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PubMed1997

cut interacts with Notch and protein kinase A to regulate egg chamber formation and to maintain germline cyst integrity during Drosophila oogenesis.

Communications between the germline and the soma during Drosophila oogenesis have been previously shown to be essential for the formation of egg chambers and to establish polarity in the developing oocyte. In this report, we demonstrate that the function of a somatically expressed gene, cut, is critical for maintaining the structural integrity of germline-derived cells and their arrangement within an egg chamber. Genetic manipulations of cut activity resulted in defective packaging of germline-derived cysts into egg chambers and disintegration of the structural organization of oocyte-nurse cell complexes to generate multinucleate germline-derived cells. We also found that cut interacts genetically with the Notch gene and with the catalytic subunit of Protein kinase A gene during egg chamber morphogenesis. Since cut expression is restricted to the somatic follicle cells and cut mutant germline clones are phenotypically normal, we propose that the defects in the assembly of egg chambers and the changes in germline cell morphology observed in cut mutant egg chambers are the result of altered interactions between follicle cells and germline cells. cut encodes a nuclear protein containing DNA-binding motifs, and we suggest that it participates in intercellular communications by regulating the expression of molecules that directly participate in this process.

Alleles↗
PubMed1999

Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues.

The mechanisms involved in the modulation of genotoxic and related effects by carotenoids and vitamin A were inferred from a critical review of an ad hoc constructed database. Almost 500 results were generated in experimental models evaluating the activity of 32 structurally, metabolically and functionally related nutrients, including beta-carotene and 26 other carotenoids, retinol, retinal, all-trans-retinoic acid and retinyl esters. As many as 67 experimental test systems, either in vitro or in vivo, used a variety of cellular targets and/or end-points suggestive of distinctive mechanisms of action. The bulk of available data support the view that carotenoids and vitamin A do not induce genotoxic effects per se. Even in the absence of any genotoxic agent, these nutrients appeared, on the contrary, to display some mechanisms which play protective roles in tumor promotion and progression, such as inhibition of N-myc gene expression resulting in antiproliferative effects, up-regulation of cell-to-cell communication, an increase in connexin 43 gene expression, a decrease in the 'spontaneous' cell transformation frequency and induction of differentiation in vitro. A large number of studies investigated the modulation by carotenoids and vitamin A of genotoxic and related effects produced by 69 genotoxicants, including biological agents, physical agents, chemical compounds and complex mixtures. In spite of some discrepant data, the general trend was that both carotenoids and vitamin A are poorly effective in acting as nucleophiles, nor do they appear to substantially interfere with the induction or repair of DNA damage produced by direct-acting agents. In contrast vitamin A and carotenoids, irrespective of their provitamin A role, in most studies inhibited those genotoxicants which require metabolic activation to electrophilic derivatives in either bacterial or mammalian cells. Coupled with biochemical data, the distinctive patterns observed with genotoxic agents belonging to different chemical classes suggest a complex modulation of both phase I and phase II enzymes involved in the metabolism of xenobiotics. Furthermore, carotenoids and vitamin A shared other protective mechanisms, such as scavenging of genotoxic oxygen species, modulation of signal transduction pathways, inhibition of cell transformation induced by physical and chemical agents, and facilitation of intercellular communication inhibited by genotoxic compounds. Therefore, carotenoids and vitamin A appear to work via multiple mechanisms, which would support a potential protective role in cancer initiation and in the pathogenesis of other mutation-related diseases. These conclusions are consistent with the recognized cancer-preventive activity of these nutrients in certain animal models and with the evidence provided by observational epidemiological studies, which suggested cancer-protective effects at many sites as related to their dietary intake or plasma levels. However, all these lines of evidence and mechanistically based premises contrast with the unexpected outcome of recent clinical intervention trials, which raised the concern that supplemental use of beta-carotene and vitamin A may increase the risk of lung cancer amongst high risk individuals such as tobacco smokers and asbestos-exposed workers.

