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PubMed1998

Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles.

We demonstrate by western analysis that the expression levels of TP53 (formerly known as p53), CDKN1A (formerly known as p21Waf1), CDC2 (formerly known as p34cdc2), CCNB1 (cyclin B1) and RAD51 are significantly modulated in confluent, density-inhibited human diploid cell populations exposed to doses where only a small fraction of the nuclei are actually traversed by an alpha-particle track. The extent of modulation of TP53 and CDKN1A is significantly reduced in the presence of the gap junction inhibitor lindane and in irradiated low-density cell populations. In situ immunofluorescence studies show that at doses where about 2% of the nuclei would be traversed by an alpha particle, induction of CDKN1A occurs in more cells than predicted. Furthermore, the induced cells are present in isolated aggregates of neighboring cells. Therefore, our studies at the gene expression level indicate that similar signaling pathways are induced in bystander cells that are not traversed by an alpha particle as in traversed cells, and that biological effects in cell populations are not restricted to the response of individual cells to the DNA damage they receive.

Alpha Particles↗
PubMed1991

Enhanced gap junction formation with LDL and apolipoprotein B.

Gap junctions are plasma membrane specializations involved in direct cell-cell communication. Intercellular communication is dependent upon the assembly of gap junction structures and would be influenced by agents which alter the assembly process. We investigated the effects of low density lipoprotein (LDL) on gap junction assembly between cultured Novikoff cells using quantitative dye transfer and freeze-fracture electron microscopic methods. We observed a concentration-dependent increase in dye transfer (maximum effect at 2.5 micrograms/ml) and a sixfold increase in the number of aggregated gap junction particles per cell. Immunoblots of Novikoff cells probed with anti-connexin43 antibody revealed no detectable increase in gap junction protein (connexin) levels. The influence of the different components of LDL on junction formation was also examined. First, we treated cells with cholesterol (0-150 microM) in serum-free BSA media and observed a decrease in junction assembly. Second, we added apolipoprotein-B (apo-B) in phosphatidyl choline vesicles to the cells and observed a concentration-dependent increase in dye transfer (maximum effect at 2.5 micrograms protein/ml) and a fivefold increase in the number of aggregated gap junction particles per cell. The addition of phosphatidyl choline vesicles without apo-B had no effect on gap junction formation. Thus, we demonstrated that gap junction assembly can be modulated by LDL and apo-B treatments.

Animals↗
PubMed1997

Modulation of dye-coupling and proliferation in cultured rat thymic epithelium by factors involved in thymulin secretion.

Cultures of rat thymic epithelium were used to measure the effect of thymulin secretagogues on dye-coupling and proliferation. Dye-coupling was assessed after the injection of lucifer yellow dextran which cannot permeate the connexin pore of gap junctions and the smaller, permeant cascade blue. In addition to gap junctional communication, larger intercellular bridges were demonstrated by the transfer of lucifer yellow dextran between cells. The extent of intercellular communication was found to be influenced by both cell density and the number of passages. In control cultures, intercellular communication was reduced in cell groups of low (< 20 cells/group) or high cell densities (> 100 cells/group) compared with groups of 20-60 cells. The highest coupling indices were found in subcultures 20-30. Taking these factors into account, significant decreases in coupling index were observed after pretreatment of test cultures with factors known to influence the secretion of thymulin (5 U/ml interleukin 1 (alpha and beta), 1 microM progesterone, 1 microM oestrogen, 1 microM testosterone, 1 ng/ml adrenocorticotropic hormone, 100 nM rat growth hormone) but 7.5 ng/ml thymulin had no effect on dye-coupling. The nonspecific gap junction uncoupler, octanol, abolished dye-coupling. Cellular proliferation, as measured by the uptake of tritiated thymidine, showed that the same factors that reduced coupling also increased proliferation. None of these factors affected the number of multinucleate cells present, except interleukin-1beta which caused a significant reduction in the average number of nuclei per cell. Thus rat thymic epithelium in vitro provides a model for the study of the direct action of factors on cells of the thymic microenvironment.

1-Octanol↗
PubMed1986

Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid.

Intercellular gap-junctional communication was measured using metabolic co-operation in co-cultures of argininosuccinate synthetase-deficient and argininosuccinate lyase-deficient human fibroblasts. 18-alpha-glycyrrhetinic acid (AGA) was found to inhibit communication by more than 95% at concentrations as low as 2 microM. Concentrations up to 100 microM were not cytotoxic over a period of 2 hours. Communication inhibition was of rapid onset and was readily reversible. Communication remained continuously yet reversibly blocked in cells cultured in the presence of AGA for 20 days. The related compounds 18-beta-glycyrrhetinic acid and carbenoxolone also caused communication inhibition. The effect is probably not mediated via mineralocorticoid or glucocorticoid receptors since aldosterone and glucocorticoids had no effect on communication. AGA thus has properties of a useful inhibitor in the study of intercellular junctional communication.

