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Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and α catenin

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第9期274卷 5981-5986页

作者： Itoh, M Morita, K Tsukita, S Kyoto Univ Fac Med Dept Cell Biol Sakyo Ku Kyoto 606 Japan Kyoto Univ Fac Med Dept Dermatol Sakyo Ku Kyoto 606 Japan

ZO-2, a member of the MAGUK family, was thought to be specific for tight junctions (TJs) in contrast to ZO-1, another MAGUK family member, which is localized at TJs and adherens junctions (AJs) in epithelial and nonepithelial cells, respectively. Mouse ZO-2 cDNA was isolated, and a specific polyclonal antibody was generated using corresponding synthetic peptides as antigens. Immunofluorescence microscopy with this polyclonal antibody revealed that, similarly to ZO-1, in addition to TJs in epithelial cells, ZO-2 was also concentrated at AJs in nonepithelial cells such as fibroblasts and cardiac muscle cells lacking TJs. When NH2-terminal dig-like and COOH-terminal non-dig-like domains of ZO-2 (N-ZO-2 and C-ZO-2, respectively) were separately introduced into cultured cells, N-ZO-2 was colocalized with endogenous ZO-1/ZO-2, i.e. at TJs in epithelial cells and at AJs in non-epithelial cells, whereas C-ZO-2 was distributed along actin filaments. Consistently, occludin as well as a: catenin directly bound to N-ZO-2 as well as the NH2-terminal dig-like portion of ZO-1 (N-ZO-1) in vitro. Furthermore, immunoprecipitation experiments revealed that the second PDZ domain of ZO-2 was directly associated with N-ZO-1. These findings indicated that ZO-2 forms a complex with ZO-1/occludin or ZO-1/alpha catenin to establish TJ or AJ domains, respectively.

关键词：抗体/免疫学细胞培养的克隆分子细胞支架蛋白质类/代谢 DNA 互补膜蛋白质类/遗传学膜蛋白质类/免疫学膜蛋白质类/代谢磷蛋白类/代谢蛋白质结合亚细胞部分/代谢紧密连接部/代谢 α连环素动物小鼠

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Dodecylphosphocholine-mediated enhancement of paracellular permeability and cytotoxicity in Caco-2 cell monolayers

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第11期88卷 1161-1168页

作者： Liu, DZ LeCluyse, EL Thakker, DR Univ N Carolina Sch Pharm Div Drug Delivery & Disposit Chapel Hill NC 27599 USA

The intestinal epithelium is a significant barrier for oral absorption of hydrophilic drugs because they cannot easily traverse the lipid bilayer of the cell membrane and their passage through the intercellular space (paracellular transport) is restricted by the tight junctions. in this report we show that dodecylphosphocholine (DPC) can improve the paracellular permeability of hydrophilic compounds across Caco-2 cell monolayers by modulating the tight junctions. The results show that the alkyl chain as well as the zwitterionic head group of DPC are required for its activity. DPC appears to act by modulating the permeability of tight junctions as evidenced by the fact that treatment of Caco-2 cell monolayers by this agent results in a decreased transepithelial electrical resistance (TEER), increased permeability of paracellular markers (e.g., mannitol) with no change in the permeability of the transcellular marker testosterone, and redistribution of the tight junction-associated protein ZO-1. The effect of DPC on Caco-2 cells (e.g., decrease in TEER) is reversible, and is not caused by gross cytotoxicity las indicated by the MTT test) or by nonspecific disruption of the cell membrane las indicated by only slight nuclear staining due to the nonpermeable DNA-specific dye propidium iodide). We propose in the present study a parameter, potency index, that allows comparison of various enhancers of paracellular transport in relation to their cytotoxicity. The potency index is a ratio between the IC50 value (concentration at which 50% inhibition of control mitochondrial dehydrogenase activity occurs in the MTT test) and the EC50 value (concentration at which TEER drops to 50% of its control (untreated) value). By this parameter, DPC is significantly safer than the commonly used absorption enhancer palmitoyl carnitine (PC), which has the potency index of similar to 1 (i.e., no separation between effective and toxic concentration).

