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PubMed2000

Cooperation of bcl-2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication.

The objectives of this study were to isolate several rat liver epithelial cell clones containing the human bcl-2 and myc/bcl-2 genes in order to study their potential cooperative effect on neoplastic transformation and gap junction-mediated intercellular communication (GJIC) and to test the hypothesis that the loss of GJIC leads to tumorigenesis. Using anchorage-independent growth as a surrogate marker for neoplastic transformation, we transfected both normal rat liver epithelial cells, WB-F344, and a WB-F344 cell line overexpressing v-myc with human bcl-2 cDNA. Those cell lines that only expressed v-myc or human bcl-2 were unable to form colonies in soft agar. However, those cell lines that overexpressed both v-myc and human bcl-2 showed varying ability to form colonies in soft agar, which did not correlate with their human bcl-2 expression level. In order to test if there was a correlation between cell line growth in soft agar and the ability to communicate through gap junctions, we performed scrape load dye transfer and fluorescence recovery after photobleaching assays. Our results show that v-myc and human bcl-2 can cooperate in the transformation of normal cells, but the degree to which the cells are transformed is dependent on the cells' ability to communicate through gap junctions.

Animals↗
PubMed1977

Intercellular gap junctions in the developing retina and pigment epithelium of the chick.

Gap junctions are found in the pigment epithelium, between retina and pigment epithelium and in the retina of 5-14 day chick embryos, they are identified using block staining and extracellular tracer techniques. In the pigment epithelium gap junctions are found between cell bodies and interdigitating processes and many change their position during development. Gap junctions between retina and pigment epithelium are only made by undifferentiated retinal ventricular cells and may provide intercytoplasmic pathways important for photoreceptor differentiation. Retinal gap junctions are found in an outer zone next to the pigment epithelium and inner zone near the vitreous, they are only seen between ventricular cells but may provide pathways for ganglion cell specification. The role of gap junctions in the generation of retinal neurons is discussed.

Animals↗
PubMed1993

Cancer prevention by carotenoids. Mechanistic studies in cultured cells.

In 10T1/2 cells several dietary carotenoids have been shown to be capable of inhibiting carcinogen-induced neoplastic transformation. Their action appears qualitatively similar to the previously documented action of retinoids in this cell system; however, higher concentrations (10-1000-fold) are required. Both types of compound were found to strongly upregulate gap junctional intercellular communication, and these activities were statistically correlated. Upregulation of gap junctional intercellular communication was caused by the increased expression of connexin 43, a structural protein of the gap junction. Increased junctional communication has been proposed to be mechanistically linked to inhibition of transformation in 10T1/2 cells. In this model the gap junction serves as a conduit for growth regulatory signals from normal to initiated cells. These putative signals act to suppress transformation of the carcinogen-initiated cell.

Animals↗
PubMed2005

Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wild-type connexin43.

Oculodentodigital dysplasia, a rare condition displaying congenital craniofacial deformities and limb abnormalities, has been associated with over 20 known human connexin43 (Cx43) mutations. The localization of two of these mutants, G21R and G138R, was examined in Cx43-positive normal rat kidney cells (NRK) and Cx43-negative gap junctional intercellular communication-deficient HeLa cells. Green fluorescent protein-tagged and untagged Cx43 G21R and G138R mutants were transported to the plasma membrane and formed punctate structures reminiscent of gap junction plaques in both NRK and HeLa cells. Further localization studies revealed no significant trafficking defects as subpopulations of Cx43 mutants were found in both the Golgi apparatus and lysosomes, not unlike wild-type Cx43. Dual patch clamp functional analysis of the mutants expressed in gap junctional intercellular communication-deficient N2A cells revealed that neither G21R nor G138R formed functional gap junction channels, although they successfully reached cell-cell interfaces between cell pairs. Importantly, when either mutant was expressed in NRK cells, dye coupling experiments revealed that both mutants inhibited endogenous Cx43 function. These studies suggest that, although patients suffering from oculodentodigital dysplasia possess one wild-type Cx43 allele, it is likely that Cx43-mediated gap junctional intercellular communication is reduced below 50% because of a dominant-negative effect of mutant Cx43 on wild-type Cx43.