Carbenoxolone↗
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↗
PubMed2000

Melatonin effects on intercellular junctional communication in MCF-7 human breast cancer cells.

Melatonin exerts a direct antiproliferative effect on estrogen-responsive MCF-7 cells in culture. Recently, the importance of the anti-invasive actions of melatonin as a part of the oncostatic action of this indolamine has been reported. Gap junctional intercellular communication is known to be involved in controlling cell proliferation and differentiation, and a decrease in intercellular junctional communication has been described in highly invasive mammary cancer cells. Because melatonin at physiological doses (1 nM) shifts MCF-7 cells to a lower invasive status, we postulate that melatonin could modulate the levels of gap junctional intercellular communication in these tumor cells. To test our hypothesis, we studied gap junctional intercellular communication in MCF-7 human breast cancer cells previously (7-8 days) treated, or not, with melatonin (10 microM or 1 nM). Using the scrape-loading assay dye-transfer technique to introduce 0.05% Lucifer yellow into cells, we measured the ability of the tumor cells to transfer dye to adjacent cells. Rhodamine dextran (0.05%) was used as a control dye to verify that dye-transfer occurs through intercellular junctions. The presence of melatonin (10 microM or 1 nM) in the culture medium significantly increased (P < 0.01) the transfer of the dye to adjacent cells through gap junctions. This increase was greater at 10 microM melatonin, and averaged scan profiles of cells treated with melatonin 10 microM showed a statistically significant increase (P < 0.01) in the integrated optical density values, and a broadening of the densitometric scan. These findings suggest that melatonin could exert its antitumor action, at least in part, by increasing regulatory signals that are passed between adjacent epithelial cells through intercellular junctions.

Breast Neoplasms↗
PubMed2005

Cellular sublocalization of Cx43 and the establishment of functional coupling in IMR-32 neuroblastoma cells.

Neuroblastoma (NB) is the most common solid pediatric tumor. IMR-32 cells are a highly malignant human NB cell line with uncontrolled proliferation but with the potential to be differentiated under specific conditions. Preliminary research indicated that connexin 43 (Cx43), the most widespread of the Cx family, is aberrantly located in IMR-32 cells, which renders these cells incapable of gap junction (GJ) intercellular communication. Functioning GJ intercellular communication has been strongly associated with growth control and a decrease in tumorigenicity. 8-br-cAMP, known to initiate the differentiation process in cancer cells, was used to examine changes in Cx43 localization and expression via immunocytochemistry, Western blot analysis, and flow cytometry. Exposure of IMR-32 cells to 8-br-cAMP decreased cell proliferation, restored the abnormally localized Cx43 from around the nucleus to the cell membrane, increased de novo Cx43 protein expression, and appeared to phosphorylate Cx43 on serine (Ser) 255 and Ser262. Forskolin, an activator of cAMP dependent protein kinase (PKA), produced identical results to 8-br-cAMP demonstrating the effect that was not unique to a cAMP analog. The use of a PKA inhibitor further confirmed the specificity of 8-br-cAMP and forskolin's effect on Cx43. The cellular relocation of Cx43, combined with the increased protein expression, established first ever GJ intercellular communication between IMR-32 cells as revealed by scrape loading. These results suggest that the GJ-mediated return of growth control, as a prerequisite for further differentiation, offers a new therapeutic avenue in the treatment of NB.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

A novel technique for the study of intercellular, junctional communication: electroporation of adherent cells on a partly conductive slide.

One of the effects of neoplastic transformation by a variety of factors is a decrease in gap junctional, intercellular communication (GJIC). The investigation of junctional permeability is usually conducted through the microinjection of the fluorescent dye, Lucifer yellow, followed by observation of its migration into neighboring cells. This is a time-consuming approach, requiring expensive equipment. To overcome these problems, a novel technique was devised which takes advantage of the ability of short electric pulses to create transient "pores" on the cell membrane through which Lucifer yellow can enter, simultaneously and into large numbers of cells, with minimal disturbance to cellular metabolism. Cells were grown on a glass slide, half of which was coated with electrically conductive, optically transparent, indium-tin oxide. An electric pulse was applied in the presence of Lucifer yellow, causing its penetration into the cells growing on the conductive half of the slide, and the migration of the dye to the nonelectroporated cells growing on the nonconductive area was microscopically observed under fluorescence illumination. Using this technique, we investigated the relationship between expression of the middle tumor antigen of polyoma virus (mT) and GJIC in two representative cell systems with different responses to mT. The results show that low mT expression levels, although unable to transform rat F111 cells fully, are able to interrupt GJIC. Although parts of this mechanism might be mediated through protein kinase C (PKC), mT appears to have additional functions. PKC, however, had the opposite effect upon junctional permeability in a clone of mouse NIH-3T3 fibroblasts; intercellular communication in these cells appears to require PKC activity.

