap junction intercellular communication are of crucial importance in malignant glioma cell growth and development. Cx43 gene may be a target for gene therapy of gliomas.

Blotting, Northern↗
PubMed1988

Suppression of intercellular communication in acinar cells from rat submandibular gland by cholinergic and adrenergic agonists.

The effects of cholinergic and adrenergic agonists on intercellular communication in isolated acini of rat submandibular gland were evaluated using dye-coupling. Cells injected with Lucifer Yellow CH showed diffusion of the dye to their coupled neighbors under the control condition. Addition of acetylcholine (ACh) and carbachol (CCh) at concentrations higher than 10(-6) M rapidly and reversibly suppressed the dye-coupling. This effect by 10(-4) M ACh or 10(-4) M CCh was blocked by the addition of 10(-6) M atropine. The suppressive effects of 10(-4) M adrenaline and 10(-4) M noradrenaline were weaker than those of 10(-4) M ACh. Treatment with 10(-4) M isoproterenol did not inhibit the dye-coupling and the suppressive effect by 10(-4) M adrenaline was blocked by the addition of 10(-5) M phenoxybenzamine. The inhibition of dye-coupling by ACh and adrenaline was blocked by the addition of 10(-5) M verapamil, 10(-4) M W-7 and 1.5 x 10(-5) M H-7, but not by 1.5 x 10(-5) M HA1004. These results suggest that the muscarinic action of cholinergic agonists and the alpha-action of adrenergic agonists might suppress the intercellular communication of the acinar cells in the rat submandibular gland, possibly through the increase of calcium influx and the activation of protein kinase C.

Acetylcholine↗
PubMed1983

Oncogenes, inhibited intercellular communication and tumor promotion.

Homeostatic control of proliferation and differentiation is characteristic of normal, but not malignant, cells. Gap junction-mediated intercellular communication provides one mode of this homeostatic control for cells in physical juxtaposition. Many chemicals, both natural and human-made, can modulate the function of gap-junctional communication and by doing so, alter the control of proliferation and differentiation of cells. Many of these chemicals are known tumor promoters. Oncogenes appear to be highly conserved genes influencing proliferation and differentiation of cells. We have speculated that certain oncogenes might play a role in tumor promotion by their influence on the regulation of gap-junctional intercellular communication. If this hypothesis is correct, a mechanism would exist to unify radiation, chemical and viral carcinogenesis.

Animals↗
PubMed1995

Role of blocked gap junctional intercellular communication in non-genotoxic carcinogenesis.

Gap junctional intercellular communication mediates the transfer of small molecules from the cytoplasm of one cell to that of neighbouring cells. Connexins are the proteins that form the channels responsible for this type of communication. Aberrant expression and function of connexins are often found in cells exposed to tumor-promoting agents and during carcinogenesis, both in cell culture systems and in tissues freshly removed directly from patients and exposed animals. Transfection of connexin genes into tumorigenic cells often exerts negative growth control, suggesting that connexins act as a family of tumor-suppressor genes. Connexin gene mutations appear to be the cause of two human diseases, i.e. X-linked Charcot-Marie-Tooth syndrome and visceroatrial heterotaxia. Connexin genes are therefore important for the maintenance of homeostasis and thus their dysfunction could lead to various forms of disease.

Animals↗
PubMed2001

Role of PKC and MAP kinase in EGF- and TPA-induced connexin43 phosphorylation and inhibition of gap junction intercellular communication in rat liver epithelial cells.

Gap junction intercellular communication (GJIC) is involved in the regulation of many cellular processes. The gap junction channels are made up of connexins and the flow of polar low molecular weight molecules through these channels is inhibited by several groups of substances, such as tumour promoters and growth factors. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), chlordane and the growth factor epidermal growth factor (EGF) are potent inhibitors of GJIC in several cell types, including the rat liver epithelial cell line IAR6.1. The induced inhibition of communication by TPA and EGF in IAR6.1 cells is associated with hyperphosphorylation of connexin43, the connexin responsible for GJIC. Two enzyme inhibitors, PD98059, a specific inhibitor of MEK kinase, and GF109203X, a selective inhibitor of protein kinase C (PKC), were used to study the signalling pathways involved in the effect of EGF and TPA on GJIC, with the following conclusions. The inhibition of cell communication in IAR6.1 cells by EGF is likely to be mediated by direct phosphorylation of connexin43 by MAP kinase. TPA blocks GJIC mainly by the direct action of PKC, but also partly through cross-talk with the MAP kinase pathway. Connexin43 hyperphosphorylation induced by TPA is, as for EGF, mediated through MAP kinase, while PKC seems to block GJIC either through other substrates or induces a type of connexin43 phosphorylation that causes no significant electrophoresis mobility shift.