Abnormalities, Multiple↗
PubMed1992

[The mechanism of formation of alveolar pores (Kohn's pores) in neonatal rabbits].

The mechanism of the formation of alveolar pores (Kohn's pores) in neonatal male rabbits was studied by scanning electron microscopy and scanning electron microscopic morphometric analysis. The number of alveolar pores per alveolus was increased after birth. About 80 percent of alveolar pores had Type II alveolar epithelial cells on their edges when the rabbits were 1-day old. This percentage decreased thereafter. Circle-like intercellular junctions of Type I cells were frequently observed in or around the alveolar pores and Type II cells frequently attached to these junctions in the early neonatal stage. The alveolar pores with Type II cells which were mainly faced this side of alveolar lumen, and Type II cells which were separated from the pores tended to be found at the points where three or more Type I alveolar epithelial cells gathered in the early neonatal stage. However, alveolar pores with Type II cells which were mainly faced other side of the alveolar lumen, and alveolar pores without Type II cells tended to be found between two Type I cells. At the rims of the pore, crescent-shaped Type II cells located between circle-like intercellular junctions were frequently observed in the early neonatal stage. In conclusion. 1) One of the function of Type II cells is to form the alveolar pores. 2) Alveolar pores are formed by Type II cells which have penetrated into the alveolar wall and faced both sides of the alveolar lumina. Type II cells combine the Type I alveolar epithelial cells of both sides of the alveolar wall and make pores with circle-like intercellular junctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interleukin-1 alpha suppresses gap junction-mediated intercellular communication in human endothelial cells.

Interleukin-1 alpha (IL-1 alpha) is a potent modulator of endothelial cell-surface properties and function as well as an inhibitor of endothelial cell proliferation. The present experiments demonstrate that IL-1 alpha can also suppress gap junction activity as measured by dye-coupling assays on human umbilical vein endothelial cells (HUVEC). The effect of IL-1 alpha is dose- and time-dependent, inhibitable by IL-1 receptor antagonist, independent of changes in intracellular [Ca+2], and distinguishable from the short-term effects of phorbol 12-myristate 13-acetate. Interestingly, IL-1 alpha was not effective in reducing cell communication in senescent HUVEC which exhibit lower coupling than early-passage cells and for which elevated levels of IL-1 alpha transcript and polypeptide had been reported previously. These results suggest a novel role for IL-1 alpha in the regulation of intercellular communication, which may be related to its role as a regulator of endothelial differentiation and senescence.

Alkaloids↗
PubMed1988

An ultrastructural analysis of plasma membrane in the U18666A cataract.

Because the cholesterol concentration of lens fiber cell membrane in general and lens intercellular junctions in particular is comparatively high, it is likely that it plays a major role in maintaining these structures. In addition, the high concentration of cholesterol in fiber cell membrane is also likely to influence membrane fluidity. Subcutaneous injections of U18666A (3 beta-(2-diethylaminoethoxy) androst-5-en-17-one HCl) into rats effects: (1) a blockade of sterolgenesis in the lens; (2) a depletion of lens fiber cell membrane cholesterol; and (3) the development of irreversible nuclear cataracts. In the present study we have analyzed the ultrastructure of lens fiber cell membrane in adult rats, these by the freeze-etch technique. Whereas it has been previously demonstrated that intercellular junctions comprise approximately one-third of the intermediate cortical fiber cell membrane in adult rats, these junctions were completely absent between comparable fiber cells taken from opaque regions of the U18666A cataractous lenses. There was also a concomitant increase in the extracellular space between the opaque fiber cells and a substantial redistribution of intramembrane proteins in the exoplasmic and protoplasmic faces of these cells. These findings support a "hypothesis" that inhibition of endogenous lens cholesterol production leads to damage and/or degeneration of lens fiber cell membrane in general and in intercellular junctions in particular, resulting in the production of an irreversible nuclear cataract.

Androstenes↗
PubMed1983

Ionic selectivity of the paracellular shunt path across rabbit corneal endothelium.

