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At least 811 records · Page 45Linked to original sources
PubMed2002

Intercellular communication and human prostate carcinogenesis.

Gap-junction-mediated intercellular communication (GJIC) is required for completion of embryonic development, tissue homeostasis, and regulation of cell proliferation and death. Although, as emphasized in several reports, defects or disruption of GJIC may be important in carcinogenesis, the potential role of GJIC in the onset and progression of human prostate cancer remains ill-defined. The gap junction channel-forming connexins (Cx) comprise a multigene family of highly conserved proteins that are differentially expressed in a tissue- and development-specific manner; changes in connexin expression are also commonly seen during cellular differentiation. However, when multiple connexins are concurrently expressed, gap junction channels may consist of more than one connexin species. This is important, because only certain pairings give rise to functional channels. In our studies, we investigated GJIC in a panel of both nontumorigenic (RWPE-1) and malignant (RWPE-2, LNCaP, DU-145) human prostate epithelial cells, compared to a normal rat liver epithelial F344 (WB-1) cell line, as it was found to be junctionally proficient. In addition, expression and regulation of Cx43 and Cx32 were also inspected using western blot analysis. The ability of hormones, antihormones, and the antihypertensive drug forskolin to restore GJIC in nontumorigenic and malignant human prostate epithelial cells was examined by the scrape-loading/dye transfer (SL/DT) or fluorescence recovery after photobleaching (FRAP) methods using an Ultima laser cytometer. Results from both assays showed that neither nontumorigenic nor malignant prostate cells have functional GJIC. However, both estrone (E1) and forskolin (FK) induced a significant increase (4.4- and 2.8-fold, respectively) in cell-cell communication only in the RWPE-1 cells. Interestingly, the use of Matrigel, a solubilized basement membrane, as substrate for cell attachment and growth resulted in the rescue of GJIC activity in RWPE-1 cells, as revealed by the SL/DT method. Furthermore, E1 induced a twofold increase in connexin 43 (Cx43), whereas forskolin caused a 50% reduction in Cx32 expression in RWPE-1 cells. These data suggest that agents that increase Cx43:Cx32 ratio may restore GJIC in junctionally deficient cells, providing a basis for the development of new strategies for the prevention and treatment of human prostate cancer.

Carcinogenicity Tests↗
PubMed1967

Intercellular communication and tissue growth. I. Cancerous growth.

Intercellular communication was examined with intracellular electrical techniques in primary and transplanted rat liver cancers. Normal liver cells communicate rather freely with each other through permeable junctional membranes. Cancer liver cells show no communication at all; their surface membrane is a strong barrier to diffusion all around the cell. Cancer cells induce alterations in membrane permeability in normal liver cells; communication among the latter is markedly reduced when cancer cells grow near them.

Animals↗
PubMedDate not supplied

Vesicle traffic through intercellular bridges in DU 145 human prostate cancer cells.

We detected cell-to-cell communication via intercellular bridges in DU 145 human prostate cancer cells by fluorescence microscopy. Since DU 145 cells have deficient gap junctions, intercellular bridges may have a prominent role in the transfer of chemical signals between these cells. In culture, DU 145 cells are contiguous over several cell diameters through filopodial extensions, and directly communicate with adjacent cells across intercellular bridges. These structures range from 100 nm to 5 microm in diameter, and from a few microns to at least 50-100 microm in length. Time-lapse imagery revealed that (1) filopodia rapidly move at a rate of microns per minute to contact neighboring cells and (2) intercellular bridges are conduits for transport of membrane vesicles (1-3 microm in diameter) between adjacent cells. Immunofluorescence detected alpha-tubulin in intercellular bridges and filopodia, indicative of microtubule bundles, greater than a micron in diameter. The functional meaning, interrelationship of these membrane extensions are discussed, along with the significance of these findings for other culture systems such as stem cells. Potential applications of this work include the development of anti-cancer therapies that target intercellular communication and controlling formation of cancer spheroids for drug testing.

Carbocyanines↗
PubMed2003

Involvement of microglia-neuron interactions in the tumor necrosis factor-alpha release, microglial activation, and neurodegeneration induced by trimethyltin.