Animals↗
PubMed1989

Cellular communication inside the liver. Binding, conversion and metabolic effect of prostaglandin D2 on parenchymal liver cells.

The major eicosanoid produced within the rat liver, prostaglandin (PG) D2, wa studied for its ability to interact with the various liver cell types. It appeared that PGD2 bound specifically to parenchymal liver cells, whereas the binding of PGD2 to Kupffer and endothelial liver cells was quantitatively unimportant. Maximally 700 pg of PGD2/mg of parenchymal-cell protein could be bound by a high-affinity site (1 x 10(6) PGD2-binding sites/cell). The recognition site for PGD2 is probably a protein because trypsin treatment of the cells virtually abolished the high-affinity binding. High-affinity binding of PGD2 was a prerequisite for the induction of a metabolic effect in isolated parenchymal liver cells, i.e. the induction of glycogenolysis. High-affinity binding of PGD2 by parenchymal cells was coupled to the conversion of PGD2 into three metabolites, whereas no conversion of PGD2 by Kupffer and endothelial liver cells was noticed. The temperature-sensitivity of the conversion of PGD2 was consistent with a conversion of PGD2 on or in the vicinity of the cell membrane. One of the PGD2 metabolites could be identified as 9 alpha, 11 beta-PGF2. It can be calculated that the conversion rate of PGD2 by parenchymal liver cells exceeds the production rate of PGD2 by Kupffer plus endothelial liver cells, indicating that PGD2 is meant to exert its activity within the liver. The present finding that PGD2 formed by the non-parenchymal liver cells is recognized by a specific receptor on parenchymal liver cells and that binding, conversion and metabolic effect of PGD2 are interlinked by this receptor provides further support for the specific role of PGD2 in the intercellular communication in the liver.

Alprostadil↗
PubMed1997

Heterogeneity of astrocyte resting membrane potentials and intercellular coupling revealed by whole-cell and gramicidin-perforated patch recordings from cultured neocortical and hippocampal slice astrocytes.

Astrocytes are thought to regulate the extracellular potassium concentration by mechanisms involving both voltage-dependent and transport-mediated ion fluxes combined with intercellular communication via gap junctions. Mechanisms regulating resting membrane potential (RMP) play a fundamental role in determining glial contribution to buffering of extracellular potassium and uptake of potentially toxic neurotransmitters. We have investigated the passive electrophysiological properties of cultured neocortical astrocytes and astrocytes recorded in hippocampal slices from 18-25 d postnatal rats. These experiments revealed a wide range of astrocyte RMPs that were independent of developmental factors, length of culturing, cellular morphology, the electrophysiological techniques used (whole-cell vs perforated recording), cell-specific expression of Na+/2HCO3- co-transporters, or voltage-dependent Na+ channels. Exposure of cultured astrocytes to differentiation-inducing factors (such as cAMP) or inhibition of proliferation (by serum deprivation) did not significantly influence RMP. Expression of ATP-sensitive potassium channels was absent in these glia; thus, K(ATP)-related mechanisms did not contribute to cell resting potential. In both cultured and slice astrocytes, spontaneous electrophysiological changes were commonly observed. These reversible events, which resulted in differential sensitivity to potassium channel blockers (cesium and barium) and sudden current-voltage profile changes, were attributable to dynamic changes in cell-to-cell coupling, as confirmed by recordings from isolated pairs of cells. We conclude that the heterogeneity of astrocytic RMP and intercellular coupling both in culture and in situ are intrinsic properties of glia that may contribute to transcellular transport of potassium. We propose a model in which spatial buffering may be facilitated by heterogeneous mechanisms controlling glial RMP in combination with dynamic changes in intercellular coupling.

ATP-Binding Cassette Transporters↗
PubMed2004

Enhanced effect of gap junction uncouplers on macroscopic electrical properties of reperfused myocardium.

