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PubMed2004

[Gap junctions and their role in physiology and pathology of the digestive tract].

Gap junctional intercellular communication (GJIC) is a mechanism of direct cell-to-cell signalling and is mediated by gap junctions (GJs), consisting of transmembrane proteins called connexins (Cxs). GJIC plays a critical role in tissue development and differentiation and is important in the maintenance of tissue homeostasis resulting from homeostasis through the exchange of ions, signalling molecules, nucleotides, and other small molecules (less than 1kDa) between adjacent cells. Because gap junctions are sites of the propagation or conduction of action potentials between adjacent cells, it is possible that they participate in the generation of rhythmic peristaltic movements by contributing to synchronous contraction in the muscle layer. Many physiological roles have been proposed for gap junctions, such as the maintenance of tissue homeostasis, regulation of tissue development, electrical and metabolic coupling, as well as the regulation of cellular growth, differentiation and apoptosis. Altered expressions of connexins have been observed in various pathological processes of the digestive tract, such as Hischsprung's disease, esophageal cancer, gastric cancer, and colorectal cancer. Using a variety of techniques such as transmission electron microscopy, Lucifer Yellow transfer and immunohistochemistry, gap junctions in the digestive tracts of mammalian species have been identified. This work is a review of recent studies on the role of GJIC in the physiology and pathology of the digestive tract.

Action Potentials↗
PubMed2004

Expression of connexins 26, 32 and 43 in the human colon--an immunohistochemical study.

Gap junctional intercellular communication (GJIC) is a mechanism for direct cell-to-cell signalling and is mediated by gap junctions (GJs), which consist of proteins called connexins (Cxs). GJIC plays a critical role in tissue development and differentiation and is important in maintenance of tissue homeostasis. The purpose of the study was to evaluate the expression of Cx26, Cx32 and Cx43 in the human colon. Surgical specimens were obtained from patients who underwent surgical resection of colorectal tumours. Tissue samples (50 cases) were collected from normal colon, at the maximum distance from the tumor. Using antibodies for Cx26, Cx32 and Cx43, immunohistochemical detection was made. In epithelial cells, strong Cx26 immunoreactivity was found, whereas Cx32 and Cx43 were sparsely distributed. Strong Cx43 immunostaining in muscularis mucosae was observed. In the circular layer of muscularis externa, expression of Cx43 and Cx26 was seen, but only in the portion closest to the submucosa. No immunoreactivity was found in the longitudinal muscle layer. Small vessels stained positively only for Cx43. Furthermore, there was no difference in staining between samples derived from various sections of the colon. This study showed immunohistochemically for the first time the expression of Cx26 in human colon mucosa.

Colon↗
PubMed2006

The gap junction cellular internet: connexin hemichannels enter the signalling limelight.

Cxs (connexins), the protein subunits forming gap junction intercellular communication channels, are transported to the plasma membrane after oligomerizing into hexameric assemblies called connexin hemichannels (CxHcs) or connexons, which dock head-to-head with partner hexameric channels positioned on neighbouring cells. The double membrane channel or gap junction generated directly couples the cytoplasms of interacting cells and underpins the integration and co-ordination of cellular metabolism, signalling and functions, such as secretion or contraction in cell assemblies. In contrast, CxHcs prior to forming gap junctions provide a pathway for the release from cells of ATP, glutamate, NAD+ and prostaglandin E2, which act as paracrine messengers. ATP activates purinergic receptors on neighbouring cells and forms the basis of intercellular Ca2+ signal propagation, complementing that occuring more directly via gap junctions. CxHcs open in response to various types of external changes, including mechanical, shear, ionic and ischaemic stress. In addition, CxHcs are influenced by intracellular signals, such as membrane potential, phosphorylation and redox status, which translate external stresses to CxHc responses. Also, recent studies demonstrate that cytoplasmic Ca2+ changes in the physiological range act to trigger CxHc opening, indicating their involvement under normal non-pathological conditions. CxHcs not only respond to cytoplasmic Ca2+, but also determine cytoplasmic Ca2+, as they are large conductance channels, suggesting a prominent role in cellular Ca2+ homoeostasis and signalling. The functions of gap-junction channels and CxHcs have been difficult to separate, but synthetic peptides that mimic short sequences in the Cx subunit are emerging as promising tools to determine the role of CxHcs in physiology and pathology.

Animals↗
PubMed1996

Ras is involved in gap junction closure in proliferating fibroblasts or preadipocytes but not in differentiated adipocytes.