3T3 Cells↗
PubMed2006

Cx26 inhibits breast MDA-MB-435 cell tumorigenic properties by a gap junctional intercellular communication-independent mechanism.

It has been well established that the restoration of connexin expression in tumor cells often leads to a partial reversion of tumor cell phenotypes and increased growth control. In this study, a less-aggressive variant of MDA-MB-435 cells obtained from the MDA-MB-435 cell line was engineered to express gap junctional intercellular communication (GJIC)-competent Cx26, a GJIC-incompetent cell surface transported GFP-Cx26 chimera, or a Golgi apparatus-localized, disease-linked Cx26 mutant (D66H). Collectively, these cell lines were designed to establish whether Cx26 regulates tumor properties, such as migration, invasion and growth, by (i) a GJIC-dependent pathway; (ii) a mechanism requiring Cx26 transport to the cell surface; or (iii) a mechanism where Cx26 expression alone was sufficient. The expression of Cx26 and green fluorescent protein (GFP)-Cx26 decreased cell proliferation while all three Cx26 variants inhibited anchorage-independent cell growth. All three Cx26 variants also altered the distribution of filamentous actin and significantly reduced cell migration, while only the D66H mutant failed to inhibit cell invasion through matrigel. Furthermore, expression of all the Cx26 variants reduced the levels of total beta1 integrin, and decreased the activity of matrix metalloproteinase-9 (MMP-9) while increasing tissue inhibitors of MMP-1 (TIMP-1) activity. Interestingly, the expression of Cx43 regulated the same gene products without significantly affecting the tumorigenic properties of the MDA-MB-435 cells. Together, these results suggest that Cx26 expression, independent of the necessity for gap junctional intercellular communication, partially reverted MDA-MB-435 cell properties associated with tumorigenesis, and regulated the expression of genes important in cell migration and invasion.

Animals↗
PubMed2004

Interplay between paracrine signaling and gap junctional communication in ovarian follicles.

Intercellular communication is required for ovarian folliculogenesis. This is apparent in mice lacking connexin43 (Cx43, a gap junction protein strongly expressed in granulosa cells), or growth/differentiation factor-9 (GDF9, an oocyte-specific growth factor that stimulates granulosa cell proliferation and differentiation), or in mice expressing a mutant form of Kit ligand (KITL, a paracrine factor that, in the ovary, is secreted by granulosa cells to stimulate oocyte growth). In all of these mutant lines, follicle growth is impaired suggesting a possible interaction between paracrine signaling and gap junctional communication. To assess this possibility, we analyzed gene expression in mutant ovaries. Despite the lack of gap junctional coupling between granulosa cells of Cx43 null mutant ovaries, expression of the genes encoding KITL and its receptor, KIT, is maintained. Furthermore, GDF9 expression is maintained. In GDF9 null mutant ovaries, there is no apparent change in Cx43 expression and, correspondingly, the granulosa cells remain coupled. There is also no increase in granulosa cell apoptosis in ovaries lacking Cx43 or GDF9. Staining for proliferating cell nuclear antigen (PCNA) revealed that the granulosa cells of Cx43 null mutant ovaries have a reduced frequency of DNA synthesis. Using both radiolabeled thymidine incorporation and PCNA staining in vitro, we showed that recombinant GDF9 could restore the proliferation of coupling-deficient granulosa cells to the level of control cells. These results indicate that impaired folliculogenesis in mice lacking Cx43 is due at least in part to reduced responsiveness of granulosa cells to oocyte-derived GDF9, indicating an interaction between these two modes of intercellular communication.

Animals↗
PubMed1985

Effects of 12-O-tetradecanoylphorbol-13-acetate and retinoids on intercellular junctional communication measured with a citrulline incorporation assay.

