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PubMedDate not supplied

Relationship between intercellular communication and adriamycin resistance in non-small cell lung cancer.

The adriamycin chemosensitivity and extent of gap junctional intercellular communication were assessed in a panel of seven human non-small cell lung cancer (NSCLC) cell lines. Communication was assessed by autoradiographic detection of transfer of 3H uridine nucleotides between coupled cells. The strength of coupling varied widely between the cell lines and they could be separated into 3 groups: those which exhibited strong coupling, L-DAN and A549; those which exhibited weak coupling, SK-MES-1, Calu-3 and NCI-H125; and an intermediate group, WIL and NCI-H23. Adriamycin chemosensitivity was assessed by both clonogenic and MTT assays. The range of IC50 values as measured by either assay was extremely narrow, with no important differences between the lines. Thus, despite the wide spectrum of intercellular communication observed in these lines, this did not correlate with their adriamycin resistance.

Autoradiography↗
PubMed1994

Loss of gap junctions from DDT-treated rat liver epithelial cells.

The mechanism by which the liver tumor promoter 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT) inhibits gap junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells could involve gap junction loss and/or decreased gap junction channel permeability. We examined these two possibilities in the present study. Immunohistochemical studies using antibodies specific to connexin43, the major gap junction protein expressed by these cells, revealed that gap junction number and size were reduced during exposure to DDT. The reductions in gap junctions (33-91%) correlated with dose-dependent (1-10 microM) and time-dependent (0.5-4 h) decreases in cell-to-cell fluorescent dye-coupling (64-85%), as well as cellular levels of phosphorylated connexin43. These effects were reversible following removal of the tumor promoter from the culture medium, although cycloheximide reduced the level of gap junction reformation. The losses in gap junctions were not due to decreased connexin43 gene expression since steady-state levels of connexin43 mRNA were not similarly affected by DDT. Fenarimol (10 microM), a structural analog of DDT, did not inhibit GJIC and had no effect on gap junction structure or connexin43 expression. These data suggest that the inhibition of GJIC by DDT resulted from the removal of gap junctions from the plasma membrane and their degradation rather than simply a decrease in their permeability.

Animals↗
PubMed1998

Tight junctions.

Tight junctions are the most apical intercellular junctions of epithelial and endothelial cells and create a regulatable semipermeable diffusion barrier between individual cells. On a cellular level, they form an intramembrane diffusion fence that restricts the intermixing of apical and basolateral membrane components. In addition to these well defined functions, more recent evidence suggests that tight junctions are also involved in basic cellular processes like the regulation of cell growth and differentiation.

Animals↗
PubMed1989

Brain edema in delayed radiation necrosis: study of capillary ultrastructure--case report.

A 42-year-old male was found to have cerebral radiation necrosis 2 years after a split course of radiation therapy following subtotal excision of a left parasagittal meningioma. The surgical specimens were studied by means of conventional ultrathin sectioning and freeze-fracture replication techniques. The electron density of the capillary endothelium was decreased, as was the degree of surface infolding. The width was irregular, and there was an unusually large number of pinocytotic vesicles (37/micron 2). The endothelium was also discontinuous, and the basal laminae were irregular in thickness. The pericapillary space was markedly enlarged, and accumulation of a fibrin-like substance was noted in the extravascular space. The pericapillary zone contained inflammatory cells. However, the tight junctions were preserved and the intercellular junctions were composed of five strands that appeared to consist of continuous particles. The authors conclude that activated pinocytotic vesicles play an important role in increasing vessel permeability in delayed cerebral radiation necrosis and that leakage may occur through interruptions in the endothelium.

Adult↗
PubMed1981

Prepontine epithelium-lined cyst. Case report.

A 30-year-old woman presented with recurrent episodes of severe headache associated with visual disturbances. Neurological examination showed minimal neurological defects. Angiography, computerized tomography, and radioisotope cisternography revealed a large cyst in the prepontine region, which did not communicate with either the subarachnoid space or the ventricular system. Histologically, the cyst was lined by columnar and/or cuboidal cells, which contained materials positive on periodic acid-Schiff staining. Ultrastructurally, there were two types of cells, ciliated and noncillated. Characteristic findings were continuous basement membrane, microvilli covered with electron-dense material, several intercellular junctional devices, and an open intercellular space which was occasionally filled with a migrating cell. These findings would support the view that the epithelial cyst with such features was derived from endodermal tissues rather than from neuroepithelium. Electron microscopic examination is indispensable in making a correct diagnosis of intracranial cysts.