A decrease in gap junctional, intercellular communication (GJIC) has been associated with cells neoplastically transformed by a variety of factors. To investigate the role of the Ras oncogene product in gap junction function, a panel of murine C3H10T1/2 (10T1/2) fibroblasts was constructed in which the levels of ras gene expression could be effectively up- or down-regulated. Intercellular communication was measured using a novel technique of in situ electroporation of adherent cells on a partly conductive slide. The introduction of increasing amounts of activated Ras(leu61) in mouse 10T1/2 fibroblasts proportionally reduced GJIC, while the downregulation of endogenous c-ras gene expression increased junctional permeability. These results indicate that Ras plays an important role in the junction closure pathway leading to the proliferation of normal cells. However, differentiation of c-Ras-deficient preadipocytes entirely abolished their initially extensive GJIC, indicating that junction closure in response to adipocytic differentiation is independent of Ras.

Adipocytes↗
PubMedDate not supplied

Changes in the expression of junctional and nonjunctional complex component genes when inter-sertoli tight junctions are formed in vitro.

Throughout spermatogenesis, germ cells move progressively from the basal to the adluminal compartment, which is accompanied by continual disassembly and reassembly of intercellular junctions suggesting germ cell movement is composed of intermittent phases of junction disassembly and reassembly. A study was performed to correlate the expression of junctional-complex components (such as zonula occludens-1 [ZO-1], a tight-junction component protein) and nonjunctional complex components (such as urokinase-type plasminogen activator [uPA], a serine protease; cathepsin L, a cysteine protease; alpha2-macroglobulin, a nonspecific protease inhibitor; and cystatin C, a cysteine protease inhibitor) at the time when inter-Sertoli tight junctions were established in vitro. This is an attempt to investigate whether the expression of nonjunctional component genes also correlates with the formation of inter-Sertoli tight junctions in vitro. This is part of an effort to understand the physiologic elements of germ cell movement in the epithelium. Sertoli cells cultured in vitro are known to undergo programmed cell death. To ensure that the changes in target gene expression were not the result of apoptosis, Sertoli cells were cultured in vitro at densities of 0.25, 0.75, and 3 x 10(6) cells/cm2 for up to 7 days on bicameral culture units coated with Matrigel (Collaborative Research) and were assessed by morphologic analysis and agarose gel electrophoresis. It was noted that many of the Sertoli cells cultured at 3 x 10(6) cells/cm2 underwent apoptosis by day 7, in contrast to cultures at 0.25 and 0.75 x 10(6) cells/cm2 illustrating the Sertoli cell number per unit of area may be an important parameter to be considered when studying Sertoli cell function in vitro. Also, it was shown that the expression of ZO-1 increased significantly between days 2 and 3 prior to the establishment of inter-Sertoli tight junctions assessed by transepithelial resistance measurement (TER), which illustrates that ZO-1 can be used as a marker to monitor this cellular event. More interestingly, there was also a transient increase in the expression of uPA and cathepsin L between days 2 and 3 at the time preceding the formation of tight junctions. In Sertoli cells cultured at low density (2 x 10(4) cells/cm2), when a confluent monolayer of cells could not form, there were no changes in the expression of either ZO-1, uPA, or cathepsin L throughout the 7-day culture period. These results show that the establishment of specialized junctions, such as tight junctions between Sertoli cells in vitro, may require the participation of both junctional and nonjunctional complex components.

Animals↗
PubMed1998

Nerve injury and inflammatory cytokines modulate gap junctions in the peripheral nervous system.

In the peripheral nervous system (PNS), myelinating Schwann cells express the gap junction protein connexin32 (Cx32) and lower levels of connexin43 (Cx43). Although the function of Cx43 in Schwann cells is not yet known, in adult mammals Cx32 is thought to form reflexive contacts within individual myelinating glial cells and provide direct pathways for intracellular ionic and metabolic exchange from the cell body to the innermost periaxonal cytoplasmic regions. In response to nerve injury, Schwann cells in the degenerating region down-regulate expression of Cx32 and there is increased expression of connexin46 (Cx46) mRNA and protein. The cascade of Schwann cell responses seen after the injury-induced decrease in Cx32, and the observation that dividing Schwann cells express Cx46, and possibly other connexins, and are coupled through gap junction channels, raise the intriguing possibility that there are coordinated changes in Schwann cell proliferation and connexin expression. Moreover, intercellular junctional coupling among cells in general may be important during injury responses. Consistent with this hypothesis, dividing Schwann cells are preferentially coupled through junctional channels as compared to non-dividing cells, which are generally uncoupled. Moreover, the strength of junctional coupling among cultured Schwann cells is modulated by a number of cytokines to which Schwann cells are exposed to in vivo after nerve injury, and Cx46 mRNA and protein levels correlate with the degree of coupling. Other injury-induced cellular changes in connexin expression that may be functionally important during injury responses include a transient increase in Cx43 in endoneurial fibroblasts. This paper reviews what is known about connexin expression and function in the adult mammalian PNS, and focuses on some of the changes that occur following nerve injury. Moreover, evidence that inflammatory cytokines released after injury modulate connexin expression and junctional coupling strength is presented.