Animals↗
PubMed2002

The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide.

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.

Agaricales↗
PubMed2001

Intercellular communication in cultured human vascular smooth muscle cells.

Intercellular communication through gap junction channels plays a fundamental role in regulating vascular myocyte tone. We investigated gap junction channel expression and activity in myocytes from the physiologically distinct vasculature of the human internal mammary artery (IMA, conduit vessel) and saphenous vein (SV, capacitance vessel). Northern and Western blots documented the presence of connexin43 (Cx43) in frozen tissues and cultured cells from both vessels. Northern blots also confirmed the presence of Cx40 mRNA in cultured IMA and SV myocytes. Dual whole cell patch-clamp experiments revealed that macroscopic junctional conductance was voltage dependent and characteristic of that observed for Cx43. In the majority of records, in both vessels, single-channel activity was dominated by a main-state conductance of 120 pS, with subconducting events comprising less than 10% of the amplitude histograms. However, some records showed "atypical" unitary events that had a conductance similar to Cx40 (approximately 140-160 pS), but gating behavior like that of Cx43. As such, it is conceivable that the presence and coexpression of Cx40 and Cx43 in IMA and SV myocytes may result in heteromeric channel formation. Nonetheless, in terms of gating, Cx43-like behavior clearly dominates.

Aged↗
PubMed1989

[A study of intercellular communication of human transitional cell carcinoma cell lines].

Intercellular communication (IC) was investigated by a dye transfer method in 5 human bladder carcinoma cell lines, JTC-29, JTC-30, JTC-32, HUB-41 and T-24 which showed various histological anaplasia when transplanted into nude mice. IC was investigated as follows; 1) IC among cells of each bladder carcinoma cell lines, 2) IC between various combination of different cell lines and 3) IC between cells of bladder carcinoma cell lines and fibroblasts prepared from the human skin or prostate. High IC was observed among JTC-30 cells which showed a differentiated pattern when transplanted into nude mice. JTC-32 and HUB-41, of which transplanted tumors showed poorly differentiated patterns, demonstrated lower IC than JTC-30. Statistical significance was present only between JTC-30 and JTC-32 cells (p less than 0.05). T-24 which formed histologically anaplastic tumor in nude mice demonstrated markedly poor IC. Second, IC between two different cell lines was demonstrated only between JTC-30 and JTC-32. Third, fibroblast from the skin and prostate had high IC but showed apparent IC with none of bladder carcinoma cell lines. These findings indicate that ICs of bladder tumor cells vary with cell lines tested and appear to decrease with progress of malignant anaplasia. Furthermore, the fact that there is sometimes high IC and sometimes lack of IC between differentiated and undifferentiated tumor cells suggests a possible role of IC in prevention of malignant progression. The present study provides no evidence of IC between bladder tumor cells and fibroblasts, which in some reports have been suggested to be an important phenomenon in evaluating the metastatic capacity of cancer cells.

Animals↗
PubMed1989

Close relationship between modulation of serum-induced stimulation of DNA synthesis and changes in gap-junctional intercellular communication in quiescent 3T3-L1 cells caused by cyclic AMP and the tumor-promoting phorbol ester TPA.

Involvement of gap-junctional intercellular communication in the stimulation of growth was investigated in quiescent 3T3-L1 cells. When the cells in monolayer were growth-arrested by culture in a low concentration of calf serum, addition of dibutyryl cyclic AMP enhanced dye-coupling and suppressed the enhancement of DNA synthesis, induced by calf serum, in quiescent cells. 12-O-Tetradecanoylphorbol-13-acetate (TPA) suppressed dye-coupling in quiescent cells and enhanced DNA synthesis in both quiescent and serum-treated cells. When about 5000 cells were cultured in contact to form a colony, growth arrest of the cells was observed in the central region of such colonies rather than in the peripheral region, but addition of calf serum induced DNA synthesis in the cells in both the peripheral and central regions of the colonies. Addition of TPA enhanced serum-induced DNA synthesis in the cells in the central region of colonies rather than in the peripheral region. These results suggest that the ability of quiescent cells to escape from growth arrest is inversely correlated to the extent of gap-junctional intercellular communication.