Transient inhibition of gap junction (GJ)-mediated communication with heptanol during myocardial reperfusion limits infarct size. However, inhibition of cell coupling in normal myocardium may be arrhythmogenic. The purpose of this study was to test the hypothesis that the consequences of GJ inhibition may be magnified in reperfused myocardium compared with normal tissue, thus allowing the inhibition of GJs in reperfused tissue while only minimally modifying overall macroscopic cell coupling in normal myocardium. Concentration-response curves were defined for the effects of heptanol, 18alpha-glycyrrhetinic acid, halothane, and palmitoleic acid on conduction velocity, tissue electrical impedance, developed tension and lactate dehydrogenase (LDH) release in normoxically perfused rat hearts (n= 17). Concentrations lacking significant effects on tissue impedance were added during the initial 15 min of reperfusion in hearts submitted to 60 min (n= 43) or 30 min (n= 35) of ischaemia. These concentrations markedly increased myocardial electrical impedance (resistivity and phase angle) in myocardium reperfused after either 30 or 60 min of ischaemia, and reduced reperfusion-induced LDH release after 1 h of ischaemia by 83.6, 57.9, 51.7 and 52.5% for heptanol, 18alpha-glycyrrhetinic acid, halothane and palmitoleic acid, respectively. LDH release was minimal in hearts submitted to 30 min of ischaemia, independently of group allocation. In conclusion, the present results strongly support the hypothesis that intercellular communication in postischaemic myocardium may be effectively reduced by concentrations of GJ inhibitors affecting only minimally overall electrical impedance in normal myocardium. Reduction of cell coupling during initial reperfusion was consistently associated with attenuated lethal reperfusion injury.

Action Potentials↗
PubMed1998

Extensive apoptotic death of rat colonic cells deprived of crypt habitat.

Apoptosis in cells of different lineages is restrained by survival signals which depend upon cell-to-cell communication. The aim of this study was to determine whether colonic cells deprived of crypt ambient are doomed to die prior to their normal chronological demise. Apoptosis was studied in rat whole colonic tissue, in isolated intact crypts, and in colonic cell populations collected from the crypt axis at different stages of proliferation and differentiation. In a number of experiments, cell harvest was performed in the presence of either a tetrapeptide (YVAD-CMK) inhibitor of interleukin-1beta-converting enzyme (ICE), or tyrphostin A25, a protein tyrosine kinase inhibitor, or sodium-orthovanadate, a phosphatase inhibitor. DNA fragmentation was assessed by electrophoretic and nonisotopic-labeling procedures. The ultrastructure of colonic tissue specimens and isolated cells was examined by transmission electron microscopy. Apoptosis in whole colonic tissue and in isolated crypts was confined predominantly to cells resident in the upper crypt regions. In contrast, extensive apoptotic death was observed in isolated colonic cells, irrespective of their developmental stage and positional hierarchy within the crypt continuum at harvest time. An apoptotic gradient, however, was evident. Exposure to YVAD-CMK resulted in a marked decrease in the number of apoptotic cells. Treatment with tyrphostin A25 caused a sharp rise in the apoptotic index; conversely, vanadate significantly impeded apoptosis. Cumulatively, these results indicate that disordered intercellular communication provokes unscheduled ICE-mediated apoptosis of colonocytes, and that local signals along the crypt continuum control both the reprieve from death and the timely demise of distinct colonic cell populations. Attenuation of tyrosine phosphorylation may be a contributory event in the acquisition of the apoptotic phenotype.

Amino Acid Chloromethyl Ketones↗
PubMed1995

Studies on the tumor-promoting activity of polyethylene: inhibitory activity of metabolic cooperation of polyethylene films containing an antioxidant.