Trimethyltin (TMT) is a neurotoxicant known to induce early microglial activation. The present study was undertaken to investigate the role played by these microglial cells in the TMT-induced neurotoxicity. The effects of TMT were investigated in monolayer cultures of isolated microglia or in neuron-enriched cultures and in neuron-microglia and astrocyte-microglia cocultures. The end points used were morphological criteria; evaluation of cell death and cell proliferation; and measurements of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) release in culture supernatant. The results showed that, in cultures of microglia, TMT (10(-6) M) caused, after a 5-day treatment, an increased release of TNF-alpha, without affecting microglial shape or cell viability. When microglia were cocultured with astrocytes, TNF-alpha release was decreased to undetectable levels. In contrast, in neuron-microglia cocultures, TNF-alpha levels were found to increase at lower concentrations of TMT (i.e., 10(-8) M). Moreover, at 10(-6) M of TMT, microglia displayed further morphological activation, as suggested by process retraction and by decrease in cell size. No morphological activation was observed in cultures of isolated microglial cells and in astrocyte-microglia cocultures. With regard to neurons, 10(-6) M of TMT induced about 30% of cell death, when applied to neuron-enriched cultures, whereas close to 100% of neuronal death was observed in neuron-microglia cocultures. In conclusion, whereas astrocytes may rather dampen the microglial activation by decreasing microglial TNF-alpha production, neuronal-microglial interactions lead to enhanced microglial activation. This microglial activation, in turn, exacerbates the neurotoxic effects of TMT. TNF-alpha may play a major role in such cell-cell communications.

Animals↗
PubMed2000

Association of enhanced expression of gap junctions with in vitro chondrogenic differentiation of rat nasal septal cartilage-released cells following their dedifferentiation and redifferentiation.

The nasal septum is an important centre of endochondral ossification during the development of the facial region. Previous studies have shown that it is possible to recapitulate the differentiation programme of 21-day-old rat nasal chondrocytes in vitro. The purpose now was to investigate, in vitro, the cell condensation phase that represents the earliest morphological event associated with cartilage differentiation in skeletal development. The study focuses on the ability of the cells to form condensations before overt differentiation, with special emphasis on gap-junction expression. The gap-junction protein connexin 43 was localized by indirect immunofluorescence as primarily intracellular and, on day 5, at the condensation stage, as spot-like contacts between cells. Intracellular injection of the permeable dye Lucifer yellow led to the staining of up to 20 neighbouring cells, indicating functional gap junctions and coupling. In contrast, treatment of cultures with the gap-junction blocker glycyrrhetinic acid inhibited dye coupling and reduced cartilage differentiation. Northern blotting of connexin 43 mRNA showed a faint band during the first days of culture, with a striking increase after day 4. In addition, the mRNA of the homeodomain-containing gene Cart-1 began to be expressed in prechondrogenic condensations and corresponded to the expression of type II collagen mRNA. These data indicate that the early stage of in vitro chondrocyte differentiation is the formation of cell condensations and the ability to establish cell-to-cell communication. Connexin 43, together with other molecular mechanisms, mediates the condensation phase of chondrogenesis and sets up the optimal environment in which nasal septal cells may terminally differentiate into chondrocytes.

Animals↗
PubMed2000

Genetic analysis of the Drosophila DNAprim gene. The function of the 60-kd primase subunit of DNA polymerase opposes the fat facets signaling pathway in the developing eye.

The Drosophila DNAprim gene encodes the large subunit (60 kD) of DNA primase, the part of DNA polymerase alpha that synthesizes RNA primers during DNA replication. The precise function of the 60-kD subunit is unknown. In a mutagenesis screen for suppressors of the fat facets (faf) mutant eye phenotype, we identified mutations in DNAprim. The faf gene encodes a deubiquitinating enzyme required specifically for patterning the compound eye. The DNA sequences of four DNAprim alleles were determined and these define essential protein domains. We show that while flies lacking DNAprim activity are lethal, flies with reduced DNAprim activity display morphological defects in their eyes, and unlike faf mutants, cell cycle abnormalities in larval eye discs. Mechanisms by which DNA primase levels might influence the faf-dependent cell communication pathway are discussed.

Alleles↗
PubMed2003

Stochastic model of autocrine and paracrine signals in cell culture assays.

Autocrine signaling systems are commonly studied under cell culture conditions. In a typical cell culture assay, a layer of liquid medium covers a random two-dimensional dispersion of cells, which secrete ligands. In a growing number of experiments, it is important to characterize the spatial range of autocrine and paracrine cell communication. Currently, the spatial distribution of diffusing signals can be analyzed only indirectly, from their effects on the intracellular signaling or physiological responses of autocrine cells. To directly characterize the spatial range of secreted ligands, we propose a stochastic model for autocrine cell cultures and analyze it using a combination of analytical and computational tools. The two main results derived within the framework of this model are 1), an expression for the fraction of autocrine trajectories, i.e., the probability for a ligand to be trapped by the same cell from which it has been secreted; and 2), an expression for the spatial distribution of trapping points of paracrine trajectories. We test these analytical results by stochastic simulations with efficient Brownian dynamics code and apply our model to analyze the spatial operation of autocrine epidermal growth factor receptor systems.