Animals↗
PubMedDate not supplied

Retinaldehyde, a potent inhibitor of gap junctional intercellular communication.

Retinaldehyde and retinoic acid are derivatives of vitamin A, and retinaldehyde is the precursor for the synthesis of retinoic acid, a well-known inhibitor of gap junctional intercellular communication. In this investigation, we asked the question if retinaldehyde has similar effects on gap junctions. Gap junctional intercellular communication was measured by scrape-loading and preloading dye-transfer methods, and studies were carried out mainly on cultured liver epithelial cells. Retinaldehyde was found to be a more potent inhibitor (dye transfer reduced by 50% at 2.8 microM) than retinoic acid (dye transfer reduced by 50% at 30 microM) and glycyrrhetinic acid (dye transfer reduced by 50% at 65 microM). Both the 11-cis and all-trans forms of retinaldehyde were equally effective. Retinaldehyde inhibited dye transfer of both anionic Lucifer yellow and cationic Neurobiotin. Inhibition by retinaldehyde developed in less than two minutes at 50 microM, but unlike the reported case with retinoic acid, recovery was slower, though full. In addition to liver epithelial cells, retinaldehyde inhibited gap junctional communication in lens epithelial cells, retinal pigment epithelial cells and retinal ganglion cells.

Animals↗
PubMed2002

Decreased gap junctional intercellular communication in hexachlorobenzene-induced gender-specific hepatic tumor formation in the rat.

Hexachlorobenzene (HCB), an epigenetic carcinogen, HCB induces the formation of liver tumors in female rats, whereas only a small percentage of males are responsive. Intercellular communication via gap junctions is decreased in carcinogenesis. Gap junctions are composed of proteins termed connexins (Cxs). The objectives of this study were (i) to determine if HCB-induced tumor development is associated with a loss of gap junctional communication; (ii) to assess if HCB causes a gender-specific decrease in the expression of Cx32 and Cx26; and (iii) to establish if these effects result from gender differences in the constitutive expression of these Cxs. Rats were given HCB by gavage for five consecutive days. In the first experiment, control and HCB-treated female rats were sampled on day 100. Intercellular communication was significantly decreased in HCB-treated females compared to controls. To investigate if changes in Cx levels occur prior to day 100, experiments done using male and female rats sampled on day 50. Hepatic mRNA levels for Cx26 and Cx32 were significantly lower only in HCB-treated females as compared to controls. Cx26 mRNA levels were 3-fold higher and Cx32 mRNA levels were 8-fold lower in females compared with males. In a third experiment, ovariectomy abolished any differences between male and female controls for both Cxs, while estradiol had a partial role in the regulation of Cx32. This suggests that the sexual dimorphism in hepatic Cx levels is determined by the ovarian hormones. However, the HCB-induced decrease in Cx32 and Cx26 mRNA levels was maintained in ovariectomized rats, suggesting that the HCB effects are not mediated via an ovary-dependent pathway. Overall results show that HCB exposure induces gender-specific long-term alterations in intercellular gap junctional communication in female rat liver. This effect appears to be a critical mechanism of HCB-induced liver carcinogenesis and tumor promotion.

Animals↗
PubMed1985

Inhibition of intercellular communication and enhancement of morphological transformation of Syrian hamster embryo cells by TPA. Use of TPA-sensitive and TPA-resistant cell lines.

The possible role of blocked intercellular communication in the process of cell transformation has been studied with Syrian hamster embryo cell lines which are sensitive or resistant to TPA-induced enhancement of morphological transformation. Both the TPA-sensitive (BPNi) and the TPA-resistant (83-106 and 74-100) cell lines showed gap-junctional communication when measured by a dye-transfer method. However, TPA inhibited the communication only in TPA-sensitive cells, and not in TPA-resistant cells. These results are consistent with the idea that blocked intercellular communication is involved in a late stage of cell transformation and/or expression of the transformed phenotype.