Tumor-promoting activity, inhibitory activity on the gap-junctional intercellular communication of polyethylene (PE) film containing a model antioxidant, 2,2'-methylene-bis(4-methyl-6-tert-butylphenol) (MBMBP), at various amounts was assessed by V79 metabolic cooperation (MC) assay. The extracts prepared from PE film containing MBMBP showed the inhibitory activities and the potencies of the inhibitory activities depended on the amount of MBMBP involved in the film, whereas the extract prepared from MBMBP-free PE film did not show any inhibitory activities. However, the inhibitory activities were observed when MC assay was carried out on the surface of the MBMBP-free film. These findings indicate that tumor-promoting activity of PE film is influenced by the surface property of the film as well as by amount and kind of additives incorporated.

Antioxidants↗
PubMed2006

Enhanced connexin 43 immunoreactivity in penumbral areas in the human brain following ischemia.

Astrocytes support neurons not only physically but also chemically by secreting neurotrophic factors and energy substrates. Moreover, astrocytes establish a glial network and communicate through gap junctions in the brain. Connexin 43 (Cx43) is one of major component proteins in astrocytic gap junctions. Heterozygote Cx43 KO mice and astrocyte specific Cx43 KO mice exhibited amplified brain damage after ischemic insults, suggesting a neuroprotective role for astrocytic gap junctions. However, some reports mentioned unfavorable effects of gap junctions in neuronal support. Therefore, the role of astrocytic gap junctions under ischemic condition remains controversial. Since these studies have been performed using animal models, we investigated the Cx43 expression in human brain after stroke. Brain slice sections were prepared from pathological samples in our hospital. Embolic stroke brains sectioned because of the stroke were considered as acute ischemic models. Multiple infarction brains sectioned because of pneumonia or cancer were considered as chronic models. We observed the levels of Cx43 in both lesioned and intact areas, and compared them with acute and chronic models. As the results, astrocytes were strongly activated in penumbral lesions both of acute and chronic ischemic models. The Cx43 immunoreactivity was significantly amplified in the penumbra of chronic model compared to that of the acute model. Neurons were well preserved in chronic model compared to acute model. These findings suggested that the brain may generate neuronal protection by increasing the levels of Cx43 and amplifying the astrocytic gap junctional intercellular communication under hypoxic condition.

Acute Disease↗
PubMed2005

Nitric oxide specifically reduces the permeability of Cx37-containing gap junctions to small molecules.

Gap junction intercellular communication (GJIC) plays a significant role in the vascular system. Regulation of GJIC is a dynamic process, with alterations in connexin (Cx) protein expression and post-translational modification as contributing mechanisms. We hypothesized that the endothelial autacoid nitric oxide (NO) would reduce dye coupling in human umbilical vein endothelial cells (HUVECs). In our subsequent experiments, we sought to isolate the specific Cx isoform(s) targeted by NO or NO-activated signaling pathways. Since HUVEC cells variably express three Cx (Cx37, Cx40, and Cx43), this latter aim required the use of transfected HeLa cells (HeLaCx37, HeLaCx43), which do not express Cx proteins in their wild type form. Dye coupling was measured by injecting fluorescent dye (e.g., Alexa Fluor 488) into a single cell and determining the number of stained adjacent cells. Application of the NO donor SNAP (2 microM, 20 min) reduced dye coupling in HUVEC by 30%. In HeLa cells, SNAP did not reduce dye transfer of cells expressing Cx43, but decreased the dye transfer from Cx37-expressing cells to Cx43-expressing cells by 76%. The effect of SNAP on dye coupling was not mediated via cGMP. In contrast to its effect on dye coupling, SNAP had no effect on electrical coupling, measured by a double patch clamp in whole cell mode. Our results demonstrate that NO inhibits the intercellular transfer of small molecules by a specific influence on Cx37, suggesting a potential role of NO in controlling certain aspects of vascular GJIC.

Capillary Permeability↗
PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗
PubMed1987

Cell membrane and transepithelial voltages and resistances in isolated rat hepatocyte couplets.