Algorithms↗
PubMed2002

Co-ordinated Ca(2+)-signalling within pancreatic islets: does beta-cell entrainment require a secreted messenger.

Isolated beta-cells are heterogeneous in sensory, biosynthetic and secretory capabilities, however, to enable efficient and appropriate secretion, cellular activity within the intact islet is synchronised. Historically, the entrainment of activity to a common pattern has been attributed to gap-junction mediated cell-to-cell communication. Although clearly influential, the possibility remains for other local synchronising mechanisms. In this study, we have used small clusters of insulin-secreting MIN6 cells to assess how contact-dependent, homotypic interactions between cells influences nutrient- and non-nutrient- evoked Ca(2+)-handling and insulin secretion, and to determine whether a secreted product plays a role in the synchronisation of oscillatory activity. Tolbutamide evoked a concentration-dependent recruitment of active cells within cell clusters, both in terms of numbers of cells and amplitude of the evoked Ca(2+)-response. The change in [Ca(2+)](i) was characteristically oscillatory above a mean elevated plateau, and was in phase between member cells of an individual cluster. Even at maximal concentrations (100 microM) some cells within a cluster responded before their immediate neighbours. Subsequent oscillatory behaviour then became entrained between member cells within that cluster. Inhibiting exocytosis using the microtubule inhibitors vincristine and nocodazole, or the adrenergic agent noradrenaline, did not prevent tolbutamide-evoked oscillatory changes in [Ca(2+)](i) but did reduce the probability of obtaining synchronous activity within an individual cluster. Above a threshold glucose concentration, the number of cells secreting insulin increased, without a commensurate change in secretory efficiency. This recruitment of cells secreting insulin mirrored Ca(2+) data that showed a glucose-dependent increase in cell number, without a change in the mean basal-to-peak change in [Ca(2+)](i). Together these data suggest that synchronised behaviour in MIN6 cells is dependent, in part, on a secreted factor that acts in a local paracrine fashion to recruit heterogeneous individual cellular activity into an organised group response.

Animals↗
PubMed2002

Short-range cell interactions and cell survival in the Drosophila wing.

During development of multicellular organisms, cells are often eliminated by apoptosis if they fail to receive appropriate signals from their surroundings. Here, we report on short-range cell interactions that support cell survival in the Drosophila wing imaginal disc. We present evidence showing that cells incorrectly specified for their position undergo apoptosis because they fail to express specific proteins that are found on surrounding cells, including the LRR transmembrane proteins Capricious and Tartan. Interestingly, only the extracellular domains of Capricious and Tartan are required, suggesting that a bidirectional process of cell communication is involved in triggering apoptosis. We also present evidence showing that activation of the Notch signal transduction pathway is involved in triggering apoptosis of cells misspecified for their dorsal-ventral position.

Animals↗
PubMed2005

Alterations of phosphorylation state of connexin 43 during hypoxia and reoxygenation are associated with cardiac function.

Gap junctions formed by connexins mediate cell-cell communication by electrical and chemical coupling. Recently, it has been shown that alterations in the phosphorylation state of the connexins result in functional alteration of cell-cell communication through gap junctions. Therefore, we focused on the association of alterations of phosphorylation state of connexin 43 (Cx43) with cardiac function in vivo. Rat hearts were transferred to Langendorff apparatus and submitted to hypoxia and then reoxygenated. In the control heart, Cx43 was phosphorylated and located at the intercalated disk. When the hearts were subjected to hypoxia, Cx43 at gap junctions was dephosphorylated and changed its localization to the entire plasma membrane. The area of cardiomyocytes stained with anti-phosphorylated Cx43 antibody was decreased in a time-dependent manner. Immunoblot data supported the decrease of phosphorylated Cx43 during hypoxia. ZO-1 did not change its localization at the intercalated disk during the hypoxic period. We also found that the area occupied by dephosphorylated Cx43 was correlated with the decrease of percent of rate-pressure product. These data indicate that dephosphorylation and redistribution of Cx43 is an early sign of cardiac injury after hypoxia. Detection of dephosphorylated Cx43 may serve as a diagnostic tool for examining ischemic heart disease.

Animals↗
PubMed1989

[The appearance and changes of gap junctions during myogenesis of Cynops embryos].