We have measured the dilution and biionic potentials across the isolated rabbit corneal endothelium in order to learn about the ionic selectivity of its intercellular junctions. Single-salt dilution potentials have been measured as a function of [NaCl] or [NaHCO3] gradients across the tissue. Biionic potentials were similarly measured by replacing Na+ with K+ on either side of the tissue. The potentials thus measured were fit to the constant field equation and to an approximation of it to obtain the ionic permeabilities for K+, HCO-3 and Cl- relative to Na+. The permeability sequence obtained was PK greater than PNa greater than PHCO3 approximately equal to PCl. Potentials were also measured after imposing an osmotic gradient across the preparation using sucrose. The results obtained with all these methods are consistent and suggest that this tissue is slightly more permeant to cations than anions, but that the selectivity of the intercellular junction is relatively low. From these experiments, a 30 mM gradient of salt across the endothelial layer would be needed in order to explain the observed spontaneous potential difference (about 1 mV, aqueous negative) across that layer if the potential was due to the selectivity of the intercellular junctions. Such a value for the gradient is much larger than theoretical estimates of it; therefore, we favor electrogenic transport of HCO-3 as a better explanation for the origin of the spontaneous potential difference.

Animals↗
PubMed1976

The distribution of intercellular gap junctions in the developing retina and pigment epithelium of Xenopus laevis.

The distribution of gap junctions in the developing retina and pigment epithelium of Xenopus has been examined from optic vesicle to photoreceptor outer segment stages. In the retina and pigment epithelium walls of the optic vesicle gap junctions are found between ventricular cells in the apical contact zone and close to the outside wall; a neural tube type of distribution. Optic cup formation brings the retina and pigment epithelium into contact and gap junctions form between them. After the stage of retinal specification gap junctions, previously more numerous dorsally, are more often found in the ventral retina and pigment epithelium. They continue to be found in the retinal centre between ventricular cell processes in the apical contact zone and near the vitreal basement lamella above the ganglion cell layer until stage 35. Gap junctions are occasionally made by ganglion cells and their axons, providing possible pathways initiating cell differentiation. After stage 35 gap junctions seem to be confined to the peripheral rim of the eye cup where new cells are formed throughout larval life. The observed distribution suggests that gap junctions may provide intercytoplasmic pathways for retinal specification intrinsic to the retina and pigment epithelium.

Animals↗
PubMed1998

Deficient epithelial-fibroblast heterocellular gap junction communication can be overcome by co-culture with an intermediate cell type but not by E-cadherin transgene expression.

Epithelial, fibroblast and intermediate cell lines were employed to examine the mechanism(s) essential for heterocellular gap junction intercellular communication in vitro. These cell lines were characterized extensively for cell type based on morphology, intermediate cytoskeletal proteins, cell adhesion molecules and their associated proteins, tight junction proteins as well as functional differentiation. All cell types expressed connexin43 and were dye-coupled in homocellular culture. Epithelial and intermediate cells or fibroblasts and intermediate cells readily assembled heterocellular connexin43-positive gap junction plaques when co-cultured, while gap junction plaques in mixed cultures of epithelial cells and fibroblasts were rare. Dye microinjection studies were used to show that there was little gap junction intercellular communication between epithelial cells and fibroblasts. However, intermediate cells were able to communicate with epithelial cells and, to a lesser extent, fibroblasts and could transfer dye to both epithelial cells and fibroblasts when all three cell types were cultured together. Fibroblasts that were stably transfected with a cDNA encoding E-cadherin had a greater tendency to aggregate and exhibited a more epithelial-like phenotype but heterocellular gap junction intercellular communication with epithelial cells, which endogenously express E-cadherin, was not enhanced. These results suggest that mutual expression of E-cadherin is insufficient to stimulate gap junction formation between epithelial cells and fibroblasts. Moreover, our results also demonstrate that communication gaps between epithelial cells and fibroblasts can be bridged by intermediate cells, a process that may be important in mammary gland development, growth, differentiation and cancer.

Animals↗
PubMed2004

[Effect of borneol on the intercellular tight junction and pinocytosis vesicles in vitro blood-brain barrier model].

