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PubMed2001

Effects of second messengers on gap junctional intercellular communication of ovine luteal cells throughout the estrous cycle.

Corpora lutea (CL) from Days 5, 10, and 15 after superovulation were enzymatically dispersed, and a portion of the cells were elutriated to obtain fractions enriched with small or large luteal cells. Mixed, small, and large luteal cell fractions were incubated with no treatment or with agonists or antagonists of cAMP (dbcAMP or Rp-cAMPS), protein kinase C (PKC; TPA or H-7), or calcium (A23187, EGTA, or A23187 + EGTA). The rate of contact-dependent gap junctional intercellular communication (GJIC) was evaluated by laser cytometry. Media were collected for progesterone (P(4)) radioimmunoassay, and luteal cells cultured with no treatment were fixed for immunocytochemistry or frozen for Western blot analysis. Luteal cells from each stage of the estrous cycle exhibited GJIC. The dbcAMP increased (P < 0.05) GJIC for all cell types across the estrous cycle. The Rp-cAMPS decreased (P < 0.05) GJIC for small luteal cells on Day 5 and for all cell types on Days 10 and 15. The TPA inhibited (P < 0.01), but H-7 did not affect, GJIC for all cell types across the estrous cycle. The A23187 decreased (P < 0.05) GJIC for large luteal cells touching only small or only large luteal cells, whereas A23187 + EGTA decreased (P < 0.05) GJIC for all cell types across the estrous cycle. For the mixed and large luteal cell fractions, dbcAMP increased (P < 0.05), but TPA and A23187 + EGTA decreased (P < 0.05), P(4) secretion. The A23187 alone decreased (P < 0.05) P(4) secretion by large, but not by mixed, luteal cells. For all days and cell types, the rate of GJIC and P(4) secretion were correlated (r = 0.113-0.249; P < 0.01). Connexin 43 was detected in cultured luteal cells by immunofluorescence and Western immunoblotting. Thus, intracellular regulators like cAMP, PKC, or calcium appear to regulate GJIC, which probably is an important mechanism for coordinating function of the ovine CL.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

Comparative in vivo hepatic effects of Di-isononyl phthalate (DINP) and related C7-C11 dialkyl phthalates on gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat and mouse liver.

The short-term hepatic effects of DINP (CAS 68515-48-0, designated DINP-1) in rats and mice were evaluated at tumorigenic and nontumorigenic doses from previous chronic studies. Groups of male F344 rats were fed diets with DINP-1 at concentrations of 0, 1000, or 12,000 ppm and male B6C3F1 mice at 0, 500, or 6000 ppm DINP-1. After 2 or 4 weeks of treatment, changes in liver weight, gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and replicative DNA synthesis were examined. In addition, hepatic and serum concentrations of the parent compound and major metabolites were determined. Relative to controls in both species, increased liver weight and PBOX at the high dose of DINP-1 were consistent with peroxisomal proliferation. Hepatic GJIC was inhibited and DNA synthesis was increased at the high dose of DINP-1, which is also consistent with the tumorigenic response in rats and mice reported in other chronic studies at these doses. These hepatic effects were not observed at the low doses of DINP-1. At comparable low doses of DINP-1 in other chronic studies, no liver tumors were observed in rats and mice. The monoester metabolite (MINP-1) was detected in the liver at greater concentrations in mice than rats. This result is also consistent with the dose-response observations in rat and mouse chronic studies. Additionally, other structurally similar dialkyl phthalate esters ranging from C7 to C11 were evaluated using a similar protocol for comparison to DINP-1; these included an alternative isomeric form of DINP (DINP-A), di-isodecyl phthalate (DIDP), di-isoheptyl phthalate (DIHP), di-heptyl, nonyl undecyl phthalate (D711P), and di-n-octyl phthalate (DNOP). Collectively, these data indicate that in rats and mice, DINP-1 and other C7-C11 phthalates exhibit a threshold for inducing hepatic cellular events. Further, where previous chronic data were available for these compounds, these phthalates elicited hepatic effects at doses that correlated with the tumorigenic response. Overall, these studies suggest a good correlation between the inhibition of GJIC when compared with the data on production of liver tumors in chronic studies.

Animals↗
PubMed1984

Intercellular junctions in upper airway submucosal glands of the rat: a tracer and freeze fracture study.