The appearance and changes of gap junctions during the development of striated muscle cells of Cynops orientalis have been studied by paraffin section, ultrathin-section and freeze-etching techniques. Gap junctions first appear between the somitic mesoderm cells in the late gastrula. A marked increase of the number of gap junctions occurs at the end of gastrulation. The number of gap junctions remains at a high level from neural plate stage up to nasal pit stage. After the stage of muscle contraction, the number of gap junctions decreases. Gap junctions do not disappear until muscle cells have attained their final differentiation and neuromuscular junctions have fully developed. The changes of size of gap junctions parallel with the changes in number. In addition, the number and size of gap junctions are both at the high level before cell fusion. Therefore, it is possible to conclude that cell communication is closely correlated with the development of striated muscle cells. The role of communications in cell determination and differentiation and in cell fusion of muscle cells are discussed.

Animals↗
PubMed1993

Effects of carotenoids on cells.

When added to cells, carotenoids display a variety of properties, including inhibition of mutagenesis, genotoxicity, malignant transformation, and growth of tumor cells. In addition, carotenoids increase cell-cell communication, and may have direct effects as cellular antioxidants.

Animals↗
PubMed2006

Computational methodologies for modelling, analysis and simulation of signalling networks.

This article is a critical review of computational techniques used to model, analyse and simulate signalling networks. We propose a conceptual framework, and discuss the role of signalling networks in three major areas: signal transduction, cellular rhythms and cell-to-cell communication. In order to avoid an overly abstract and general discussion, we focus on three case studies in the areas of receptor signalling and kinase cascades, cell-cycle regulation and wound healing. We report on a variety of modelling techniques and associated tools, in addition to the traditional approach based on ordinary differential equations (ODEs), which provide a range of descriptive and analytical powers. As the field matures, we expect a wider uptake of these alternative approaches for several reasons, including the need to take into account low protein copy numbers and noise and the great complexity of cellular organisation. An advantage offered by many of these alternative techniques, which have their origins in computing science, is the ability to perform sophisticated model analysis which can better relate predicted behaviour and observations.

Algorithms↗
PubMed2000

Induction of a bystander mutagenic effect of alpha particles in mammalian cells.

Ever since the discovery of X-rays was made by Röntgen more than a hundred years ago, it has always been accepted that the deleterious effects of ionizing radiation such as mutation and carcinogenesis are attributable mainly to direct damage to DNA. Although evidence based on microdosimetric estimation in support of a bystander effect appears to be consistent, direct proof of such extranuclear/extracellular effects are limited. Using a precision charged particle microbeam, we show here that irradiation of 20% of randomly selected A(L) cells with 20 alpha particles each results in a mutant fraction that is 3-fold higher than expected, assuming no bystander modulation effect. Furthermore, analysis by multiplex PCR shows that the types of mutants induced are significantly different from those of spontaneous origin. Pretreatment of cells with the radical scavenger DMSO had no effect on the mutagenic incidence. In contrast, cells pretreated with a 40 microM dose of lindane, which inhibits cell-cell communication, significantly decreased the mutant yield. The doses of DMSO and lindane used in these experiments are nontoxic and nonmutagenic. We further examined the mutagenic yield when 5-10% of randomly selected cells were irradiated with 20 alpha particles each. Results showed, likewise, a higher mutant yield than expected assuming no bystander effects. Our studies provide clear evidence that irradiated cells can induce a bystander mutagenic response in neighboring cells not directly traversed by alpha particles and that cell-cell communication process play a critical role in mediating the bystander phenomenon.

Alpha Particles↗
PubMed1989

Stimulation of limb cartilage differentiation by cyclic AMP is dependent on cell density.

Cyclic AMP (cAMP) has been implicated in the regulation of limb cartilage differentiation. This study represents an attempt to clarify potential mechanisms by which cAMP might regulate chondrogenesis. We have found that the ability of cAMP to stimulate limb cartilage differentiation in vitro is dependent on cell density. Dibutyryl cAMP (dbcAMP) elicits a striking increase in the accumulation of Alcian blue, pH 1.0-positive cartilage matrix, and a corresponding three- to fourfold increase in the accumulation of 35S-labeled glycosaminoglycans (GAG) by limb mesenchymal cells cultured in low serum medium at densities greater than confluence (i.e. micromass cultures established with 1-2 x 10(5) cells in 10 microliters of medium). Moreover, dbcAMP causes a striking (two- to fourfold) increase in the steady-state cytoplasmic levels of mRNAs for cartilage-characteristic type II collagen and the core protein of cartilage-specific sulfated proteoglycan in these high density, supraconfluent cultures. In contrast, cAMP does not promote the chondrogenesis of limb mesenchymal cells cultured at subconfluent densities (i.e. cultures initiated with 2.5-5 x 10(4) cells in 10 microliters of medium). In these low density cultures, dbcAMP does not promote the formation of cartilage matrix, sulfated GAG accumulation or the accumulation of cartilage-specific mRNAs. These observations suggest that cAMP may exert its regulatory effect in part by facilitating cell-cell communication during the critical condensation phase of chondrogenesis.