Animals↗
PubMed2005

Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation.

Gap junction proteins, connexins, are dynamic polytopic membrane proteins that exhibit unprecedented short half-lives of only a few hours. Consequently, it is well accepted that in addition to channel gating, gap junctional intercellular communication is regulated by connexin biosynthesis, transport and assembly as well as the formation and removal of gap junctions from the cell surface. At least nine members of the 20-member connexin family are known to be phosphorylated en route or during their assembly into gap junctions. For some connexins, notably Cx43, evidence exists that phosphorylation may trigger its internalization and degradation. In recent years it has become apparent that the mechanisms underlying the regulation of connexin turnover are quite complex with the identification of many connexin binding molecules, a multiplicity of protein kinases that phosphorylate connexins and the involvement of both lysosomal and proteasomal pathways in degrading connexins. This paper will review the evidence that connexin phosphorylation regulates, stimulates or triggers gap junction disassembly, internalization and degradation.

Animals↗
PubMed1970

Electrical coupling between embryonic cells by way of extracellular space and specialized junctions.

The meroblastic egg of the teleost, Fundulus heteroclitus, was studied electrophysiologically from cleavage to mid-gastrula stages. The yolk is an intracellular inclusion surrounded by a membrane of high resistivity (50 k ohmcm(2)). This membrane generates a cytoplasm-negative resting potential in later stages. Cells of all stages studied are coupled electrically. In gastrulae, coupling is both by way of specialized junctions between cells and by way of intra-embryonic extracellular space, the segmentation cavity. The latter mode is present because the segmentation cavity is sealed off from the exterior by a high resistance barrier, and the outer membrane of surface cells is of high resistance (50-100 k ohmcm(2)) compared to the inner membrane. It can be inferred that clefts between surface cells are occluded by circumferential junctions. Isolated cells from late cleavage stages develop coupling in vitro, confirming the existence of coupling by way of intercellular junctions. Both modes of coupling could mediate communication between cells that is important in embryonic development.

Animals↗
PubMed2003

Besides affecting intracellular calcium signaling, 2-APB reversibly blocks gap junctional coupling in confluent monolayers, thereby allowing measurement of single-cell membrane currents in undissociated cells.

2-aminoethoxydiphenyl borate (2-APB) has been widely used as a blocker of the IP3 receptor and TRP channels, including store-operated calcium channels. We now show in monolayers of normal rat kidney cells (NRK/49F) that 2-APB completely and reversibly blocks gap junctional intercellular communication at concentrations similar to that required for inhibition of PGF2alpha-induced increases in intracellular calcium. Gap junctional conductances between NRK cells were estimated with single-electrode patch-clamp measurements and were fully blocked by 2-APB (50 microM), when applied extracellularly but not via the patch pipette. Half maximal inhibition (IC50) of electrical coupling in NRK cells was achieved at 5.7 microM. Similar results were obtained for human embryonic kidney epithelial cells (HEK293/tsA201) with an IC50 of 10.3 microM. Using 2-APB as an electrical uncoupler of monolayer cells, we could thus measure inward rectifier potassium, L-type calcium, and calcium-dependent chloride membrane currents in confluent NRK monolayers, with properties similar to those in dissociated NRK cells in the absence of 2-APB. The electrical uncoupling action described here is a new 2-APB property that promises to provide a powerful pharmacological tool to study single-cell properties in cultured confluent monolayers and intact tissues by electrical and chemical uncoupling of the cells without the need of prior dissociation.

Animals↗
PubMed1999

Myotonic dystrophy protein kinase expressed in rat cardiac muscle is associated with sarcoplasmic reticulum and gap junctions.