The structure of intercellular tight junctions of rat airway submucosal glands was examined by freeze fracture techniques and their permeability assessed by the use of colloidal lanthanum. The submucosal glands were organized into three distinct regions: a) serous tubules and b) mucous tubules lined, respectively, by serous and mucous cells, and c) ducts lined by cuboidal epithelial cells, containing few secretory granules, and some ciliated cells. The mean number of parallel fibrils constituting the tight junctions between serous cells was 3.6 +/- 0.4, which was significantly smaller than those between any of the other cell types. Colloidal lanthanum permeated the tight junctions between serous cells up to the level of the acinar lumen. There was a progressive increase in the mean number of parallel fibrils of tight junctions between mucous (5.1 +/- 0.6), ductal (5.4 +/- 0.5), and ciliated cells (8.5 +/- 0.7); none of these junctions was permeated by colloidal lanthanum. These results imply that tight junctions between serous cells are more permeable to small water-soluble solutes than those present in the more proximal portions of the gland. Gap junctions were observed between serous cells and between mucous cells, suggesting that these secretory cells may be electotronically and metabolically coupled.

Animals↗
PubMed2001

Mechanism of up-regulated gap junctional intercellular communication during chemoprevention and chemotherapy of cancer.

To develop a strategy for efficacious intervention in order to prevent or treat various cancers, one must understand the basic mechanism(s) by which various anticancer dietary factors prevent or reverse the tumor promotion or progression phases. Carcinogenesis is a multistage, multimechanism process, involving the irreversible alteration of a stem cell (the "initiation" phase), followed by the clonal proliferation of the initiated stem cell (the "promotion" phase), from which the acquisition of the invasive and metastatic phenotypes are generated (the "progression" phase). While intervention to prevent or treat cancer could occur at each step, the objective of this presentation will focus on the rate limiting step, the promotion phase.Gap junctional intercellular communication (GJIC) has been hypothesized to regulate growth control, differentiation and apoptosis. Most normal, contact-inhibited cells have functional GJIC, while most, if not all, tumor cells have dysfunctional homologous or heterologous GJIC. Cancer cells are characterized by the lack of growth control, by the inability to terminally differentiate and by resistance to apoptosis. Chemical tumor promoters (phorbol esters, DDT, phenobarbital, unsaturated fatty acids, saccharin, etc.) inhibit GJIC in a reversible fashion and at doses above particular chemical thresholds. Various oncogenes (e.g. ras, raf, neu, src, mos) down-regulate GJIC while several tumor suppressor genes can up-regulate GJIC. Antitumor promoters (retinoids, carotenoids, green tea components) and antioncogene drugs (i.e. lovastatin) can up-regulate GJIC. Transfection of gap junction genes ("connexins") into GJIC-deficient tumor cells can restore GJIC, growth control and reduce tumorigenicity. On the other hand, antisense gap junction genes can convert the phenotype of a non-tumorigenic cell to that of a tumorigenic one. Recently, a specific connexin knockout mouse was shown to have a higher frequency of spontaneous and induced liver cancers. Evidence from these studies clearly suggests that dietary factors can modulate GJIC by inducing various signal transducing systems. The modulation can either down-regulate GJIC and lead to tumor promotion or it can up-regulate GJIC and lead to suppression of the initiated cells. Multiple mechanisms of up- or down-regulation of GJIC exist, as well as multiple types of pre-malignant and malignant tumor cells that are unable able to have functional GJIC. GJIC can be down-regulated by mutations and by epigenetic means. Alteration of gene expression at the transcriptional, translational or post-translational levels would require specific dietary prevention or treatment of cancer. In conclusion, if dietary prevention or treatment of cancer is to occur, it must ameliorate the growth-stimulatory effects, above threshold levels, of chemicals, growth factors or hormones, that trigger various mitogenic/antiapoptotic signal transducing systems that block GJIC.

Animals↗
PubMed1994

Influence of the herbicide Linuron on growth rate and gap-junctional intercellular communication of cultured endothelial cells.