OBJECTIVE: To explore the mechanism of borneol in opening the blood-brain barrier (BBB). METHODS: Borneol contained serum was prepared and using Matin-Darby canine kidney epithelium (MDCKE) cell line as the in vitro BBB model to observe the effects of borneol on intercellular tight junction (ICTJ) and pinocytosis vesicles of BBB model. RESULTS: Borneol reduced the ICTJ and caused increase of the number and enlarged the diameter of vesicles. The ICTJ was opened firstly 4 hrs after borneol treatment, then the pinocytosis was affected 24 hrs later. The effects disappeared 24 hrs after removal of the borneol contained serum, indicating that the above-mentioned effects were reversible. CONCLUSION: Borneol could obviously loosen the ICTJ in BBB, accelerate the transportation of substance through the intercellular passage, it also could increase the number and volume of pinocytosis vesicles in BBB cells, thus to accelerate the transportation of substance by way of cell pinocytosis.

Animals↗
PubMed2004

Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants.

In the testis, Sertoli cells establish intercellular junctions that are essential for spermatogenesis. The SerW3 Sertoli cell line displays some features of native Sertoli cells. Western blot and immunofluorescence analyses showed that SerW3 Sertoli cells expressed typical components of tight (occludin and zonula occludens-1), anchoring (N-cadherin) and gap (connexin 43) junctions. Testicular toxicants (DDT, pentachlorophenol, dieldrin, dinitrobenzene, cadmium chloride, cisplatin, gossypol, bisphenol A and tert-octylphenol) affected intercellular junctions by either reducing the amount or inducing aberrant intracellular localization of these membranous proteins. Phosphodiesterase inhibitors (isobutyl methylxantine, rolipram, zaprinast, zardaverine) did not alter junctional-complex component levels but caused a rapid and reversible redistribution of these proteins to the cytoplasmic compartment. The present study showed that occludin, ZO-1, N-cadherin and specifically Cx43 could be early targets for testicular toxicants. The SerW3 cell line therefore appears as a useful in vitro model to evaluate molecules with potential anti-reproductive effects.

Animals↗
PubMed2003

[The scientific and clinical value of molecular genetic changes in the intercellular gap junctions observed in colon cancer].

Colon cancer is one of the most widespread pathologies with high mortality due to recurrence and metastasis. The molecular methods of diagnosis, prognostication and biotherapy in colorectal cancer enjoyed a rapid progress during the recent decades. The hypothesis on the key role of impaired intercellular gap junctions in the onset and progression of malignant tumors is a promising trend in carcinogenesis research. We have recently discovered a variety of tumor-specific mutations of connexin 43 gene in advanced colorectal cancer (Oncogene. -2002.-Vol.21, No.32-pp.4992-4996), which confirms the above hypothesis in malignant tumor progression. We believe that further studies of connexins' mutation changes in tumor growth is a promising trend in research of its etiology and pathogenesis and in designing new methods of diagnostics and treatment of colonic and other gastrointestinal cancers.

Adenocarcinoma↗
PubMed2003

ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs.

INTRODUCTION: The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion. METHODS AND RESULTS: Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by 69% +/- 20% in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in alpha-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline: 1.0 +/- 0.2 nM: 6/12 vs 0/12; 7.7 +/- 0.6 nM: 7/13 vs 1/12; and 69.2 +/- 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size. CONCLUSION: The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.

Animals↗
PubMed1977

"Tight" junctions in the sheath of normal and regenerating motor nerves of the crayfish, Orconectes virilis.

"Tight" or occluding intercellular junctions occur between adjacent glial processes in normal and regenerating crayfish motor nerve sheaths. Although infrequent, these junctions possess the ridge and groove configuration characteristics of freeze-cleaved occluding junctions. When present, nerve sheath tight junctions consist of a single, or at most a few, parallel intramembrane ridges situated on the EF membrane face of the glial plasma membrane. Consequently, such contacts are rarely recognized in thin sections of plastic-embedded nerve sheaths. Crayfish nerve sheath tight junctions are of the fascia occludens type and, therefore, do not impede solute flow across the nerve sheath. Fasciae occludentes of regenerating nerve sheaths occur in close proximity to discoid plaque-like aggregates of particles assumed to represent maculae adhaerentes. This relationship, which was not observed in normal nerve sheaths, suggests a functional association between the two types of junctions, perhaps developmental transformation of one junction type into the other. Although ridges and grooves of tight junctions occur next to cross-fractured trans-glial channels, no functional significance is proposed for this relationship. This study is the first report of tight intercellular junctions in crustacean glial nerve sheaths.