Animals↗
PubMed2001

A novel role for FGF and extracellular signal-regulated kinase in gap junction-mediated intercellular communication in the lens.

Gap junction-mediated intercellular coupling is higher in the equatorial region of the lens than at either pole, a property believed to be essential for lens transparency. We show that fibroblast growth factor (FGF) upregulates gap junctional intercellular dye transfer in primary cultures of embryonic chick lens cells without detectably increasing either gap junction protein (connexin) synthesis or assembly. Insulin and insulin-like growth factor 1, as potent as FGF in inducing lens cell differentiation, had no effect on gap junctions. FGF induced sustained activation of extracellular signal-regulated kinase (ERK) in lens cells, an event necessary and sufficient to increase gap junctional coupling. We also identify vitreous humor as an in vivo source of an FGF-like intercellular communication-promoting activity and show that FGF-induced ERK activation in the intact lens is higher in the equatorial region than in polar and core fibers. These findings support a model in which regional differences in FGF signaling through the ERK pathway lead to the asymmetry in gap junctional coupling required for proper lens function. Our results also identify upregulation of intercellular communication as a new function for sustained ERK activation and change the current paradigm that ERKs only negatively regulate gap junction channel activity.

Animals↗
PubMed1997

Stimulation of gap junctional intercellular communication by thalidomide and thalidomide analogs in human skin fibroblasts.

It has been speculated that gap junctional intercellular communication (GJIC), an intercellular signalling pathway, is involved in embryogenesis by coupling compartments of the same developmental potential. We found that thalidomide induces GJIC in human fibroblasts after activation by liver microsomes in concentrations as low as 10(-7) M. Treatment of cells with the thalidomide analog EM-12 increased GJIC without prior activation. No alteration of GJIC was detected with phthalimide and glutamate, the components of thalidomide. However, 2-phthalimido glutaric acid (PGA), a hydrolysis product of thalidomide, stimulated GJIC without activation at concentrations between 10(-10) M and 10(-5) M. We suggest modification of GJIC as a biochemical mechanism responsible for pharmacological and toxicological properties of thalidomide and related compounds.

Cell Communication↗
PubMed2006

[Effect of PM2.5 collected during the dust and non-dust periods on the viability and gap junctional intercellular communication in human lung fibroblasts].

OBJECTIVE: To investigate the effects of PM2.5 collected during the dust and non-dust periods on the viability and gap junctional intercellular communication (GJIC) in human lung fibroblasts. METHODS: Human lung fibroblasts were treated with PM2.5 suspension and its organic and inorganic extracts at various concentrations for 24 h. The cellular viability was measured with MTT methods, and the GJIC between human lung fibroblasts was detected by the scrape loading dye transfer assay. RESULTS: PM2.5 suspension from both sources and the inorganic extracts of dust PM2.5 significantly decreased the viability of human lung fibroblast in a dose-dependent manner. Compared with other preparations, the dust PM2.5 suspension had the highest effect. Gap junctional intercellular communication between human lung fibroblasts was significantly inhibited by the different composition of PM2.5 from both sources in a dose-dependent manner. The inhibitory effects on GJIC were in the order of organic extract of PM2.5 > suspension > inorganic extract. CONCLUSION: Composition and source of PM2.5 are important factors which influnce the toxic effects on cells. The composition of PM2.5 from both sources can inhibit GJIC, suggesting decreasing GJIC may be related to the biological mechanisms of toxicity caused by PM2.5.

Air Pollutants↗
PubMed1996

Pulse treatment with the tumor promoter TPA delays the onset of desensitization response and prolongs the inhibitory effect on gap junctional intercellular communication of a rat liver epithelial cell line WB F-344.