Myotonic dystrophy (DM) is one of the most prevalent muscular diseases in adults. The molecular basis of this autosomal disorder has been identified as the expansion of a CTG repeat in the 3' untranslated region of a gene encoding a protein kinase (DMPK). The pathophysiology of the disease and the role of DMPK are still obscure. It has been previously demonstrated that DMPK is localized at neuromuscular junctions, myotendinous junctions, and terminal cisternae of the sarcoplasmic reticulum (SR), in the skeletal muscle, and at intercalated discs in the cardiac muscle. We report here new findings about specific localization of DMPK in the heart. Polyclonal antibodies raised against a peptide sequence of the human DMPK were used to analyze the subcellular distribution of the protein in rat papillary muscles. Confocal laser microscopy revealed a strong although discontinuous reactivity at intercalated discs, together with transverse banding on the sarcoplasm. At higher resolution with immunogold electron microscopy, we observed that DMPK is localized at the cytoplasmic surface of junctional and extended junctional sarcoplasmic reticulum, suggesting that DMPK is involved in the regulation of excitation-contraction coupling. Along the intercalated disc, DMPK was found associated with gap junctions, whereas it was absent in the two other kinds of junctional complexes (fasciae adherentes and desmosomes). Immunogold labeling of gap junction purified fractions showed that DMPK co-localized with connexin 43, the major component of this type of intercellular junctions, suggesting that DMPK plays a regulatory role in the transmission of signals between myocytes.

Animals↗
PubMed1989

Connexin32, a gap junction protein, is a persistent oogenetic product through preimplantation development of the mouse.

Gap junctions appear de novo during compaction in the eight-cell stage of mouse development. This is a critical event in the life of the embryo, because gap junctional intercellular communication is an essential requirement for maintaining compaction and, hence, for development of the blastocyst. Recently, a family of genes encoding gap junction proteins (connexins) has been identified and cloned, and we have taken advantage of the availability of antibodies and cDNA probes to investigate the expression of these genes in early development. We found that a protein with antigenic and size similarity to the "liver" gap junction protein, connexin32, is present throughout preimplantation development from the zygote through the late morula. Connexin32 mRNA, however, could not be detected in any preimplantation stage. This, and the presence of connexin32 in zygotes before activation of embryonic transcription, leads us to conclude that this protein is inherited as an oogenetic product that persists well beyond the transition from the oogenetic to embryonic program of gene expression. Furthermore, we found that mRNA for another gap junction protein, connexin43, is fairly abundant in preimplantation embryos. We conclude that it is more likely connexin43, and not connexin32, that is used to assemble new connexons as the level of intercellular coupling increases after compaction.

Animals↗
PubMed2004

Connexin 32 dominant-negative mutant transgenic rats are resistant to hepatic damage by chemicals.

Connexins are subunits of gap junction channels, which allow direct transfer of ions, secondary messenger molecules, and other metabolites between contacting cells. Gap junctions are believed to be involved in tissue homeostasis, embryonic development, and control of cell proliferation. Several studies have shown that cell damage signals are transmitted through gap junctions when cells are irradiated or when cells bearing the herpes simplex virus-thymidine kinase (HSV-TK) gene are treated with ganciclovir. We established 2 lines of transgenic rats with a dominant-negative mutant of connexin 32 gene under control of the albumin promoter. In the livers of transgenic rats, membrane localization of normal endogenous connexin 32 protein is disturbed, and gap junction capacity measured by scrape dye-transfer assay in vivo is markedly decreased when compared with wild-type rats. The present investigation concerned susceptibility to the liver-toxic substances D-galactosamine and carbon tetrachloride. These toxicants induced massive liver cell death and elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the wild-type rats; however, much fewer liver cells were damaged and serum enzyme elevation was much lower in the transgenic rats. In conclusion, gap junctional intercellular communication (GJIC) plays an important role in toxic effects of chemicals; damage or death signals may pass through gap junctions in the rat liver in vivo.

Alanine Transaminase↗
PubMed1996

Changes in cellular distribution of connexins 32 and 26 during formation of gap junctions in primary cultures of rat hepatocytes.