On the basis of in vivo toxicological long-term tests performed on rodents, the herbicide Linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea] has been classified by the U.S. Environmental Protection Agency (EPA) (1988) as a class C carcinogen (possibly carcinogenic to humans). However, when Linuron was analyzed for genotoxicity, negative results were obtained. An epigenetic, tumor-promoting potential was hence suspected to be responsible for the oncogenic activity of the molecule. In the absence of in vivo data concerning the tumor-promoting activity of the herbicide and being well established that tumor promoters interfere with the cell growth rate and gap-junctional permeability, the effects of technical grade Linuron and of its trade formulation (Linuron 50) on these parameters were investigated. This is especially important in the case of the formulated preparation for a correct estimate of the health hazard to humans. Cytotoxicity and gap-junctional intercellular communication (GJIC) assays were performed on the endothelial cell line F-BAE GM 7373, an in vitro cell system known to be responsive to the biological effects of tumor promoters. A time- and dose-related cytotoxic effect was found for both Linuron and Linuron 50, the latter being the far more cytotoxic of the two. However, when tested at noncytotoxic concentrations over a period of 48 h, neither Linuron nor Linuron 50 altered the capacity of F-BAE GM 7373 cells to intercommunicate. On the basis of the results obtained, the possibility that Linuron and Linuron 50 are endowed with tumor-promoting activity is discussed. In vivo studies on tumor-promoting and genotoxic activity are in progress to complement the information available on the toxicological properties of Linuron and its trade preparation.

Cell Communication↗
PubMed2004

Potent inhibition of gap junctional intercellular communication by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in BALB/c 3T3 cells.

The chlorohydroxyfuranones (CHFs) MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone], MCA [3,4-dichloro-5-hydroxy-2(5H)-furanone], CMCF [3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone], and MCF [3-chloro-4-methyl-5-hydroxy-2(5H)-furanone] are genotoxic disinfection by-products of drinking water chlorination. MX, MCA, and MCF also promote foci formation in the two-stage cell transformation assay. The cellular mechanisms underlying this apparent promotional effect are not known. In the present study, the effects of MX, MCA, CMCF, and MCF on gap junctional intercellular communication (GJIC) were measured in BALB/c 3T3 cells using the scrape loading dye technique. The effect of MX on apoptosis in the same cell line was explored by assaying caspase-3-like protease activity. All the four CHFs inhibited GJIC after 30 min exposure in a dose-dependent fashion but there was a marked difference in the ranges of their active concentrations. MX was almost as potent an inhibitor of GJIC (inhibition at nanomolar concentrations) as 12-O-tetradecanoylphorbol-13-acetate (TPA) (positive control), while MCA was 10 times weaker, CMCF 10,000 times weaker, and MCF 20,000 times weaker than MX. After prolonged exposure periods (up to 6 h), GJIC recovered somewhat upon MX and MCA exposures, the inhibition of GJIC by MCF remained constant but CMCF showed an irreversible increasing inhibitory effect. MX caused apoptosis as a "window" effect at concentrations 2000-4000-fold higher than those needed to inhibit GJIC. The results indicate that MX is a potent inhibitor of GJIC in BALB/c 3T3 cells and this inhibition might be one mechanism by which MX can promote malignant foci formation. MCA also has a specific potential to inhibit GJIC whereas MCF and CMCF affected GJIC at concentrations, similar to those evoking genotoxicity in vitro.

Animals↗
PubMed2001

Role of stem cells and gap junctional intercellular communication in human carcinogenesis.

Epidemiological data, experimental animal bioassays, studies of in vitro neoplastic transformation, and molecular oncology studies have implicated a multistage, multimechanism process in human carcinogenesis. From animal carcinogenesis studies, the operational concept of a single normal cell being irreversibly altered during the first step in carcinogenesis is called initiation. The subsequent interruptible or reversible clonal expansion of these initiated cells by non-cytotoxic mitogenic stimuli, compensatory hyperplasia due to cell death by necrosis, or inhibition of apoptosis is referred to as the promotion phase. Last, when one of these clonally expanded, initiated cells acquires sufficient genetic/epigenetic alterations to become neoplastically transformed and acquire the phenotypes of promoter independence, invasiveness and metastasis, it is referred to as the progression step of carcinogenesis. This report hypothesizes that the single normal cell that is initiated is a pluripotent stem cell. By assuming that the normal pluripotent stem cell is immortal and becomes mortal when induced to terminally differentiate, initiation would be viewed as the irreversible process by which a stable alteration in a finite number of proto-oncogenes and/or tumor suppressor genes could block terminal differentiation or "mortalization". Promotion would involve the reversible inhibition of gap junctional intercellular communication (GJIC) and while progression occurs with the stable down-regulation of GJIC.