Adult↗
PubMed2003

Ultrastructural and ultracytochemical study of the human nasal respiratory epithelium in vasomotor rhinitis.

OBJECTIVES: Several pieces of evidence have suggested that nitric oxide (NO) fulfills important functions in the respiratory mucosa, under both normal and pathological conditions. This study was performed to investigate the role of NO in the nasal respiratory epithelium of patients affected by vasomotor rhinitis. The structure and ultrastructure of the epithelium were also examined. MATERIAL AND METHODS: The localization of NO synthase activity was determined by means of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase ultracytochemistry. Nasal mucosa was obtained from patients who had undergone surgical therapy for reduction of the inferior turbinate. RESULTS: Examination of hematoxylin-eosin-stained sections revealed that most of the nasal mucosa covering the surgical samples was characterized by severe epithelial damage. The ultrastructural study confirmed the light microscopic observations. Ciliary loss, absence of the intercellular junctions and distension of the intercellular spaces were found in the damaged epithelium. The basement membrane was frequently interrupted. Some epithelial cells were identified as basal cells. Other cells of the damaged epithelium were probably involuted ciliated and goblet cells. The ultracytochemical study showed that the basal cells were NADPH-diaphorase-negative in healthy subjects and strongly NADPH-diaphorase-positive in subjects with vasomotor rhinitis. CONCLUSIONS: It is suggested that NO has cytotoxic effects and causes inhibition of mitotic activity in the basal cells, leading to epithelial disruption and breakdown of the protective functions of the epithelium.

Adult↗
PubMed1985

Permeability studies of the guinea pig placental labyrinth. II. Tracer permeation and freeze-fracture of fetal endothelium.

Permeability of the fetal endothelium within the guinea pig placental labyrinth is studied by means of horseradish peroxidase (HRP) and ionic lanthanum as diffusion tracers. The paracellular transport of HRP is restricted by the occluding junctions of the fetal endothelium. In contrast, ionic lanthanum readily permeates most of the intercellular junctions and rapidly infiltrates the basal lamina. Freeze-fracture replicas reveal zonulae occludentes connecting the fetal endothelial cells. The network of the zonulae occludentes is variable, exhibiting highly complex areas as well as single strand interconnections. A correlation between the permeability studies and freeze-fracture findings is discussed.

Animals↗
PubMed2001

Cell-cell adhesion in human fibroblasts requires calcium signaling.

In connective tissues, intercellular adhesion is essential for tissue morphogenesis, development and wound healing. However, the signaling mechanisms initiated by cell-cell adhesion in fibroblasts and that regulate it are not known. In this study we tested the hypothesis that intracellular calcium signaling is required to mediate intercellular adhesion between fibroblasts. Fura-2 or fluo-3 labeled human fibroblasts were used to investigate calcium homeostasis during intercellular adhesion. After contact with suspended fibroblasts there was a rise in cytosolic free calcium ([Ca2+]i) and multiple calcium oscillations in substrate-attached cells. Antibodies against the extracellular but not the cytoplasmic domain of cadherin induced a similar calcium response, indicating that these responses were initiated by cadherin binding. As shown by the near-plasma membrane Ca2+ indicator (Fura-C18) and by confocal microscopy of fluo-3-loaded cells, [Ca2+]i transients probably originated at sites of cell-cell contact. Cell-cell adhesion was dependent on both calcium influx through membrane channels and release of Ca2+ from internal calcium stores, because the calcium channel inhibitor LaCl3 or pretreatment of cells with thapsigargin significantly inhibited (>35%) cell-cell attachment. The [Ca2+]i changes induced by cell-cell adhesion were temporally correlated with increased recruitment of intercellular junctional proteins into the cytoskeleton and movement of GFP-actin to sites of cell-cell contact. [Ca2+]i responses induced by intercellular adhesion were essential for both junctional protein recruitment and the establishment of strong cell-cell contacts, as loading cells with BAPTA/AM significantly inhibited cell-cell adhesion and recruitment of cadherins and beta-catenin to the actin cytoskeleton. Actin depolymerization by cytochalasin D dramatically reduced cell-cell adhesion and recruitment of cadherins and catenin to the actin cytoskeleton. These results demonstrate that cadherin-cadherin interaction induces [Ca2+]i transients during cell-cell adhesion in fibroblasts, and these calcium signals regulate cell-cell adhesion through remodeling of cortical actin and recruitment of cadherins and beta-catenin into intercellular junctions.