Animals↗
PubMed2005

FIA/MS analysis of temporally ozonated benzo[a]pyrene and pyrene and their reaction products: inhibition of gap junction-mediated intercellular communication.

In this study, the polycyclic aromatic hydrocarbons, benzo[a]pyrene (BaP) and pyrene, were subjected to temporal ozonation. The products from ozonation of 5 mg l(-1) BaP and 5 mg l(-1) pyrene, for varying time intervals (0, 1, 2, 3, 4, 5, 6, 8, 10, 20, and 30 min) were tested for their effects on gap junction-mediated intercellular communication (GJIC) in Clone 9 rat liver cells. Additionally, the ozonation products were also analyzed by flow injection analysis/mass spectrometry (FIA/MS) and the results were compared with the toxicity observed in the GJIC assay. Treatment of the Clone 9 cells with 5 mg l(-1) of ozonated BaP products resulted in a decrease in GJIC that was inversely proportional to the length of ozonation. The products from 1 min of ozonation resulted in a 92% decrease in the rate of GJIC, but with >5 min ozonation, the products did not suppress GJIC. In contrast, pyrene (0.5 mg l(-1)) required >10 min of ozonation to alleviate its effects on GJIC. FIA/MS, using atmospheric pressure chemical ionization (APCI), demonstrated products with higher molecular weights (MW) than their corresponding parent compounds, BaP (MW 252) and pyrene (MW 202). Ozonation of pyrene formed significantly fewer products than BaP. More importantly, pyrene ozonation products were constant from 1 to 10 min, while BaP ozonation products seemed to vary between time intervals. With the longer ozonation times (20 and 30 min), BaP and pyrene formed similar products (m/z peaks 157, 111, and 96). The suppression of GJIC by ozonated products seemed to correlate with oxidation of the aromatic ring framework. Further oxidation (longer ozonation times) to lower MW products correlated with restoration of normal GJIC.

Animals↗
PubMed2005

Single-cell microinjection of cytochrome c can result in gap junction-mediated apoptotic cell death of bystander cells in head and neck cancer.

BACKGROUND: Gap junction intercellular channels are required for metabolic cooperation between cells and regulate normal tissue homeostasis by means of the transfer of small molecules between contacting cells. Not surprisingly, the gap junction phenotype is frequently lost during carcinogenesis in human tissues (including those of the upper aerodigestive tract), freeing individual cancer cells from the growth control signals of normal surrounding tissues and less aggressive adjacent cancer cells. We hypothesized that gap junctional intercellular communication (GJIC) could mediate a bystander effect (apoptotic cell death) in squamous cell carcinoma of the head and neck (SCCHN) cells adjacent to individually targeted SCCHN cells. METHODS: Single-cell microinjection of cytochrome c was used to induce apoptosis in target SCCHN cells with endogenous GJIC activity and in an SCCHN cell line with exogenously introduced GJIC activity. Apoptosis was followed in target and surrounding bystander cells through light and time course microscopic characterization. All of the preceding experiments were carried out in the absence and presence of 18-beta-glycerretinic acid, a pharmacologic inhibitor of GJIC. RESULTS: When cytochrome c was introduced into SCCHN cells with endogenous GJIC activity through single-cell microinjection, bystander effects (apoptosis of nontarget cells) were observed. When GJIC activity was blocked with the specific pharmacologic inhibitor of gap junctions, 18-beta-glycerretinic acid, a bystander effect was never seen in GJIC active SCCHN cell lines. CONCLUSIONS: Gap junction intercellular channels can mediate a bystander effect in SCCHN. Inconsistencies in our data will be discussed in the context of recent advances in this field, as well as our future research directions.

Apoptosis↗