Animals↗
PubMed1995

Freeze-fracture replica electron microscopy combined with SDS digestion for cytochemical labeling of integral membrane proteins. Application to the immunogold labeling of intercellular junctional complexes.

We propose a new electron microscopic method, the sodium dodecylsulphate (SDS)-digested freeze-fracture replica labeling technique, to study the two-dimensional distribution of integral membrane proteins in cellular membranes. Unfixed tissue slices were frozen with liquid helium, freeze-fractured, and replicated in a platinum/carbon evaporator. They were digested with 2.5% SDS to solubilize unfractured membranes and cytoplasm. While the detergent dissolved unfractured membranes and cytoplasm, it did not extract fractured membrane halves. After SDS-digestion, the platinum/carbon replicas, along with attached cytoplasmic and exoplasmic membrane halves, were processed for cytochemical labeling, followed by electron microscopic observation. As an initial screening, we applied this technique to the immunogold labeling of intercellular junction proteins: connexins (gap junction proteins), occludin (tight junction protein), desmoglein (desmosome protein), and E-cadherin (adherens junction protein). The immunogold labeling was seen superimposed on the image of a fracture face visualized by platinum/carbon shadowing. The immunoreaction was specific, and only the structures where the proteins were expected were labeled. For instance, anti-occludin immunogold complexes were observed immediately adjacent to the tight junction strands on the protoplasmic and exoplasmic fracture faces. No significant levels of gold label were associated with non-tight-junctional regions of plasma membranes. The procedures of the SDS-digested freeze-fracture replica labeling and its potential significance are discussed.

Animals↗
PubMed2004

Effects of phenolics in Empire apples on hydrogen peroxide-induced inhibition of gap-junctional intercellular communication.

The present study investigated antioxidant and antitumor-promoting activities of major phenolic phytochemicals of apples. The contents of each antioxidant in Empire apples was quantified and their contributions to total antioxidant activity of apples were determined using assay for inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced superoxide radical generation in cell culture model and expressed in vitamin C equivalent antioxidant capacity (VCEAC). The estimated contribution of major phenolics and vitamin C to total anitoxidant capacity of 100 g fresh Empire apples is as follows: quercetin (60.05 VCEAC) > chlorogenic acid (12.32) > phloretin (7.41) > procyanidin B2 (7.22) > vitamin C (6.61) > epicatechin (5.10) in superoxide radical scavenging assay. Recent reports suggest that the mechanism of carcinogenic process of hydrogen peroxide (H2O2) may be associated with the inhibition of gap-junctional intercellular communication (GJIC), which is involved in tumor promotion process. Apple extracts showed the protective effects against the inhibition of GJIC by H2O2 in a dose-dependent manner. Quercetin exerted the strongest protective effects among major antioxidants in apples on H2O2-induced inhibition of GJIC, following epicatechin, procyanidin B2, and vitamin C, while chlorogenic acid and phloretin had no effects. Our results indicate that cancer chemopreventive activity of apples is associated with the combined antioxidant capacity and antitumor-promoting activities of diverse antioxidants.

Antioxidants↗
PubMed2000

Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication.

Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "bystander effect," by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon, gap junctional intercellular communication (GJIC) is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.

Animals↗
PubMed2002

Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter.

Indole-3-carbinol (I3C) is a naturally occurring substance that shows anti-carcinogenic properties in animal models. Besides its clear anti-carcinogenic effects, some studies indicate that I3C may sometimes act as a tumor promoter. Indolo[3,2-b]carbazole (ICZ), which is formed in the acidic environment of the stomach after intake of I3C, has a similar structure to, and shares biological effects with, the well-known tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, we hypothesized that ICZ could be responsible for the potential tumor-promoting activity of I3C. The aim of the present study was to investigate the effect of ICZ on gap junctional intercellular communication (GJIC) in primary cultured rat hepatocytes co-cultured with the rat liver epithelial cell line WB-F344. Indolo[3,2-b]carbazole inhibited GJIC in the rat hepatocytes in a dose- and time-dependent manner. Significant inhibition was observed after 8 and 12 h of treatment with 1 and 0.1 micro M ICZ, respectively. Maximum GJIC inhibition (cell-cell communication only 5% of control values) was observed after 24-48 h of ICZ treatment. Continued exposure to 1 micro M ICZ suppressed GJIC until approximately 120 h. Both ICZ and TCDD treatment reduced the Cx32 mRNA level as well as the plasma membrane Cx32 staining. Indolo[3,2-b]carbazole increased the Cyp1a1, Cyp1a2 and Cyp1b1 mRNA levels concurrently with an increase in 7-ethoxyresorufin O-deethylase (EROD) activities. Maximum EROD activity and Cyp1a1 mRNA levels were observed after approximately 12 h, whereas Cyp1a2 and Cyp1b1 mRNA levels peaked after 48 h. This study shows that ICZ may possess tumor promoter activity down-regulating GJIC by mechanisms, which seem to include activation of the Ah receptor and/or Cyp1 activity. Further studies are needed in order to clarify the anticarcinogenic/carcinogenic effects of I3C and ICZ before high doses of I3C may be recommended as a dietary supplement.

