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PubMed2006

von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxia-inducible factor-independent mechanisms.

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is responsible for the development of renal cell cancers (RCC), pheochromocytomas, and tumors in other organs. The best known function of VHL protein (VHL) is to target the hypoxia-inducible factor (HIF) for proteasome degradation. VHL is also required for the establishment of an epithelial-like cell shape in otherwise fibroblastic-like RCC cell lines. However, the underlying mechanisms and whether this is linked to HIF remain undetermined. Because the breakage of intercellular junctions induces a fibroblastic-like phenotype in multiple cancer cell models, we hypothesized that VHL may be required for the assembly of intercellular junctions in RCC cells. Our experiments showed that VHL in RCC cell lines is necessary for the normal organization of adherens and tight intercellular junctions, the maintenance of cell polarity, and control of paracellular permeability. Additionally, 786-O cells reconstituted with wild-type VHL and with a constitutively active form of HIF-2alpha did not reproduce any of the phenotypic alterations of VHL-negative cells. In summary, we show that VHL inactivation in RCC cells disrupts intercellular junctions and cell shape through HIF-independent events, supporting the concept that VHL has additional functions beside its role in the regulation of HIF.

Basic Helix-Loop-Helix Proteins↗
PubMedDate not supplied

Role for gap junctional intercellular communications in wound repair.

The participation of fibroblasts in wound repair is a coordinated effort requiring sequential cellular modulations to behavior including migration (entering), proliferation (increasing cell numbers), synthesis (depositing a collagen matrix), remodeling (organizing collagen), transformation into myofibroblasts, apoptosis, and elimination. Disruptions in that orderly sequence of behaviors will alter repair. Insights into controlling wound repair have focused on soluble factors such as cytokines and growth factors. Here we examine the direct communications between coupled cells through gap junctional intercellular communications. Molecules of less than 1000 MW pass directly between cells through gated gap junction channels. Sugars, amino acids, and oxygen, as well as second messengers such as cAMP, inositol phosphates, and calcium can pass directly between coupled cells. Does gap junctional intercellular communication affect fibroblast phenotype progression in granulation tissue maturation? In rats gap junctional intercellular communication uncouplers heptanol and endosulfan were injected daily into polyvinyl alcohol sponge implants. At 7 days, uncoupler-treated implants had capsules with increased fibroblast density, reduced cell penetration into the sponge, and diminished numbers of myofibroblasts. By polarized light, the uncouplers reduced the deposition and organization of collagen and thereby disrupted the coordinated phenotypic changes seen in fibroblasts during the repair process. It is proposed that gap junctional intercellular communication is critical for fibroblast progression from migratory cell to apoptosis as granulation tissue matures into scar.

Animals↗
PubMed1995

Reversible inhibition of gap junctional intercellular communication, synchronous contraction, and synchronism of intracellular Ca2+ fluctuation in cultured neonatal rat cardiac myocytes by heptanol.

We analyzed by Fotonic Sensor, a fiber-optic displacement measurement instrument, the effects of heptanol on synchronized contraction of primary neonatal rat cardiac myocytes cultured at confluent density. We also examined the effect of heptanol on the changes in gap junctional intercellular communication by using the microinjection dye transfer method, and on intercellular Ca2+ fluctuation by confocal laser scanning microscopy of myocytes loaded with the fluorescent Ca2+ indicator fluo 3. In addition, we studied expression, phosphorylation, and localization of the major cardiac gap junction protein connexin 43 (Cx43) using immunofluorescence and Western blotting. At Day 6 of culture, numerous myocytes exhibited spontaneous, synchronous contractions, excellent dye coupling, and synchronized intracellular Ca2+ fluctuations. We treated the cells with 1.5, 2.0, 2.5, and 3.0 mmol/liter heptanol. With 1.5 mmol/liter heptanol, we could not observe significant effects on spontaneous contraction of myocytes. At 3.0 mmol/liter, the highest concentration used in the current experiment, heptanol inhibited synchronous contractions and even after washing out of heptanol, synchronous contraction was not rapidly recovered. On the other hand, at the intermediate concentrations of 2.0 and 2.5 mmol/liter, heptanol reversely inhibited synchronized contraction, gap junctional intercellular communication, and synchronization of intracellular Ca2+ fluctuations in the myocytes without preventing contraction and changes of intracellular Ca2+ in individual cells. Brief exposure (5-20 min) to heptanol (2.0 mmol/liter) did not cause detectable changes in the expression, phosphorylation, or localization of Cx43, despite strong inhibition of gap junctional intercellular communication. These results suggest that gap junctional intercellular communication plays an important role in synchronous intracellular Ca2+ fluctuations, which facilitate synchronized contraction of cardiac myocytes.