Actin Cytoskeleton↗
PubMedDate not supplied

Connexin26 regulates the expression of angiogenesis-related genes in human breast tumor cells by both GJIC-dependent and -independent mechanisms.

We previously reported that over-expression of connexins in mammary tumor cells retarded tumor growth in vivo in the absence of appreciable gap junction formation, highlighting a possible connexin-linked, but gap junctional intercellular communication (GJIC)-independent mechanism. In the current study, we engineered GJIC-deficient MDA-MB-435 human breast tumor cells to express a chimeric Cx26 where the green fluorescent protein was fused to the amino-terminal of Cx26 (GFP-Cx26). Characterization of this chimeric protein revealed that GFP-Cx26 assembled into non-functional gap junction-like clusters that were impermeable to Lucifer Yellow. In contrast, expression of wild-type Cx26 or Cx26 tagged at the carboxy terminal with yellow fluorescent protein, efficiently rescued GJIC in these tumor cells. Interestingly, by screening 96 tumor-related genes, we observed that the expression of Cx26 or GFP-Cx26 in the tumor cells up-regulated both the transcription and the translation of thrombospondin-1 (TSP-1), an anti-angiogenic molecule. Affymetrix array analysis extended the list of Cx26 or GFP-Cx26 regulated genes by ten candidates including connective tissue growth factor (CTGF), another angiogenesis-related gene. CTGF mRNA and protein levels were found to be down-regulated by both Cx26 and GFP-Cx26. Thus, our data indicates that Cx26 regulates angiogenesis-related molecules by mechanisms that are both GJIC-dependent and -independent.

Connective Tissue Growth Factor↗
PubMed1977

Endothelial cell morphology in areas of in vivo Evans blue uptake in the aorta of young pigs. II. Ultrastructure of the intima in areas of differing permeability to proteins.

The fine structure of the intima of the pig aortic arch is described for areas of spontaneously differing in vivo endothelial permeability, as demarcated by uptake of the protein-binding azo dye Evans blue. Areas of enhanced permeability (blue areas) consistently show a variety of features not observed in areas devoid of dye accumulation (white areas). The subendothelial space of blue areas is markedly thickened and edematous, containing collagen, elastic tissue elements, and undifferentiated cells dispersed in an amorphous floccular matrix of low electron density. Endothelial cells in blue areas are generally cuboidal, with relatively short, frequently vacuolated junctions. In contrast, endothelial cells from white areas are flat and elongate, with long intercellular junctions exhibiting many interdigitations. Cytoplasmic differences include a well-developed rough endoplasmic reticulum and more frequent lysosomal bodies in blue areas and a prominent Golgi apparatus in the endothelium of white areas. Additionally, endothelial cell injury or death with and without denudation occurs with a significantly greater frequency in blue relative to white areas. An endothelial glycocalyx is some threefold thicker over the surface of white relative to blue areas. It is concluded that neither endothelial structure nor function are homogeneous within the aortic arch of the young pig and that areas of spontaneously differing permeability to proteins are associated with a spectrum of alterations in endothelial and intimal morphology.

Animals↗
PubMed1992

Transcellular openings through microvascular walls in acutely inflamed frog mesentery.

Openings in the endothelium of frog mesenteric microvessels associated with acute inflammation following mild thermal injury have been examined by reconstruction from serial ultrathin sections. While all the openings lay close to the intercellular junctions only a minority (seven out of thirty-eight) were continuous with the intercellular clefts. The majority of gaps or openings (thirty-one out of thirty-eight) were transcellular and passed through the peripheral cytoplasm of one endothelial cell, separated from the intercellular cleft by a cellular process which was usually less than 2 microns wide.