Inhibition of intercellular junctional communication by 12-O-tetradecanoylphorbol-13-acetate (TPA) and retinoids was investigated using a citrulline incorporation assay. This new assay uses metabolic co-operation between argininosuccinate lyase-deficient human fibroblasts and arginosuccinate synthetase-deficient cells as a measure of junctional communication. Short-term exposure to TPA resulted in virtually complete inhibition of metabolic co-operation when V79 cells were used as the synthetase-deficient type. When synthetase-deficient human fibroblasts were used, inhibition by TPA was only partial. Exposure to high concentrations of TPA for prolonged periods resulted in partial reversal of communication inhibition and a refractory state in which cells were unresponsive to TPA. Retinoic acid and other retinoids also inhibited metabolic co-operation, but did not cause desensitisation of the type seen with TPA after prolonged exposure. Cultures which had been made refractory to TPA remained sensitive to inhibition by retinoic acid and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, indicating that these latter compounds inhibit junctional communication by a mechanism different from TPA. Simultaneous exposure of cultures to TPA and retinoic acid showed that the inhibitory effects on metabolic co-operation of these compounds were additive. Fluocinolone acetonide did not antagonise the effect of TPA. These results suggest that retinoic acid and fluocinolone acetonide exert their anti-tumor-promoting action by mechanisms which are not mediated by intercellular junctional communication.

Animals↗
PubMed1999

Regulation of cell-cell communication in rat bone cells: the effect of phorbol esters.

The skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent inhibitor of gap junctional intercellular communication. In the present study, the inhibition of cell-cell communication by TPA has been investigated in primary bone cells from newborn rat calvaria, with an emphasis on the involvement of intracellular pH (pH(i)) and cytosolic calcium ([Ca(+2)](i)) in this process. The results show that TPA (5 x 10(-)(8) M) caused a complete inhibition of intercellular communication within 40-60 min. The intercellular communication was fully restored after overnight incubation in the presence of TPA. This effect was found to be associated with an elevation of pH(i). However, neither an increase of pH(i) alone nor exposure to TPA, under conditions preventing pH(i)-shift, were found to affect intercellular communication. It is suggested that the inhibition of intercellular communication, in the presence of TPA, depends on the pH(i)-shift itself rather than on the absolute value of pH(i). In addition, elevation of cytosolic calcium by ionomycin led to the termination of intercellular communication after 30 min. This inhibitory effect was abolished when the cells were incubated for overnight with TPA and then intracellular calcium was elevated by the addition of ionomycin. These results indicate that shift of pH(i) and the increase of intracellular calcium are involved in repression of intercellular communication by TPA.

Animals↗
PubMed1989

Membrane perturbations and mediation of gap junction formation in response to taurine treatment in normal and injured alveolar epithelia.

Nitrogen dioxide is an air pollutant that causes pulmonary alterations. Employing light and transmission electron microscopy, we examined plastic sections and freeze-fracture replicas of alveolar epithelium of groups of hamsters exposed to nitrogen for 24 h to determine taurine-induced changes in intercellular junctions. Prior to exposure, one group of hamsters was given 0.5% taurine in their drinking water for 2 weeks. A second group of hamsters was given taurine-free water. The taurine-treated group was divided into three subgroups. The first subgroup was exposed to nitrogen dioxide at a concentration of 7 ppm for 24 h, the second subgroup was exposed to nitrogen dioxide at a concentration of 30 ppm for 24 h, and the third subgroup was exposed to normal room air for 24 h. The nontaurine-treated animals were similarly divided into three subgroups and treated as described above. The lungs of the hamsters exposed to nitrogen dioxide without the taurine pretreatment exhibited extensive inflammatory cell infiltration in the walls of the terminal bronchioles, alveolar ducts, and peribronchiolar alveoli. The degree of infiltration was proportional to the degree of nitrogen dioxide concentration. The taurine-treated animals exposed to nitrogen dioxide and the nontaurine-treated animals exposed to room aid did not show any inflammatory infiltrate. Freeze-fracture replicas of the tight junctional regions of the type I and type II pneumocytes revealed significant fragmentation in the nitrogen dioxide-exposed lungs. It was also observed that the tight junctions between the type I pneumocytes of the taurine-treated groups, whether exposed or not, revealed gap junction-like aggregates among the tight junction fibrils. The 30-ppm nitrogen dioxide exposed group exhibited larger and more frequent gap junctions between the pneumocytes than those observed in the 7-ppm nitrogen dioxide exposed group. The evidence suggests that taurine may have an effect on plasma membranes and intercellular communications. Changes in intercellular communication may contribute to decreased susceptibility to injury and increased pneumocyte survival.

Animals↗
PubMed1993

The role of gap junctions and ion channels in the modulation of electrical and chemical signals in human corpus cavernosum smooth muscle.