In the adult rat hepatocyte, gap junction proteins consist of connexin 32 (Cx32) and connexin 26 (Cx26). Previously, we reported that both Cx32 and Cx26 were markedly induced and maintained in primary cultures of adult rat hepatocytes. The reappearing gap junctions were accompanied by increases in both the proteins and the mRNAs, and they were well maintained together with extensive gap junctional intercellular communication (GJIC) for more than 4 weeks. In the present study, we examined the cellular location of the gap junction proteins and the structures in the hepatocytes cultured in our system, using confocal laser microscopy and immunoelectron microscopy of cells processed for Cx32 and Cx26 immunocytochemistry and freeze-fracture analysis. In immunoelectron microscopy, the size of Cx32-immunoreactive gap junction structures on the plasma membrane increased with time of culture, and some of them were larger than those in liver sections in vivo. Freeze-fracture analysis also showed that the size of gap junction plaques increased and that the larger gap junction plaques were composed of densely packed particles. These results suggest that in this culture system, not only the synthesis of Cx proteins but also the size of the gap junction plaques was increased markedly. In the adluminal lateral membrane of the cells, Cx32-immunoreactive lines were observed and many small gap junction plaques were closely associated with a more developed tight junction network. In the basal region of the cells, small Cx32- and Cx26-immunoreactive dots were observed in the cytoplasm and several annular structures labeled with the antibody to Cx32 were observed in the cytoplasm. These results indicated the formation and degradation of gap junctions in the cultured hepatocytes.

Animals↗
PubMed1982

Immunoelectron microscopic study of plasma protein pathways through the different segments of the rat intestinal vasculature.

Nineteen Brown-Norway (BN) rats received intravenous injections of sheep anti-peroxidase (HRP) antibodies. Four BN rats were immunized to HRP. The anti-HRP antibodies were used to trace permeability pathways of large physiological molecules across different vessels of the small intestine. This organ was chosen because of the possibility of convenient "in situ" fixation and for the diversity of vessel types it contains. It was shown that: 1) There were no obvious transendothelial pathways in arteries with an elastic lamina. 2) The antibodies readily crossed fenestrated capillaries through the fenestrae. 3) There were two possible pathways through muscle capillaries and pericytic venules, namely transcytoplasmic vesicular "cactus-like" channels and interendothelial junctions. 4) Interendothelial permeability was a possible factor in veins with an elastic lamina. 5) Lymphatics were readily permeable through intercellular junctions and cytoplasmic vesicles.

Animals↗
PubMed2002

An ultrastructural study of interstitial implantation in captive-bred, short-tailed fruit bats, Carollia perspicillata: trophoblastic adhesion and penetration of the uterine epithelium.

Trophoblastic adhesion to, and penetration of, the uterine epithelium during implantation have been examined in captive-bred Carollia perspicillata at the light and electron microscopic levels. Initial adhesion is localized to marginal ridges immediately over the apical intercellular junctions of the epithelial cells. Penetration then involves the intrusion of trophoblastic processes between the epithelial cells and the formation of junctional complexes between the two cell types. As larger areas of adhesion develop, they still occur most often near the intercellular boundaries between the more flattened epithelial cells or on their lateral sides. This suggests that many (if not all) of these broad areas of adhesion to the trophoblast had actually formed along what had originally been part of the lateral (rather than the apical) surfaces of the epithelial cells. Portions of the apical cell surfaces further removed from their intercellular boundaries usually were not adherent to the trophoblast and still had microvilli. Upon reaching the basal lamina of the uterine epithelium, invasion of the endometrium is temporarily retarded, and trophoblast cells migrate instead between the basal lamina and the epithelial cells. This occurs extensively along both the luminal and glandular epithelia around the implantation site, but not significantly along their apical surfaces. This again indicates that adhesive interactions between the trophoblast and those apical surfaces are at most very limited in Carollia. The epithelial cells appear to be viable until separated from their basal laminae by the trophoblast. They are then phagocytized by the trophoblast. During initial penetration of the uterine luminal epithelium, the trophoblast is still entirely of the cellular variety. Syncytiotrophoblast does not begin to appear until later, when the trophoblast first comes into contact with endometrial capillaries.

Animals↗
PubMed2003

Connexin 40 expression in bovine and rat retinas.

Retinal neurons are extensively coupled through gap junction intercellular channels, but few connexin subtypes have been identified in mammalian retinal neurons. Based on previous findings that retinal gap junctional coupling is modulated by both dopamine and nitric oxide, presumably through connexin phosphorylation, we examined whether the connexin phosphoprotein subtype, connexin 40 (Cx40), was expressed in mammalian retinas. Immunostaining of rat and bovine retinas using Cx40-specific antibodies from two independent sources showed punctate staining between cells in the outer nuclear layer (ONL) and a sublayer of cells within the inner nuclear layer (INL). In addition, sparse punctate staining was detected in the ganglion cell/axon fiber layers (GCL/AFL). No punctate staining was observed in the outer (OS) or inner segment (IS) layers, and rarely in the outer plexiform layer (OPL) or inner plexiform layer (IPL). Double immunostaining of bovine retinas with antibodies to G(o), which stains bipolar cells, and to Cx40, showed little overlap, suggesting these bipolar cells do not express Cx40. Western blot analysis of alkaline-extracted bovine retinal membranes revealed Cx40 immunopositive bands of about 40 kD (monomer) and 80 kD (dimer). In both locations (monomer and dimer), the bands appeared as doublets, and their immunoreactivity was abolished when the antibody was pre-adsorbed with immunogenic Cx40 peptide. The doublet at 40 kD co-migrated with an immunopositive doublet present in heart membranes. Treatment with alkaline phosphatase altered the banding pattern of Cx40. The results suggest that the connexin phosphoprotein subtype, Cx40, is expressed within the neural layers of the mammalian retina.