Animals↗
PubMed1996

Desmoplakin expression and organization at human umbilical vein endothelial cell-to-cell junctions.

Desmoplakin is an intracellular component of desmosomes which plays a role in the anchorage of intermediate filaments to these structures. We report here that, despite the absence of desmosomes, cultured endothelial cells from human umbilical vein express desmoplakin I and II both at mRNA and protein level. Desmoplakin I/II are found only in the detergent insoluble fraction suggesting that most of the protein is linked to the cytoskeleton. Desmoplakin I/II could be detected by western blot only in long confluent cells even if desmoplakin mRNA levels are unchanged by cell confluency. This suggests that desmoplakin might be stabilized at protein level by its association with junctional components. Immunofluorescence confocal microscopy showed that desmoplakin codistributes with VE-cadherin and plakoglobin along the lateral cell membrane. In contrast, desmoplakin localization was distinct from that of PECAM, an endothelial specific junctional protein localized outside adherence junctions. Endothelial cells do not have keratins but they express vimentin. In confluent cells vimentin forms peripheral filaments which attach to the cell membrane in areas at desmoplakin localization. These data suggest that desmoplakin may participate in the molecular organization of interendothelial junctions by interacting with VE-cadherin and promoting vimentin anchorage. This new type of intercellular junction seems to correspond to the "complexus adhaerentes' described in vivo in lymphatic endothelium.

Blotting, Northern↗
PubMed1992

Cytoplasmic bridges and gap junctions in an insect cell line (Aedes albopictus).

Cell pairs of an insect cell line (Aedes albopictus, clone C6/36) were used study simultaneously the diffusional and electrical properties of intercellular junctions. Diffusion studies involved injection of fluorescent molecules into one cell of a cell pair and visual inspection of their intercellular redistribution. Electrical measurements involved a dual voltage clamp method and whole-cell recording with patch pipette. The voltage clamp protocol was aimed at examining the dependency of the junctional conductance, gj, on membrane potential, Vm. Cell pairs exhibiting a voltage-dependent gj were found to allow intercellular diffusion of Lucifer Yellow CH (molecular mass, 443 Da), but not of FITC-dextran (molecular mass, 4,400 Da). This response pattern is consistent with the presence of gap junctions in the intercellular junctions. Cell pairs showing no voltage dependence of gj were found to permit intercellular diffusion of both Lucifer Yellow CH and FITC-dextran (dextran labelled with fluorescein isothiocyanate). This behaviour is compatible with the presence of cytoplasmic bridges connecting the two adjacent cells. Hence, in culture the cells investigated express two kinds of intercellular structures, gap junctions and cytoplasmic bridges.

Aedes↗
PubMed2004

Dominant negative effect of connexin33 on gap junctional communication is mediated by connexin43 sequestration.

Gap junctional intercellular communication is involved in the control of cell proliferation and differentiation. Connexin33, a member of the multi-gene family of gap junction proteins, exerts an inhibitory effect on intercellular communication when injected into Xenopus oocytes. However, the molecular mechanisms involved remain to be elucidated. Our results show that connexin33 was only expressed within the seminiferous tubules in the testis. In contrast to the majority of connexins, connexin33 was unphosphorylated. Immunoprecipitation experiments revealed that connexin33 physically interacted with connexin43, mainly with the phosphorylated P1 isoform of connexin43 but not with connexin26 and connexin32, two other connexins expressed in the tubular compartment. In Sertoli cells and COS-7 cells, connexin43 was located at the plasma membrane, whereas in connexin33 transfected cells, the specific association of connexin33/43 was sequestered in the intracellular compartment. High-resolution fluorescent deconvolution microscopy indicated that the connexin33/43 complex was mainly found within early endosomes. Sequestration of connexin33/43 complex was associated with a complete inhibition of the gap junctional coupling between adjacent cells. These findings provide the first evidence of a new mechanistic model by which a native connexin, exerting a dominant negative effect, can inhibit gap junctional intercellular communication. In the testis, connexin33 could exert a specific role on germ cell proliferation by suppressing the regulatory effect of connexin43.