Animals↗
PubMed2002

Expression of gap junction connexin36 in adult rat retinal ganglion cells.

Electrophysiological and ultrastructural studies have demonstrated that gap junctions connect diverse types of neurons in the central nervous system, permitting direct electrical and metabolic coupling. A member of gap junction channel subunit connexin36 (Cx36), is probed for the location of cell-to-cell communication in the mammalian retina, where gap junction networks of major classes of neurons are present. We present an analysis of the expression and localization of Cx36 protein in adult Wistar rat retina, using a newly generated polyclonal antibody against a sequence in the predicted cytoplasmic loop of the Cx36 amino acid alignment, deduced from the cDNA sequence. The affinity-purified antibody, recognizing a single 36-kDa protein, consistently labeled discrete puncta of subcellular structures likely to be associated with gap junctions in the inner plexiform layer, and also cytoplasm within somata and dendrites of retinal amacrine and ganglion cells, following examination with various fixation protocols and double labeling immuno-fluorescence. These results provide that prominent cell-to-cell communication appears in mature excitatory neurons such as retinal ganglion cells, in addition to inhibitory amacrine cells, mediated by gap junctions in the adult retina.

Amacrine Cells↗
PubMed2002

Thyroid cell proliferation in response to forced expression of gap junction proteins.

Gap junctions are known to play a role in the control of cell proliferation, and connexins (Cx) are considered to be tumor suppressors. However, the effects of Cx on cell proliferation are dependent on the Cx which is expressed and on the cell type under consideration. We previously found that restoration of cell-to-cell communication by stable transfection of two independent thyroid-derived cell lines, FRTL-5 and FRT cells, with the Cx32 gene induced a marked reduction of their proliferation rate. This study aimed i) at determining whether Cx43, which is coexpressed with Cx32 by thyroid epithelial cells, exerts the same action as Cx32 on cell proliferation and ii) at identifying alterations of the cell cycle control system that might account for the Cx32-induced proliferation slowdown in thyrocytes. In contrast with previous data on different epithelial cell types, we report that restoration of intercellular communication in FRTL-5 and FRT cells by stable expression of Cx43 did not modify their proliferation properties. Cell cycle analyses revealed that the Cx32-induced proliferation slow-down was related to a lengthening of the G1 phase. The level of expression of two regulatory proteins of the Cip/Kip cyclin-dependent kinase inhibitor family, p27kip1 and p2cip1, was increased in the two cell lines expressing Cx32. In conclusion, Cx32 and Cx43, physiologically coexpressed by thyrocytes, have a differential impact on thyroid cell proliferation in vitro. The cyclin-dependent kinase inhibitors, p27kip1 and p21cip1 might represent cell cycle effectors relaying the down-regulatory effect of Cx32 on the proliferation of thyroid epithelial cells.

Animals↗
PubMed1997

Blocking gap junctional intercellular communication in myoblasts inhibits myogenin and MRF4 expression.

Cells rely heavily on cues from their extracellular environment and other cells to coordinate normal physiological processes, and the exchange of molecules via gap junctions has been suggested as on important avenue for cell-cell communication. Gap junctions are found in virtually all mammalian tissues with the notable exception of adult skeletal muscle. However, since functional gap junctions have been detected during the early stages of muscle development, gap junctional intercellular communication (GJIC) may play on important role in myogenesis. In this study, GJIC in normal 16 myoblasts was inhibited using the known blockers l-octanol and beta-glycyrrhetinic acid (beta-GA). Under differentiation promoting conditions, 16 cells fused to form multinucleated myotubes, but when treated with either octanol or beta-GA, no fusion was observed. The expression of two muscle regulatory factors (MRFs), myogenin and MRF4, was examined in both the blocked and control cells. As expected, the activation of both the myogenin and MRF4 genes coincided with the onset of differentiation in the control 16 cells. Neither of these genes were turned on in the blocked cells, even when grown under low serum conditions. This inhibition of differentiation by octanol and beta-GA was reversible, since the activation of both MRF genes as well as myoblast fusion were observed when the blocking medium was replaced with normal differentiating medium. These results suggest that intercellular communication via gap junctions plays an important role in skeletal muscle development and perhaps in the cell signaling events that trigger the activation of muscle-specific MRF genes.

1-Octanol↗