The basic electrical properties of an isolated rat hepatocyte couplet (IRHC) system have been analyzed using classical techniques of epithelial electrophysiology, including measurement of electric potentials, resistances and intracellular ion activities. Applications of these techniques are discussed with respect to their limitations in small isolated cells. Mean intracellular and intracanalicular membrane potentials ranged from -23.7 to -46.7 and -4.3 to -5.9 mV, respectively. Membrane resistances were determined using an equivalent circuit analysis modified according to the geometry of the IRHC system. Resistances of the sinusoidal (basolateral) and canalicular (luminal) cell membranes and tight junctions averaged 0.15 and 0.78 G omega and 25 m omega, respectively. The cells are electrically coupled via low resistance intercellular communications (approximately 58 M omega). Intracellular ion activities for Na+, K+ and Cl- averaged 12.2, 88.1 and 17.7 mmol/liter, respectively. The basolateral membrane potential reveals a permeability sequence of PK greater than PCl greater than PNa. The luminal potential showed minimal dependence on changes in transjunctional ion gradients, indicating a poor ion selectivity of the paracellular pathway. The electrogenic (Na+-K+)-ATPase contributes little to the luminal and cellular negative electric potential. Therefore, the luminal potential probably results from the secretion of impermeant ions and a Donnan distribution of permeant ions, a mechanism which provides the osmotic driving force for bile formation. By providing the unique opportunity to measure luminal potentials, this isolated hepatocyte system permits study of secretory mechanisms for the first time in a mammalian gland using electrophysiologic techniques.

Animals↗
PubMedDate not supplied

Dendritic type, accessory cells within the mammalian thymic microenvironment. Antigen presentation in the dendritic neuro-endocrine-immune cellular network.

During mammalian ontogenesis, the thymic "pure" endodermal epithelial anlage develops and differentiates into a complex cellular microenvironment. Beginning the 7-8th week of intrauterine development, thymic epithelial cells chemotactically regulate (induce) numerous waves of migration of stem cells into the thymus, including the CD34+, yolk sac-derived, committed hematopoietic stem cells. In vitro experiments have established that CD34+ CD38dim human thymocytes differentiate into T lymphocytes when co-cultured with mouse fetal thymic organs. Hematopoietic stem cells for myeloid and thymic stromal dendritic cells (DCs) are present within the minute population of CD34+ progenitors within the mammalian thymus. The common myeloid, DC, natural killer (NK) and T lymphocyte progenitors have also been identified within the CD34+ stem cell population in the human thymus. Interactions between the endocrine and immune systems have been reported in various regions of the mammalian body including the anterior pituitary (AP), the skin, and the central (thymus) and peripheral lymphatic system. The network of bone marrow derived DCs is a part of the reticuloendothelial system (RES) and DCs represent the cellular mediators of these regulatory endocrine-immune interactions. Folliculo-stellate cells (FSC) in the AP, Langerhans cells (LCs) in the skin and lymphatic system, "veiled" cells, lympho-dendritic and interdigitating cells (IDCs) in a number of tissues comprising the lymphatic system are the cell types of the DC meshwork of "professional" antigen presenting cells (APCs). Most of these cells express the immunocytochemical markers S-100, CD1. CD45, CD54, F418, MHC class I and II antigens, Fc and complement receptors. FSCs are non-hormone secreting cells which communicate directly with hormone producing cells, a form of neuro-endocrine-immune regulation. As a result, an attenuation of secretory responses follows stimulation of these cells. FSCs are also the cells in the AP producing interleukin-6 (IL-6), and they have also been identified as the interferon-gamma responsive elements. FSCs also express lymphatic DC markers, such as DC specific aminopeptidase, leucyl-beta-naphthylaminidase, non-specific esterase, MHC class I and II molecules and various other lymphatic immunological determinants [platelet derived growth factor-alpha chain (PDGF-alpha chain), CD13, CD14 and L25 antigen]. There is strong evidence that such DCs in the AP, and similar ones in the developing thymus and peripheral lymphatic tissue are the components of a powerful "professional" antigen presenting DC network. These APCs contain a specialized late endocytic compartment, MIIC (MHC class II-enriched compartment), that harbors newly synthesized MHC class II antigens en route to the cell membrane. The limiting membrane of MIIC can fuse directly with the cell membrane, resulting in release of newly secreted intracellular MHC class II antigen containing vesicles (exosomes). DCs possess the ability to present foreign peptides complexed with the MHC molecules expressed on their surfaces to naive and resting T cells. There are a number of "molecular couples" that influence DC and T lymphocyte interaction during antigen presentation: CD/1/CD18 integrins, intercellular adhesion molecules (ICAMs), lymphocyte function associated antigen 3 (LFA-3). CD40, CD80/B7-1, CD86/B7-2, and heat-stable antigen. The "molecular couples" are involved in adhesive or co-stimulatory regulations, mediating an effective binding of DCs to T lymphocytes and the stimulation of specific intercellular communications. DCs also provide all of the known co-stimulatory signals required for activation of unprimed T lymphocytes. It has been shown that DCs initiate several immune responses, such as the sensitization of MHC-restricted T lymphocytes, resistance to infections and neoplasms, rejection of organ transplants, and the formation of T-dependent antibodies. (ABSTRACT TRUNCATED)

