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Query: UNIPROT:P06889 (Mol)
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Preimplantation development encompasses the "free"-living period of mammalian embryogenesis, which culminates in the formation of a fluid-filled structure, the blastocyst. Cavitation (blastocyst formation) is accompanied by the expression of a novel set of gene products that contribute directly to the attainment of cell polarity with the trophectoderm, which is both the first epithelium of development and the outer cell layer encircling the inner cell mass of the blastocyst. Several of these gene products have been identified and include the tight junction (ZO-1), Na/K-ATPase (alpha and beta subunits), uvomorulin, gap junction (connexin43), and growth factors such as transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF). This review will examine the role(s) of each of these gene products during the onset and progression of blastocyst formation. The trophectodermal tight junctional permeability seal regulates the leakage of blastocoel fluid and also assists in the maintenance of a polarized Na/K-ATPase distribution to the basolateral plasma membrane domain of the mural trophectoderm. The polarized distribution of the Na/K-ATPase plays an integral role in the establishment of a trans-trophectoderm Na+ gradient, which drives the osmotic accumulation of water across the epithelium into the nascent blastocoelic cavity. The cell adhesion provided by uvomorulin is necessary for the establishment of the tight junctional seal, as well as the maintenance of the polarized Na/K-ATPase distribution. Growth factors such as TGF-alpha and EGF stimulate an increase in the rate of blastocoel expansion, which could, in part, be mediated by secondary messengers that result in an increase in Na/K-ATPase activity. Insight into the mechanism of cavitation has, therefore, directly linked blastocyst formation to trophectoderm cell differentiation, which arises through fundamental cell biological processes that are directly involved in the attainment of epithelial cell polarity.
Mol Reprod Dev 1992 Dec
PMID:The cell biology of blastocyst development. 133 76

The tight junction, or zonula occludens (ZO), forms a semi-permeable barrier in the paracellular pathway in most vertebrate epithelia. The ZO is the apical-most member of a series of intercellular junctions, collectively known as the junctional complex, found at the interface of the apical and lateral cell surface. This structure not only restricts movement of substances around the cells, but may also serve as a 'fence' acting to maintain the cell surface compositional polarity characteristic of epithelial cells. The morphology and physiology of the ZO have been well documented and are briefly reviewed here. The biochemistry of this important intercellular junction remains largely unknown, although a tight junction-specific polypeptide called 'ZO-1' has recently been identified. Preliminary observations regarding the role of this peripheral phosphoprotein in the biology of the ZO are presented.
Mol Cell Biochem 1988 Oct
PMID:The epithelial tight junction: structure, function and preliminary biochemical characterization. 305 73

The immunofluorescent distribution of ZO-1, a tight junction-associated protein, was studied in murine circumventricular organs. These regions generally express a less restrictive blood-brain barrier than is found in other areas of the CNS. In the remaining brain parenchyma, where a characteristic blood-brain barrier exists, ZO-1 was localized in discrete, continuous lines along blood vessels, presumably in association with endothelial cell tight junctions. The ependymal cells in the ventricular walls displayed a more punctate pattern of ZO-1 distribution, indicative of discontinuous tight junctions. In two of the circumventricular organs examined, the median eminence and the subfornical organ, many capillaries lacked detectable ZO-1 immunoreactivity while the apical aspects of the specialized ependymal cells (tanycytes) revealed an unbroken ZO-1 distribution. Scant labelling of ZO-1 in blood vessels was found in the area postrema, and only weak and discontinuous ZO-1 labelling was present in the ventricular wall. Capillaries of the organum vasculosum laminae terminalis expressed ZO-1 immunoreactivity which was comparable to the pattern observed in CNS regions with typical blood-brain barrier. The subcommissural organ, known to contain a blood-brain barrier, also displayed continuous ZO-1 staining in blood vessels. Unbroken ZO-1 distribution was observed in the specialized ependymal cells adjacent to both the organum vasculosum laminae terminalis and subcommissural organ. These immunocytochemical data demonstrate a distribution of ZO-1 in CNS parenchyma outside the circumventricular organs that is consistent with an organization of tight junctions which prevent free paracellular exchange of substances between blood and neuropil but which allow for continuity between CSF and the neuronal environment. The ZO-1 staining pattern in blood vessels and ventricular walls of the circumventricular organs is heterogeneous despite the prevalent absence of a functional blood-brain barrier.
Brain Res Mol Brain Res 1994 Feb
PMID:Distribution of the tight junction-associated protein ZO-1 in circumventricular organs of the CNS. 817 Mar 48