Animals↗
PubMed2006

MX, a by-product of water chlorination, lacks in vivo genotoxicity in gpt delta mice but inhibits gap junctional intercellular communication in rat WB cells.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a by-product of water chlorination, is a potent bacterial mutagen and rat carcinogen. In the present study, the in vivo mutagenicity, cell proliferative activity, and carcinogenicity of MX were investigated in gpt delta mice. Groups of 5 male and female 7-week-old gpt delta C57BL/6J transgenic mice were given MX at doses of 0, 10, 30, or 100 ppm in their drinking water for 12 weeks, and then killed to assess in vivo mutagenicity using 6-thioguanine and Spi- selection, and cell proliferative activity using immunohistochemistry for proliferating cell nuclear antigen (PCNA). Further groups of 10 male and female gpt delta mice were given 0 or 100 ppm MX for 78 weeks, and a full necropsy with histopathological examination of all organs was conducted to detect neoplastic lesions. The 12-week MX treatment did not result in mutagenicity in the livers or lungs or cell proliferative activity in several organs of the mice, and the 78-week treatment did not cause carcinogenicity. Additional investigations were conducted to evaluate the potential of MX to inhibit gap junctional intercellular communication (GJIC) in rat liver epithelial cells (WB cells) by the scrape loading/dye transfer method. Inhibition of GJIC was detected within 2 hr with a noncytotoxic dose of MX (4 microg/ml), followed by partial restoration after 5 hr. A second phase of inhibition occurred after 10 hr and then the lowered level persisted for the 24 hr-incubation period. Dose-dependent inhibition was evident at both 2 hr and 24 hr, with much stronger effects at the former time. These findings indicate that MX is not mutagenic, mitogenic or carcinogenic in mice, and suggest that the compound exerts epigenetic actions leading to GJIC inhibition.

Animals↗
PubMed2001

Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels.

The assembly of gap junctions was investigated in mammalian cells expressing connexin (Cx) 26, 32 and 43 fused to green, yellow or cyan fluorescent proteins (GFP, YFP, CFP). Targeting of Cx32-CFP and 43-GFP to gap junctions and gap junctional communication was inhibited in cells treated with Brefeldin A, a drug that disassembles the Golgi. However gap junctions constructed of Cx26-GFP were only minimally affected by Brefeldin A. Nocodazole, a microtubule disruptor, had little effect on the assembly of Cx43-GFP gap junctions, but perturbed assembly of Cx26-GFP gap junctions. Co-expression of Cx26-YFP and Cx32-CFP in cells treated with Brefeldin A resulted in assembly of gap junctions constructed of Cx26-YFP. Two amino acids that distinguish Cx26 from Cx32 in transmembrane domains were mutated in Cx32 to investigate underlying mechanisms determining trafficking routes to gap junctions. One mutation, Cx32I28L, conferred on it partial Cx26-like trafficking properties as well the post-translational membrane insertion characteristics of Cx26, suggesting that a key determinant regulating trafficking was present in the first transmembrane domain. The results provide a protein trafficking basis for specifying and regulating connexin composition of gap junctions and thus selectivity of intercellular signaling, with Cx32 and 43 trafficking through the secretory pathway and Cx26 also following an alternative pathway.

Animals↗
PubMed2007

Versican modulates gap junction intercellular communication.