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is an inhibitor of gap junctional intercellular communication (GJIC) of the rat liver epithelial cell line, WB F-344. We have previously reported that prolonged treatment of the WB cells with TPA (10 ng/ml) caused a reversal of the inhibition of GJIC that was initially induced (Oh, S.Y., et al. (1988) Carcinogenesis, 9, 135-139). Under this condition, addition of fresh TPA did not inhibit GJIC of these cells. In the present investigation we examined whether pulse exposure to TPA delays the onset of this desensitization response. Cultures were treated for 5 or 15 min with TPA and shifted to normal medium. Intercellular communication was measured at 15 min, 1 h and 6 h after the 5 or 15 min pulse treatments. Under these pulse treatment conditions, GJIC of the cells was markedly inhibited for up to 4 h and gradually reverted to near control levels by 6-8 h. At every sixth hour of pulse treatment the cells were given an additional pulse treatment (5 or 15 min) and the inhibitory effect of TPA on the GJIC of the cells was assayed 15 min after each such treatment. The results clearly showed that, when the cells were treated with 10 ng/ml TPA for 5 or 15 min every 6 h they maintained their sensitivity to the inhibitory effect of TPA on GJIC. This response to TPA was sustained for a considerably longer time when the duration of the pulse treatment was 5 min. Our data suggested that pulse exposure to TPA delays the desensitization response normally observed in prolonged treatment regimens and that this delay is possibly due to maintenance of the TPA activatable pool of protein kinase C under these conditions.

Animals↗
PubMed2003

Modulation of human fibroblast gap junction intercellular communication by hyaluronan.

The composition of the extracellular matrix changes during dermal repair. Initially, hyaluronan (HA) concentration is high, however, by day 3, HA is eliminated. HA optimizes collagen organization within granulation tissue. One possible mechanism of HA modulation of collagen packing is through the promotion of gap junction intercellular communication (GJIC). Gap junctions are gated channels that allow rapid intercellular communication and synchronization of coupled cell activities. The gap junction channel is composed of connexin (Cx) proteins that form a gated channel between coupled cells. HA is reported to enhance Cx43 expression in transformed fibroblasts. GJIC was quantified by the scrape loading technique and reported as a coupling index. The coupling index for human dermal fibroblasts was 4.6 +/- 0.2, while the coupling index for fibroblasts treated with HA more than doubled to 10.6 +/- 0.7. By Western blot analysis no differences were appreciated in the protein levels of Cx43 or beta-catenin, a protein involved in the translocation of Cx to the cell surface. By immuno-histology Cx43 and beta-catenin were evenly distributed throughout the cell in controls, but in cells treated with HA these proteins were co-localized to the cell surface. Coupled fibroblasts are reported to enhance the organization of collagen fibrils. It is proposed that HA increases the accumulation of Cx43 and beta-catenin on the cell surface, leading to greater GJIC and enhanced collagen organization.

Cell Communication↗
PubMed1996

Inhibition of gap junctional intercellular communication in heptachlor- and heptachlor epoxide-treated normal human breast epithelial cells.

Based on the concern of organochlorides in the environment and in human tissue, this study was designed to determine whether various noncytotoxic levels of heptachlor and heptachlor epoxide could inhibit, reversibly, gap junctional intercellular communication in human breast epithelial cells (HBEC). Cytotoxicity and gap junctional intercellular communication (GJIC) were evaluated by lactate dehydrogenase assay and fluorescence redistribution after photobleaching analysis, respectively. Both heptachlor and heptachlor epoxide were noncytotoxic up to 10 microg/ml. At this concentration, heptachlor and heptachlor epoxide inhibited GJIC of normal human breast epithelial cells after 1 h treatment. Within a 24 h treatment with heptachlor and heptachlor epoxide at 10 microg/ml, recovery of GJIC had not returned. GJIC completely recovered after a 12 h treatment of 1 microg/ml heptachlor epoxide, but it did not recover after a 24 h treatment of 1 microg/ml heptachlor. RT-PCR and Western blots were analyzed to determine whether the heptachlor or heptachlor epoxide might have altered the steady-state levels of gap junction mRNA and/or connexin protein levels or phosphorylation state. No significant difference in the level of connexin 43 (Cx43) message between control and heptachlor-treated cells was observed. Western blot analyses showed hypophosphorylation patterns in cells treated with 10 microg/ml heptachlor and heptachlor epoxide for 1 h with no recovery within 24 h. Immunostaining of Cx43 protein in normal HBEC indicated that heptachlor and heptachlor epoxide caused a loss of Cx43 from the cell membranes at noncytotoxic dose levels. Taken together, these results suggest that heptachlor and heptachlor epoxide can alter GJIC at the post-translational level, and that, under the conditions of exceeding a threshold concentration in the breast tissue containing 'initiated' cells for a long time and not being counteracted by anti-tumor-promoting chemicals, they could act as breast tumor promoters.

Base Sequence↗