Animals↗
PubMed2003

Increased invasive capacity of connexin43-overexpressing malignant glioma cells.

OBJECT: Malignant glioma cells, similar to astrocytes, express connexin43 (Cx43) universally but at widely varied levels. Data from previous studies have demonstrated that malignant glioma cells form functional gap junction channels among themselves as well as with astrocytes and that such a communication has the potential to modulate the phenotypic characteristics of astrocytes. Recently, gap junctions have been demonstrated to play a role in the invasive phenotype of malignant gliomas. In this study, the authors have further investigated the motility and invasion ability of Cx43-overexpressing and Cx43-deficient malignant glioma cells. METHODS: Using a standard invasion system of a Matrigel transwell invasion chamber, the authors found that the number of Cx43-transfected C6 glioma cells (C6-Cx43 cells) migrating through the Matrigel-coated membrane was similar to that of mock-transfected control cells (C6-mock cells) during the first 24 hours, but increased significantly thereafter. When these cells were cocultured with astrocytes, the number of invading C6-Cx43 cells was more than threefold greater than the number of invading C6-mock cells. Results of an in vitro cell motility assay also demonstrated that C6-Cx43 cells were more motile and scatter-active than C6-mock cells. Furthermore, zymographic analysis of MMPs, an important determinant in glioma invasion, demonstrated that the amounts of MMP-2 and MMP-9 in culture medium collected from C6-Cx43 cells were orders of magnitude higher than those from C6-mock cells. In addition, BB-94, a synthetic MMP inhibitor, significantly inhibited C6-Cx43 cell invasion. CONCLUSIONS: The overexpression of gap junction proteins in glioma cells and the intercellular communication between tumor and nontumor glia cells may play important roles in the facilitation of glioma cell invasion.

Animals↗
PubMed1998

Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours.