Alcohols↗
PubMed1989

Inhibition of gap-junctional intercellular communication between epithelial cells transformed by the activated H-ras-1 oncogene.

In order to study the effects of an activated H-ras-1 oncogene on gap-junctional intercellular communication, we introduced the EJ/T24 H-ras-1 oncogene into cells of the epithelial Clone 9-3 cell line. Gap-junctional intercellular communication was significantly reduced in H-ras-1-transformed Clone 9-3 derivatives; this result shows that transformation by the activated H-ras-1 oncogene can inhibit gap-junctional intercellular communication. We postulate that the activated H-ras-1 oncogene product could mediate this effect through a change in the phosphorylation of the major gap-junction protein.

Animals↗
PubMed1975

Intercellular junctions of rat endocardium.

The ultrastructure of the intercellular junctions of rat endocardium has been characterized following lanthanum exposure in vitro and uranyl acetate staining en bloc. The interendothelial clefts of the endocardium run either a relatively straight or convoluted course and posses one or two loci where the plasma membranes are in close apposition or form punctate fusions. Elongate restrictions, that exhibit hexagonal arrays of subunits following lanthanum immersion (gap junctions), are also present in the intercellular endocardial clefts. The occurrence of interendothelial clefts of endocardium lacking occlusive foci can account for the permeability properties of ventricular endocardium, where the direction of diffusion of macromolecules has been attributed to pressure gradients between ventricular cavity and myocardium. The relationship of gap junctions to possible electrical phenomena within the endocardium is also discussed.

Animals↗
PubMedDate not supplied

Intercellular junctions in the organ of Corti.

The intercellular junctions between adjacent supporting cells and between apposed hair and supporting cells in the organ of Corti of cat and human were studied. At the endolymphatic surface, the intercellular space was closed by a series of tight junctions (zonula occludens), whereas there were no tight junctions at the basilar membrane surface of the neuroepithelium. Beneath the adlumenal zonula occludens between adjacent supporting cells, a zonula adherens (intermediate junction, "desmosone") was found. Many gap junctions joined apposed supporting cells both within apposed hair and supporting cells, membrane specialization sharing the morphological characterics of both the macula adherens and zonula adherens was found. Between cells, there were short areas of parallel limiting membranes separated by a 20A intercellular space. These areas were suggestive but not characteristic of gap junctional specialization. The functional significance of the junctional specialization between cells in the organ of Corti is discussed.

Animals↗
PubMed1998

Methylmercury inhibits gap junctional intercellular communication in primary cultures of rat proximal tubular cells.

Methylmercury (MeHg) causes renal injury in addition to central and peripheral neuropathy. To clarify the mechanism of nephrotoxicity by MeHg, we investigated the effect of this compound on intercellular communication through gap junction channels in primary cultures of rat renal proximal tubular cells. Twenty minutes after exposure to 30 microM MeHg, gap junctional intercellular communication (GJIC), which was assessed by dye coupling, was markedly inhibited before appearance of cytotoxicity. When the medium containing MeHg was exchanged with MeHg-free medium, dye coupling recovered abruptly. However, the dye-coupling was abolished again 30 min after replacement with control medium, and the cells were damaged. Intracellular calcium concentration, [Ca2+]i, which modulates the function of gap junctions, significantly increased following exposure of the cells to 30 microM MeHg and returned to control level following replacement with MeHg-free medium. These results suggest that the inhibiting effect of MeHg on GJIC is related to the change in [Ca2+]i, and may be involved in the pathogenesis of renal dysfunction.