Animals↗
PubMed2007

The role of dynamin 3 in the testis.

We report here that dynamin 3 in the testis is associated with structures termed tubulobulbar complexes that internalize intact intercellular junctions during sperm release and turnover of the blood-testis barrier. The protein lies adjacent to an actin-Arp2/3 network that cuffs the double plasma membrane tubular invagination at the core of each complex. To explore the possible relationship between dynamin 3 and nectin-based adhesion junctions, we transiently transfected DsRed-tagged dynamin 3 into MDCK cells stably transfected with eGFP-tagged nectin 2, one of the adhesion molecules known to be expressed in Sertoli cells at adhesion junctions. Cells transfected with the dynamin 3 construct had less uniformly distributed nectin 2 at intercellular contacts when compared to control cells expressing only nectin 2 or transfected with the DsRed plasmid alone. Significantly, tubular extensions positive for nectin 2 were visible projecting into the cells from regions of intercellular contact. Our findings are consistent with the conclusion that dynamin 3 is involved with tubulobulbar morphogenesis. Dynamin 3 also occurs in concentrated deposits around the capitulum and striated columns in the connecting piece of sperm tails suggesting that the protein in these cells may function to stabilize the base of the tail or serve as a reservoir for use during or after fertilization.

Actin-Related Protein 2-3 Complex↗
PubMed1984

Metabolic cooperation between argininosuccinate synthetase and argininosuccinate lyase deficient human fibroblasts.

Human fibroblasts deficient in either argininosuccinate synthetase or argininosuccinate lyase show low levels of incorporation of [14C]citrulline into protein. However, when these two cell types are co-cultured [14C]citrulline incorporation is restored to the levels found in control cultures. This metabolic cooperation is cell-density-dependent and does not occur by diffusion of argininosuccinate into the medium. Our results indicate that argininosuccinate passes between the two cell types via intercellular junctions, and this system provides a simple and accurately quantifiable model for the study of intercellular communication.

Arginine↗
PubMed1997

Junctions between the sinus endothelial cells of rat spleen.

Junctions between the sinus endothelial cells of rat spleen were examined by electron microscopy, using both freeze-fracture and detergent-extraction techniques. Adherens and tight junctions were observed. Adherens junctions were the predominant junctional structures between endothelial cells and were located on basolateral and lateral surfaces. At the basolateral adherens junctions, actin filaments were associated with the junctional membranes and were continuous with the actin filaments in stress fibers. Cross-bridges were present in the interspaces of the adherens junctions and spacing of the bridges was fairly regular. A form of tight junction, the macula occludens, was also observed between the endothelial cells, but it was not observed at every cellular apposition. Electron-dense material, adjoining the cytoplasmic surfaces of membranes in the tight junctions, separated the junctional membranes from masses of thin filaments. At basolateral tight junctions, the actin filaments were continuous with those in the stress fibers. Based on these observations, the two intercellular junctions were considered to play important roles in sinus functions.

Animals↗
PubMed1986

Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia.

A tight junction-enriched membrane fraction has been used as immunogen to generate a monoclonal antiserum specific for this intercellular junction. Hybridomas were screened for their ability to both react on an immunoblot and localize to the junctional complex region on frozen sections of unfixed mouse liver. A stable hybridoma line has been isolated that secretes an antibody (R26.4C) that localizes in thin section images of isolated mouse liver plasma membranes to the points of membrane contact at the tight junction. This antibody recognizes a polypeptide of approximately 225,000 D, detectable in whole liver homogenates as well as in the tight junction-enriched membrane fraction. R26.4C localizes to the junctional complex region of a number of other epithelia, including colon, kidney, and testis, and to arterial endothelium, as assayed by immunofluorescent staining of cryostat sections of whole tissue. This antibody also stains the junctional complex region in confluent monolayers of the Madin-Darby canine kidney epithelial cell line. Immunoblot analysis of Madin-Darby canine kidney cells demonstrates the presence of a polypeptide similar in molecular weight to that detected in liver, suggesting that this protein is potentially a ubiquitous component of all mammalian tight junctions. The 225-kD tight junction-associated polypeptide is termed "ZO-1."

Animals↗