Animals↗
PubMed2002

Protein kinase signaling in the modulation of microvascular permeability.

The permeability of exchange microvessels is regulated through complex interactions between signaling molecules and structural proteins in the endothelium. Endothelial barrier integrity is maintained by adhesive interactions occurring at the cell-cell and cell-matrix contacts via junctional proteins and focal adhesion complexes that are anchored to the cytoskeleton. Cyclic AMP (cAMP) and cAMP-dependent kinase counteract with the nitric oxide (NO)-cyclic GMP (cGMP) pathway to protect the basal barrier function. Upon stimulation by physical stress, growth factors, or inflammatory agents, endothelial cells undergo a series of intracellular signaling reactions involving activation of protein kinase C (PKC), protein kinase G (PKG), mitogen-activated protein kinases (MAPK), and/or protein tyrosine kinases. The phosphorylation cascades trigger biochemical and conformational changes in the barrier structure and ultimately lead to an opening of the paracellular pathway. In particular, myosin light chain kinase (MLCK) activation and subsequent myosin light chain (MLC) phosphorylation in endothelial cells directly result in cell contraction and shape changes. The phosphorylation of beta-catenin may cause disorganization of adherens junctions or dissociation of vascular endothelial (VE)-cadherin-catenin complex from its cytoskeletal anchor, leading to loose or opened intercellular junctions. Additionally, focal adhesion kinase (FAK) phosphorylation-coupled focal adhesion assembly and redistribution provide an anchorage support for the conformational changes occurring in the cells and at the cell junctions. The Src family tyrosine kinases may serve as common signals that coordinate these molecular events to facilitate the paracellular transport of macromolecules. The critical roles of protein kinases in endothelial hyperpermeability implicate the therapeutic significance of protein kinase inhibitors in the prevention and treatment of diseases and injuries that are associated with microvascular barrier dysfunction.

Adherens Junctions↗
PubMed2004

Dietary carotenoids, connexins and cancer: what is the connection?

Carotenoids and retinoids are chemically related; indeed a major source of vitamin A in humans occurs through enzymic cleavage of beta-carotene. However, most dietary carotenoids cannot be converted into retinoids. Retinoids have demonstrated cancer-preventive activities in humans and experimental models; however, their toxicity has precluded wide-scale clinical use. In contrast, carotenoids are essentially non-toxic and their cancer-preventive activities, although strongly supported by epidemiological studies, have only been satisfactorily demonstrated in experimental systems. We have shown that in an experimental cell culture system consisting of carcinogen-treated 10T1/2 cells, both retinoids and all dietary carotenoids examined can reversibly inhibit neoplastic transformation in the post-initiation phase of carcinogenesis. This activity strongly correlates with their ability to increase gap junctional intercellular communication by up-regulating the expression of the gene CX43 (connexin43). Connexins comprise the structural unit of gap junctions, organelles which allow direct transfer of signals, nutrients and waste products between contacting cells. CX43 is the most widely expressed member of the gap junction family of genes, and we have demonstrated that its expression is strongly down-regulated in human cancers and in several premalignant conditions. When several human tumour cell lines were genetically engineered to conditionally express CX43 under the influence of a tetracycline promoter, their neoplastic phenotype was strongly attenuated. Specifically, induced cells were inhibited from growing in an anchorage-independent manner and, additionally, growth as xenografts in immunocompromised animals was also strongly attenuated. Growth inhibition in suspension was associated both with increased G(1) cell-cycle arrest and with increased apoptosis. We propose a model whereby junctional communication allows the transfer of growth inhibitory signals from normal to neoplastic cells and that retinoids and carotenoids, by increasing signal transfer, act to prevent cancer.

Anticarcinogenic Agents↗