Animals↗
PubMed2002

Quantitative analysis of gap-junctional intercellular communication in precision-cut mouse liver slices.

Direct intercellular communication through gap junction channels is involved in the maintenance of tissue homeostasis and suppression of carcinogenesis. Gap-junctional communication is often altered in tumor cells but it can also be modulated in response to tumor promotors or inflammatory signals. In order to evaluate the effect of nongenotoxic compounds, suggested to be involved in tumor promotion, on gap junctional intercellular communication in the liver, we have developed a direct dye transfer method. The fluorescent dye Alexa Fluor 488 was iontophoretically injected into hepatocytes of freshly prepared, precision-cut mouse liver slices (250 microm). The area of dye spreading was monitored and quantified by microscopy. Comparison of dye spreading in connexin-32-deficient versus wild-type liver revealed a 96% decrease in connexin-32-deficient tissue. Induction of an acute phase response in connexin-32-deficient mice by intraperitoneal injection of lipopolysaccharide increased dye coupling by 33%, probably due to upregulation of connexin-26-containing gap junction channels.

Animals↗
PubMed2004

A Calpha model for the transmembrane alpha helices of gap junction intercellular channels.

Gap junction channels connect the cytoplasms of apposed cells via an intercellular conduit formed by the end-to-end docking of two hexameric hemichannels called connexons. We used electron cryomicroscopy to derive a three-dimensional density map at 5.7 angstroms in-plane and 19.8 angstroms vertical resolution, allowing us to identify the positions and tilt angles for the 24 alpha helices within each hemichannel. The four hydrophobic segments in connexin sequences were assigned to the alpha helices in the map based on biochemical and phylogenetic data. Analyses of evolutionary conservation and compensatory mutations in connexin evolution identified the packing interfaces between the helices. The final model, which specifies the coordinates of Calpha atoms in the transmembrane domain, provides a structural basis for understanding the different physiological effects of almost 30 mutations and polymorphisms in terms of structural deformations at the interfaces between helices, revealing an intimate connection between molecular structure and disease.

Amino Acid Sequence↗
PubMed1984

A comparative study on the intercellular canalicular system and intercellular junctions in the pancreatic islets of some rodents.

Intercellular junctions were studied in pancreatic islets of some rodents by electron microscopy of thin sections and freeze-fracture-replicas. Junctions between islet cells can be classified into three types: macula occludens, a combination of the macula occludens and gap junction, and gap junction. The first and second types are mainly located on the cell membrane near the intercellular canaliculus, while the third type is present independently of it. The development of these types of junctions varies considerably among animal species: in mice, guinea pigs and hamsters, the second and third types are frequent, but the first type is rarely seen. In Mongolian gerbils, diminutive elements of the three types are infrequently present. In rats, only the third type is developed. In addition to intercellular communication through gap junctions, the first and second types of junctions may incompletely discriminate the intercellular canalicular lumen, and regulate the microenvironment of the islet cell.

Animals↗
PubMed1998

Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons.