Lung injury in bacterial infection is a multifactorial phenomenon that involves bacterial metabolites and host factors. Primary isolates of type II pneumocytes and established cultures of Madin-Darby canine kidney (MDCK) cells were used to study effects of Pseudomonas aeruginosa exoproducts on epithelial paracellular permeability. The results indicate that elastase (PE) and exotoxin A (Exo A) have different, but complementary, actions that diminish epithelial barrier function. We measured transepithelial electrical resistance (TER) and permeability coefficient for mannitol (Pm) across cell monolayers plated on tissue culture membranes. Application of 100 ng/ml of Exo A to the basal side decreased TER from 1,405 +/- 106 to 462 +/- 50 ohm (omega) and increased Pm for mannitol 6-fold in 16 h (P < 0.05). Application of Exo A to the apical side did not affect either TER or Pm. In contrast, PE (6.5 U/ml) applied either apically or basolaterally reduced TER to 353 +/- 66 omega and increased Pm by 10-fold within 90 min (P < 0.05). The increase in permeability correlated with the number of bacteria that traversed the epithelial monolayers. Fluorescent staining and western immunoblot analysis of toxin-treated cells showed that two tight junctional proteins, ZO-1 and ZO-2, were depleted in monolayers treated with enzymatically active PE. The junctional proteins decreased in cells treated overnight with Exo A but were not depleted. Neither agent diminished cell viability as measured by trypan blue staining or release of radioactivity from 51 Cr-labeled cells. Elastase from P. aeruginosa thus seems to increase alveolar epithelial permeability by damaging tight junction-associated proteins. Exo A, through its effect on protein synthesis, may render the cells unable to restore the junctional proteins and thus the functional junctions.
Am J Respir Cell Mol Biol 1996 Jul
PMID:Pseudomonas aeruginosa and epithelial permeability: role of virulence factors elastase and exotoxin A. 867 17

Internalization of Pseudomonas aeruginosa by epithelial respiratory cell lines has been suggested to be dependent on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Because we have observed intracellular (IC) P. aeruginosa only in cells that do not express apical CFTR, we addressed the question of whether bacterial internalization by epithelial cells depends on the degree of cell differentiation and polarity. Internalization of piliated P. aeruginosa PAO-1 and PAK by human epithelial respiratory cells in primary culture and by the 16 human bronchial epithelial 14o- cell line cultured either on thick collagen gels or on thin collagen films was evaluated by the gentamicin exclusion assay. Cells cultured on thick gels were differentiated, polarized, and tight. They exhibited CFTR at their apical membranes, expressed beta1 integrins at their basal membranes, excluded lanthanum nitrate, and uniformly expressed ZO-1 protein. In contrast, in cells cultured on thin films, CFTR was present mainly in the cytoplasm, whereas beta1 integrins were detected at apical membranes. Most cells cultured on thin films did not exclude lanthanum nitrate and rarely expressed ZO-1 protein. Cells grown on thick and thin collagen substrates differed markedly in bacterial internalization: no IC bacteria could be detected in cells cultured on gels, whereas high IC bacterial concentrations were isolated from cells cultured on thin films. Treatment of cells cultured on thin films with ethylenediaminetetraacetic acid, to disrupt intercellular junctions further, significantly enhanced P. aeruginosa internalization. Our results suggest that P. aeruginosa internalization by epithelial respiratory cells does not depend on CFTR protein expression at the epithelial cell surface but rather on cell polarity and junctional complex integrity.
Am J Respir Cell Mol Biol 1999 May
PMID:Pseudomonas aeruginosa internalization by human epithelial respiratory cells depends on cell differentiation, polarity, and junctional complex integrity. 1022 58