Versican is a large chondroitin sulfate proteoglycan and belongs to the family of lecticans. Versican possesses two globular domains, G1 and G3 domain, separated by a CS-attachment region. The CS-attachment region present in the middle region is divided into two spliced domains named CSalpha and beta. Alternative splicing of versican generates at least four versican isoforms named V0, V1, V2, and V3. We have successfully cloned the full-length cDNA of chick versican isoforms V1 and V2 and found that versican isoform V1 induced mesenchymal-epithelial transition in NIH3T3 cells. Mesenchymal-epithelial transition induced by V1 in NIH3T3 cells is characterized by expression of E-cadherin and occludin, two epithelial markers, and reduced expression of fibroblastic marker vimentin (Sheng et al., 2006, Mol Biol Cell. 17, 2009-2020). In the present studies, we found that versican V1 isoform not only induced cell transition, but also increased intercellular communication via gap junction channels composed of connexin proteins. Our results showed that V1 induces plasma membrane localization of connexin 43, resulting in increased cell communication. This was further confirmed by blocking assays. Gap junctions mediated the transfer of small cytoplasmic molecules and the diffusion of second messenger molecules between adjacent cells. The ability of versican in regulating gap junction implied a potential role of versican in coordinating functions.

Animals↗
PubMed1999

Gap junctional intercellular communication and carcinogenesis.

Intercellular communications are indispensable for the maintenance of homeostasis in the multicellular organisms. Gap-type junctions are one of the most common and perhaps most interesting intercellular connections. Of various communication systems gap junctional intercellular communication is the only means for cells to directly exchange signals. Substantial progress has recently been made in the studies on the role of gap junctions both in experimental and human tumorigenesis. The present study is a review of the potential mechanisms associated with gap junctional cellular communication included in non-genotoxic tumorigenesis.

Animals↗
PubMed2001

Peripheral myelin protein 22 is a constituent of intercellular junctions in epithelia.

Alterations in peripheral myelin protein 22 (PMP22) gene expression are associated with a host of heritable demyelinating peripheral neuropathies, yet the function of the protein remains unknown. PMP22 expression is highest in myelinating Schwann cells of peripheral nerves; however, significant levels of PMP22 mRNAs can be detected in a variety of non-neural tissue, including epithelia. To date, PMP22 protein expression and localization in non-neural tissues have not been studied in detail. In adult rat liver and intestine, and cultured epithelial cells, we detected PMP22-like immunoreactivity associated with markers of the tight junctional complex, including zonula occludens 1 (ZO-1) and occludin. Upon disruption of intercellular contacts, PMP22 was internalized into vesicles that were immunoreactive for both anti-occludin and anti-PMP22 antibodies. Nonionic detergent extraction of cultured epithelial cells did not solubilize PMP22, as the majority of the protein remained in the detergent insoluble fraction, as did ZO-1 and occludin. We also observed the targeting of exogenous myc-tagged PMP22 to apical cell junctions in polarized epithelia and to anti-ZO-1 antibody immunoreactive cell contacts of L fibroblasts. These studies support a role for PMP22 at intercellular junctions of epithelia and may indicate a similar function in myelinating Schwann cells. Furthermore, our findings could provide an explanation for certain phenotypes of PMP22 neuropathy mice that cannot be accounted for by dysmyelination.

Animals↗
PubMed1997

Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells.

Cell to cell communication via gap junctions is essential in the maintenance of the homeostatic balance of multicellular organisms. Aberrant intercellular gap junctional communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis. Oxidative stress has also been implicated in similar pathologies such as cancer. We report a potential link between oxidative stress and GJIC. Hydrogen peroxide, a known tumor promoter, inhibited GJIC in WB-F344 rat liver epithelial cells with an I50 value of 200 microM. Inhibition of GJIC by H2O2 was reversible as indicated by the complete recovery of GJIC with the removal of H2O2 via a change of fresh media. Free radical scavengers, such as t-butyl alcohol, propylgallate, and Trolox, did not prevent the inhibition of GJIC by H2O2, which indicated that the effects of H2O2 on GJIC was probably not a consequence of aqueous free radical damage. The depletion of intracellular GSH reversed the inhibitory effect of H2O2 on GJIC. The treatment of glutathione-sufficient cells with H2O2 resulted in the hyperphosphorylation of connexin43, which is the basic subunit of the hexameric gap junction protein, as determined by Western blot analysis. TPA, a well-known tumor promoter, also inhibits GJIC via hyperphosphorylation of GJIC, which is a result of protein kinase-C activation. However, H2O2 also induced hyperphosphorylation in GSH-deficient cells that had normal rates of GJIC. Therefore, the mechanism of GJIC inhibition must be different from the TPA-pathway and involves GSH.

Animals↗