Intercellular communication via gap junction membrane channels cannot occur until two apposing hemichannels (connexons) meet and dock to form a sealed cell-cell conduit. In particular, an important question is how does the structure at the extracellular surface influence the molecular recognition of the two connexons. In this study, cryoelectron microscopy and computer modeling provide evidence that the formation of the gap junction intercellular channel requires a 30 degree rotation between hemichannels for proper docking. With this amount of rotation, the peaks (protrusions) on one connexon fit into the valleys of the apposed connexon in the 3-D model, which would make for an ionically tight interface necessary for a functional cell-cell channel. Docking appears to be governed by a "lock and key" mechanism via a simple interdigitation of the six protrusions from each connexon. This interdigitation increases significantly the contact surface area and potential number of hydrogen bonds or hydrophobic interactions and/or other attractive interactions. Having a larger surface area than if the surfaces were flat would explain the biochemical requirements for conditions characterized previously for splitting of channels into hemichannels. The docked connexons were computationally fitted into two gap junction structures, which further confirmed the interdigitated manner of docking.

Cell Communication↗
PubMed1998

Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship.

Cancer is a multistage multimechanism process involving gene and/or chromosomal mutations (genotoxic events), altered gene expression at the transcriptional, translational, and post-translational levels (epigenetic events), and altered cell survival (proliferation and apoptosis or necrosis), resulting in an imbalance of the organism's homeostasis. Maintenance of the organism's homeostasis depends on the intricate coordination of genetic and metabolic events between cells via extracellular and intercellular communication mechanisms. The release of a quiescent cell, whether normal or premalignant, from the suppressing effects of communicating neighbors requires the downregulation of intercellular communication via gap junctions, thereby allowing factors that control intracellular events to exceed a critical mass necessary for the cell to either proliferate or undergo apoptosis. Therefore, determining the role an environmental pollutant must play in the multistage carcinogenic process includes mechanisms of epigenetic toxicity such as the effects of a compound on gap junctional intercellular communication (GJIC). A classic example of a class of compounds in which determination of carcinogenicity focused on genotoxic events and ignored epigenetic events is polycyclic aromatic hydrocarbons (PAHs). The study of structure-activity relationships of PAHs has focused exclusively on the genotoxic and tumor-initiating properties of the compound. We report on the structure-activity relationships of two- to four-ringed PAHs on GJIC in a rat liver epithelial cell line. PAHs containing a bay or baylike region were more potent inhibitors of GJIC than the linear PAHs that do not contain these regions. These are some of the first studies of determine the epigenetic toxicity of PAHs at the epigenetic level.

Animals↗
PubMed1996

Dependence of epithelial intercellular junction biogenesis on thapsigargin-sensitive intracellular calcium stores.

Perturbation of potentially regulatable endoplasmic reticulum (ER) calcium stores with the Ca-ATPase inhibitor, thapsigargin (TG), perturbs the formation of desmosomes and tight junctions during polarized epithelial cell biogenesis, despite the development of cell contact. In a Madin-Darby canine kidney cell model for intercellular junction assembly, TG treatment inhibited the development of transepithelial electrical resistance (TER), a measure of tight junction assembly, in a dose-dependent manner. The TG-induced inhibition of tight junction assembly was paralleled by a defect in the sorting of the tight junction protein, ZO-1. An even more dramatic delay in sorting of the desmosomal protein, desmoplakin, was observed in the presence of TG. In addition, while both ZO-1 and desmoplakin-I in control cells were shown to become associated with the Triton X-100 insoluble cytoskeleton during intercellular junction assembly, prior treatment with 100 nM TG diminished this biochemical stabilization into the detergent-insoluble fraction, particularly in the case of ZO-1. Although spectrofluorimetric measurements in fura-2 loaded Madin-Darby canine kidney cells confirmed the occurrence of TG-mediated release of calcium from internal stores, total cytosolic calcium during junction assembly remained similar to untreated cells. Therefore, the presence of cytosolic calcium alone is not sufficient for normal intercellular junction biogenesis if intracellular stores are perturbed by TG. The results indicate the presence of calcium-sensitive intracellular mechanisms involved in the sorting and cytoskeletal stabilization of both tight junction and desmosomes and suggest a role for calcium-dependent signaling pathways at an early (possibly common) step in polarized epithelial biogenesis.

Animals↗