Intercellular communication through aqueous intercellular channels, known as gap junctions, has been postulated to provide an important mechanism for coordinating the rapid and synchronous responses of corporal smooth muscle during human penile erection and detumescence. Mathematical modeling analyses of drug diffusion were utilized to examine the potential physiological importance of the intercellular pathway to the regulation of smooth muscle tone in the human corpus cavernosum. In addition, patch clamp analyses and optical imaging studies were conducted to assess the ionic basis for cellular excitability and homeostasis in cultured corporal smooth muscle cells. In short, the computer modeling studies demonstrated that intercellular communication through gap junctions is likely to be the 'preferred' pathway for coordination of cellular activation and syncytial smooth muscle responses in this tissue. Moreover, the observed ion channel diversity reveals even further complexities to the modulation of corporal smooth muscle tone.

Calcium Channels↗
PubMed2005

Decreased gap junctional communication in neurobiotin microinjected lens epithelial cells after taxol treatment.

The aim of the study was to examine gap-junction-mediated intercellular communication after experimentally induced aggregations of microtubules in cultured bovine lens epithelial cells. Intercellular communication between lens cells appears to be crucial for normal lens homeostasis. However, investigations on the maintenance of direct ion and metabolite exchange via gap junctions and its quantified dependency of cytoskeletal microtubules have not been available under conditions leading to bundling of microtubules. Thus, metabolic coupling of neighboring lens epithelial cells was quantified following microinjections of neurobiotin into single cells under various conditions. In controls, intensive gap-junction-mediated intercellular communication could be documented by dye-spreading of microinjected neurobiotin. In contrast, taxol treatment for 1-3 days impaired, but did not completely block gap-junction-mediated intercellular communication. After depletion of taxol, a complete recovery of intercellular communication was achieved. In addition, confocal laser scanning microscopy and rapid-freeze deep-etch electron microscopy revealed a displacement of actin-filaments from the perinuclear cytoplasm, accompanied by an abnormal aggregation of microtubules after taxol treatment, including impeded translocation of connexin 43 from the cytoplasm into the plasma membrane. Incubation of cells with nocodazole destroyed the microtubule network, accompanied by a clear reduction of plasma-membrane-integrated connexin 43 and significant impairment of dye spreading. Thus, in lens epithelial cells intercellular communication at gap junctions made by connexin 43 depends on the integrity of the microtubule network through the translocation of connexins to the plasma membrane.

Actin Cytoskeleton↗
PubMed1989

O-antigen from Bradyrhizobium japonicum lipopolysaccharide inhibits intercellular (symplast) communication between soybean (Glycine max) cells.

The technique of fluorescence redistribution after photobleaching was utilized to measure intercellular movement of low molecular weight fluorescent hydrophilic substances across the cell wall/membrane interface between contiguous soybean (Glycine max (L.) Merr. cv. Mandarin) root cells (SB-1 cell line) in tissue culture. Lipopolysaccharide (LPS) purified from Bradyrhizobium japonicum R110d, a Gram-negative bacterium that normally infects and induces nodulation in soybean roots in vivo, inhibits intercellular communication between the soybean cells in a dose-dependent manner. In contrast, LPS from noninfecting strains failed to yield the same effect. The inhibitory activity of the LPS was localized to the O-antigen region of the LPS.

Antigens, Bacterial↗
PubMed1985

Inhibition of intercellular junctional communication in human fibroblasts by triphenylmethane, triphenylmethylchloride, tetraphenylboron and related compounds.

Intercellular junctional communication was measured using [14C]citrulline incorporation in co-cultures of argininosuccinate synthetase-deficient and argininosuccinate lyase-deficient human fibroblasts. Triphenylmethane, triphenylmethylchloride and tetraphenylboron inhibited communication at concentrations at least 12-fold lower than cytotoxic concentrations. This inhibition was of rapid onset and was rapidly reversible by washing the co-cultures. Refractoriness to inhibition did not develop after prolonged exposure. Several other compounds also induced communication inhibition, but only at concentrations slightly below cytotoxic concentrations. Treatment of co-cultures with calcium ionophore A23187 or cycloheximide did not cause communication inhibition. It is suggested that triphenylmethane, triphenylchloride and tetraphenylboron may be useful inhibitors for studying the roles of intercellular junctional communication in some biological systems.

Argininosuccinate Lyase↗
PubMedDate not supplied

The Drosophila clock gene per affects intercellular junctional communication.

The per locus of Drosophila has been implicated in the control of behavioural rhythms. In fruitfly embryos and larvae per is expressed in salivary glands. Per mutations have striking effects on intercellular communication in salivary glands: gap junction channels are modulated so that their conductance varies inversely with the period of behavioural rhythms in the mutants. A similar effect on junctional communication in the nervous system may explain how per influences behavioural rhythms.

Animals↗