1. The blood-brain barrier is essential for the maintenance and regulation of the neural microenvironment. The blood-brain barrier endothelial cells comprise an extremely low rate of transcytotic vesicles and a restrictive paracellular diffusion barrier. The latter is realized by the tight junctions between the endothelial cells of the brain microvasculature, which are subject of this review. Morphologically, blood-brain barrier-tight junctions are more similar to epithelial tight junctions than to endothelial tight junctions in peripheral blood vessels. 2. Although blood-brain barrier-tight junctions share many characteristics with epithelial tight junctions, there are also essential differences. However, in contrast to tight junctions in epithelial systems, structural and functional characteristics of tight junctions in endothelial cells are highly sensitive to ambient factors. 3. Many ubiquitous molecular constituents of tight junctions have been identified and characterized including claudins, occludin, ZO-1, ZO-2, ZO-3, cingulin, and 7H6. Signaling pathways involved in tight junction regulation comprise, among others, G-proteins, serine, threonine, and tyrosine kinases, extra- and intracellular calcium levels, cAMP levels, proteases, and TNF alpha. Common to most of these pathways is the modulation of cytoskeletal elements which may define blood-brain barrier characteristics. Additionally, cross-talk between components of the tight junction- and the cadherin-catenin system suggests a close functional interdependence of the two cell-cell contact systems. 4. Recent studies were able to elucidate crucial aspects of the molecular basis of tight junction regulation. An integration of new results into previous morphological work is the central intention of this review.
Cell Mol Neurobiol 2000 Feb
PMID:Tight junctions of the blood-brain barrier. 1069 May 2

In the Madin-Darby canine kidney epithelial cell line, the proteins occludin and ZO-1 are structural components of the tight junctions that seal the paracellular spaces between the cells and contribute to the epithelial barrier function. In Ras-transformed Madin-Darby canine kidney cells, occludin, claudin-1, and ZO-1 were absent from cell-cell contacts but were present in the cytoplasm, and the adherens junction protein E-cadherin was weakly expressed. After treatment of the Ras-transformed cells with the mitogen-activated protein kinase kinase (MEK1) inhibitor PD98059, which blocks the activation of mitogen-activated protein kinase (MAPK), occludin, claudin-1, and ZO-1 were recruited to the cell membrane, tight junctions were assembled, and E-cadherin protein expression was induced. Although it is generally believed that E-cadherin-mediated cell-cell adhesion is required for tight junction assembly, the recruitment of occludin to the cell-cell contact area and the restoration of epithelial cell morphology preceded the appearance of E-cadherin at cell-cell contacts. Both electron microscopy and a fourfold increase in the transepithelial electrical resistance indicated the formation of functional tight junctions after MEK1 inhibition. Moreover, inhibition of MAPK activity stabilized occludin and ZO-1 by differentially increasing their half-lives. We also found that during the process of tight junction assembly after MEK1 inhibition, tyrosine phosphorylation of occludin and ZO-1, but not claudin-1, increased significantly. Our study demonstrates that down-regulation of the MAPK signaling pathway causes the restoration of epithelial cell morphology and the assembly of tight junctions in Ras-transformed epithelial cells and that tyrosine phosphorylation of occludin and ZO-1 may play a role in some aspects of tight junction formation.
Mol Biol Cell 2000 Mar
PMID:Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells. 1071 4