Gap junctional intercellular communication (GJIC) has been proposed as a cellular mechanism for tumour suppression and there is experimental evidence in support of this. If aberrant GJIC contributes to the formation of human breast tumours, one might expect that the connexins (gap junction proteins) expressed by epithelial cells in normal human breast would be down-regulated in tumour epithelial cells, or that tumour cells might show aberrant expression of other connexin family members. This study examines the immunocytochemical expression of connexins 26 (Cx26) and 43 (Cx43) in normal human breast, 11 benign breast lesions, two special-type carcinomas, and 27 invasive carcinomas of no special histological type (NST). Cx26 generally was not expressed at detectable level in normal human breast, but punctate Cx43 immunostaining of the myoepithelial cells was found. Cx43 staining of the myoepithelium was also a feature of the benign lesions and ductal carcinoma in situ (DCIS). In general, the epithelial cells of benign lesions failed to stain for either connexin. Similarly, a lobular carcinoma did not express Cx26 or Cx43, but there was punctate Cx43 in the epithelial cells of a mucoid carcinoma. Cx26 was up-regulated in the carcinoma cells of 15 of the 27 invasive NST carcinomas, although the staining was usually cytoplasmic and heterogeneous. Cx43 was expressed by stromal cells, possibly myofibroblasts, in all NST carcinomas. Furthermore, there was heterogeneous Cx43 expression in the carcinoma cells of 14 of the 27 NST carcinomas and the staining was often intercellular and punctate, characteristic of functional connexins. Up-regulated of Cx26 and/or Cx43 in the carcinoma cells of over two-thirds of invasive lesions of NST is not necessarily inconsistent with a tumour suppressor role for GJIC. However, the role of gap junctions in the formation and progression of solid human tumours is likely to be more complex than indicated from experimental systems.

Breast↗
PubMed1995

Transforming growth factor-beta 1 and forskolin modulate gap junctional communication and cellular phenotype of cultured Schwann cells.

Following peripheral nerve injury, Schwann cells undergo a series of cellular alterations that are thought to assist the regenerative process. Some of these changes are stimulated by the local release of cytokines and mitogenic factors. To test the hypothesis that cytokine regulation of gap junctional communication between cells helps to coordinate Schwann cell responses, cultured rat Schwann cells, from sciatic nerve, were utilized to study phasic changes induced by transforming growth factor-beta 1 (TGF beta 1), a cytokine released after nerve injury, or forskolin in combination with bovine pituitary extract (F-BPE), known for its mitogenic effects in vitro. In mitotically quiescent cultures, TGF beta 1 significantly decreased both electrical and dye coupling mediated by gap junctions. Single-channel analysis revealed that cultured Schwann cells expressed gap junctions with two distinct channel sizes of about 26 pS and 44 pS. TGF beta 1 treatment reduced coupling due to both populations of channels. Exposure to TGF beta 1 had a minimal effect on proliferation but significantly altered cellular morphology; cell bodies became flattened with multipolar processes within 72 hr. Additionally, immunolabeling for both low-affinity nerve growth factor receptor (L-NGFR) and glial fibrillary acidic protein (GFAP) were reduced, suggesting increased differentiation. In contrast, treatment with F-BPE significantly enhanced both electrical and dye coupling and stimulated Schwann cell proliferation. Additionally, cell bodies became more rounded with polarized, cytoplasmic processes contiguously aligned with adjacent cells. F-BPE reduced immunolabeling for L-NGFR but increased expression of both GFAP and the major peripheral myelin protein, P0. These data indicate that TGF beta 1 and/or F-BPE induce phenotypic changes in Schwann cells, including the coordinated regulation of proliferation and modulation of intercellular communication via gap junctions. Such mechanisms may underlie phasic responses that orchestrate recovery from nerve injury, indicating that Schwann cell gap junctions may be critical for peripheral nerve function.

Animals↗
PubMed1972

Three types of gap junctions interconnecting intestinal epithelial cells visualized by freeze-etching.

Gap junctions are specialized membrane regions that seem to mediate intercellular communication. They appear to contain closely packed arrays of equally sized particles all of which, upon freeze-cleaving, remain attached to one membrane leaflet and not to the other. One gap junction cleavage face, therefore, always exhibits a closely packed array of particles, while the other features a corresponding array of pits. By using these morphological criteria, we have been able to distinguish three different types of gap junctions interlinking adjacent epithelial cells of the small intestine. All three types may be found in close proximity to each other, and in all cases, the particles remain attached to the cleavage face of the cytoplasmic membrane leaflet (A-face). The most frequently encountered type-I gap junctions, which have already been observed in many other tissues, possess 8- to 9-nm (80- to 90-A) particles with a center-to-center spacing of 9-10 nm (90-100 A) when packed in a hexagonal lattice. Type-II gap junctions are always found in close association with type-I junctions. They can be distinguished from the type-I junctions by the greater size [10-11 nm (100-110 A) in diameter] and the greater spacing (190-200 A) of their hexagonally arrayed particles. In contrast, the particles of the type-III gap junctions are arranged in very small rectilinear arrays with a spacing of only 6-8 nm (60-80 A). Gap junctions may be involved in the control of intercellular flow of different types of regulatory molecules.