The tight junction is the most apical intercellular junction of epithelial cells and regulates transepithelial permeability through the paracellular pathway. To examine possible functions for the tight junction-associated protein ZO-1, C-terminally truncated mutants and a deletion mutant of ZO-1 were epitope tagged and stably expressed in corneal epithelial cell lines. Only full-length ZO-1 and one N-terminal truncation mutant targeted to cell borders; other mutants showed variable cytoplasmic distributions. None of the mutants initially disrupted the localization of endogenous ZO-1. However, long-term stable expression of two of the N-terminal mutants resulted in a dramatic change in cell shape and patterns of gene expression. An elongated fibroblast-like shape replaced characteristic epithelial cobblestone morphology. In addition, vimentin and smooth muscle actin expression were up-regulated, although variable cytokeratin expression remained, suggesting a partial transformation to a mesenchymal cell type. Concomitant with the morphological change, the expression of the integral membrane tight junction protein occludin was significantly down-regulated. The localizations of endogenous ZO-1 and another family member, ZO-2, were disrupted. These findings suggest that ZO-1 may participate in regulation of cellular differentiation.
Mol Biol Cell 2000 May
PMID:Truncation mutants of the tight junction protein ZO-1 disrupt corneal epithelial cell morphology. 1079 44

Airway epithelial cells can respond to infection by activating several signaling pathways. We examined the induction of apoptosis in response to Pseudomonas aeruginosa PAO1 in normal cells and several cystic fibrosis (CF) and corrected cell lines. Epithelial cells in monolayers with tight junctions, confirmed by apical ZO-1 staining demonstrated by confocal microscopy, were entirely resistant to PAO1-induced apoptosis. In contrast, cell lines such as 9HTEo(-) cells that do not form tight junctions were susceptible, with 50% of the population apoptotic after 6 h of exposure to PAO1. CF transmembrane conductance regulator (CFTR) dysfunction caused by different mechanisms (trafficking mutations, overexpression of the regulatory domain or antisense constructs) did not alter rates of apoptosis, nor were differences apparent in terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling detection of apoptotic airway cells from PAO1 infected cftr -/- or control mice. Bacterial expression of specific adhesins, complete lipopolysaccharide, and a functional type III secretion system were all necessary to evoke apoptosis even in susceptible epithelial cells. Unlike other mucosal surfaces, the airway epithelium is highly resistant to apoptosis, and this response is activated only when the appropriate epithelial conditions are present as well as fully virulent P. aeruginosa capable of coordinately expressing both adhesins and cytotoxins.
Am J Respir Cell Mol Biol 2000 Sep
PMID:Pseudomonas aeruginosa induction of apoptosis in respiratory epithelial cells: analysis of the effects of cystic fibrosis transmembrane conductance regulator dysfunction and bacterial virulence factors. 1097 Aug 20

The high-risk human papillomavirus (HPV) E6 proteins stimulate the ubiquitination and degradation of p53, dependent on the E6AP ubiquitin-protein ligase. Other proteins have also been shown to be targeted for degradation by E6, including hDlg, the human homolog of the Drosophila melanogaster Discs large (Dlg) tumor suppressor. We show here that the human homolog of the Drosophila Scribble (Vartul) (hScrib) tumor suppressor protein is also targeted for ubiquitination by the E6-E6AP complex in vitro and that expression of E6 induces degradation of hScrib in vivo. Characterization of the E6AP-E6-hScrib complex indicated that hScrib binds directly to E6 and that the binding is mediated by the PDZ domains of hScrib and a carboxyl-terminal epitope conserved among the high-risk HPV E6 proteins. Green fluorescent protein-hScrib was localized to the periphery of MDCK cells, where it colocalized with ZO-1, a component of tight junctions. E6 expression resulted in loss of integrity of tight junctions, as measured by ZO-1 localization, and this effect was dependent on the PDZ binding epitope of E6. Thus, the high-risk HPV E6 proteins induce the degradation of the human homologs of two Drosophila PDZ domain-containing tumor suppressor proteins, hDlg and hScrib, both of which are associated with cell junction complexes. The fact that Scrib/Vart and Dlg appear to cooperate in a pathway that controls Drosophila epithelial cell growth suggests that the combined targeting of hScrib and hDlg is an important component of the biologic activity of high-risk HPV E6 proteins.
Mol Cell Biol 2000 Nov
PMID:Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. 1102 93


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