Animals↗
PubMed2003

LuxS-based signaling in Streptococcus gordonii: autoinducer 2 controls carbohydrate metabolism and biofilm formation with Porphyromonas gingivalis.

Communication based on autoinducer 2 (AI-2) is widespread among gram-negative and gram-positive bacteria, and the AI-2 pathway can control the expression of genes involved in a variety of metabolic pathways and pathogenic mechanisms. In the present study, we identified luxS, a gene responsible for the synthesis of AI-2, in Streptococcus gordonii, a major component of the dental plaque biofilm. S. gordonii conditioned medium induced bioluminescence in an AI-2 reporter strain of Vibrio harveyi. An isogenic mutant of S. gordonii, generated by insertional inactivation of the luxS gene, was unaffected in growth and in its ability to form biofilms on polystyrene surfaces. In contrast, the mutant strain failed to induce bioluminescence in V. harveyi and was unable to form a mixed species biofilm with a LuxS-null strain of the periodontal pathogen Porphyromonas gingivalis. Complementation of the luxS mutation in S. gordonii restored normal biofilm formation with the luxS-deficient P. gingivalis. Differential display PCR demonstrated that the inactivation of S. gordonii luxS downregulated the expression of a number of genes, including gtfG, encoding glucosyltransferase; fruA, encoding extracellular exo-beta-D-fructosidase; and lacD encoding tagatose 1,6-diphosphate aldolase. However, S. gordonii cell surface expression of SspA and SspB proteins, previously implicated in mediating adhesion between S. gordonii and P. gingivalis, was unaffected by inactivation of luxS. The results suggest that S. gordonii produces an AI-2-like signaling molecule that regulates aspects of carbohydrate metabolism in the organism. Furthermore, LuxS-dependent intercellular communication is essential for biofilm formation between nongrowing cells of P. gingivalis and S. gordonii.

Bacterial Adhesion↗
PubMed1985

Junctional transfer in cultured vascular endothelium: II. Dye and nucleotide transfer.

Vascular endothelial cultures, derived from large vessels, retain many of the characteristics of their in vivo counterparts. However, the observed reduction in size and complexity of intercellular gap and tight junctions in these cultured cells (Larson, D.M., and Sheridan, J.D., 1982, J. Cell Biol. 92:183) suggests that important functions, thought to be mediated by these structures, may be altered in vitro. In our continuing studies on intercellular communication in vessel wall cells, we have quantitated the extent of junctional transfer of small molecular tracers (the fluorescent dye Lucifer Yellow CH and tritiated uridine nucleotides) in confluent cultures of calf aortic (BAEC) and umbilical vein (BVEC) endothelium. Both BAEC and BVEC show extensive (and quantitatively equivalent) dye and nucleotide transfer. As an analogue of intimal endothelium, we have also tested dye transfer in freshly isolated sheets of endothelium. Transfer in BAEC and BVEC sheets was more rapid, extensive and homogeneous than in the cultured cells, implying a reduction in molecular coupling as endothelium adapts to culture conditions. In addition, we have documented heterocellular nucleotide transfer between cultured endothelium and vascular smooth muscle cells, of particular interest considering the prevalence of "myo-endothelial" junctions in vivo. These data yield further information on junctional transfer in cultured vascular endothelium and have broad implications for the functional integration of the vessel wall in the physiology and pathophysiology of the vasculature.

Animals↗