关键词： Caco-2细胞/药物作用 Caco-2细胞/代谢 Caco-2细胞/生理学细胞膜/药物作用细胞膜/代谢细胞膜/生理学细胞膜通透性/药物作用电阻抗动力学甘露醇/药代动力学膜电位/药物作用膜蛋白质类/代谢棕榈酰卡尼丁/药理学棕榈酰卡尼丁/毒性磷脂酰胆碱类/药理学磷蛋白类/代谢磷酰胆碱/类似物和衍生物磷酰胆碱/药理学磷酰胆碱/毒性睾酮/药代动力学紧密连接部/药物作用紧密连接部/代谢紧密连接部/生理学人类

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Interaction between the transforming growth factor-β type II receptor/Smad pathway and β-catenin during transforming growth factor-β1-mediated adherens junction disassembly

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AMERICAN JOURNAL OF PATHOLOGY 2002年第5期160卷 1619-1628页

作者： Tian, YC Phillips, AO Univ Wales Coll Cardiff Coll Med Inst Nephrol Cardiff CF14 4XN S Glam Wales

The aim of the current study was to examine the influence of transforming growth factor (TGF)-beta1 on proximal tubular epithelial cell-cell interaction, with particular emphasis on the regulation of adherens junction complex formation. Stimulation of the proximal tubular cell line HK-2 cells by TGF-beta1 led to loss of cell-cell contact and disassembly of both adherens and tight junctional complexes. Adherens junction disassembly was associated with reduction of both Triton-soluble and Triton-insoluble E-cadherin, and an increase in detergent-soluble beta-catenin. Under these conditions, immunoprecipitation and Western analysis demonstrated decreased association of beta-catenin, both with E-cadherin, alpha-catenin, and the cell cytoskeleton. Confocal microscopy after immunostaining, showed decreased intensity of peripheral E-cadherin staining, and redistribution of beta-catenin expression to a perinuclear location. Tight junction disassembly was manifest by a reduction in the expression of Triton-soluble occludin and ZO-1 by Western analysis and their disassociation manifested by immunostaining and confocal microscopy. Loss of cell-cell contact and disassembly of adherens junctions were seen after addition of TGF-beta1 to the basolateral aspect of the cells. Immunoprecipitation experiments demonstrated co-localization of E-cadherin, beta-catenin, and TGF-beta1 RH in unstimulated cells. After TGF-beta1 stimulation, the TGF-beta1 RH no longer associated with either E-cadherin or beta-catenin. Dissociation of the adherens junction protein from the TGF-beta1 receptor was associated with increased beta-catenin tyrosine phosphorylation and decreased threonine phosphorylation. Furthermore after receptor ligand binding, beta-catenin became associated with the TGF-beta1-signaling molecules Smad3 and Smad4.

关键词：黏着连接/药物作用黏着连接/代谢细胞系转化细胞极性细胞大小/药物作用细胞支架蛋白质类/代谢 DNA结合蛋白质类/代谢免疫组织化学磷酰化/药物作用蛋白质结合/药物作用蛋白质丝氨酸苏氨酸激酶受体转化生长因子β/代谢信号传导/药物作用 Smad3蛋白质 Smad4蛋白质紧密连接部/药物作用紧密连接部/代谢反式激活因子类/代谢转化生长因子β/药理学转化生长因子β1 β连环素人类

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In vitro transepithelial drug transport by on-line measurement: Cellular control of paracellular and transcellular transport

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第12期88卷 1340-1347页

作者： Wielinga, PR De Waal, E Westerhoff, HV Lankelma, J Vrije Univ Amsterdam Acad Ziekenhuis Dept Med Oncol NL-1007 MB Amsterdam Netherlands Free Univ Amsterdam Bioctr Amsterdam Dept Mol Cell Biol NL-1081 HV Amsterdam Netherlands

Studies on transcellular transport across epithelial cell layers are performed mostly by discontinuous sampling of the transported compound. This has several drawbacks, e.g., it gives disturbances in volume, it limits the time-resolution, and is often laborious. In this report we introduce a method to measure transepithelial transport of fluorescent compounds continuously. The time-resolution is at the (sub)minute scale, allowing the measurement of the change in transport rate before and after transport modulation. We will describe how we used the method to measure transcellular and paracellular transport. For highly membrane-impermeable compounds, the paracellular transport and the regulation of the tight junctions was studied in wild-type and MDR1 cDNA transfected epithelial canine kidney cells (MDCKII). The effect of the multidrug transporter P-glycoprotein (Pgp) on the transepithelial transport was studied. Addition of the Pgp inhibitor SDZ PSC 833 showed a modulation of the idarubicin (IDA) and daunorubicin (DNR) transport, which was larger during transport from the basolateral to the apical side than in the reverse direction. By modeling the transepithelial transport;we found that in these cells Pgp had more effect on the basolateral to apical transport than vice versa, which can be attributed to a relatively large passive permeation coefficient for the cellular basolateral plasma membrane.

关键词：算法生物转运主动细胞系细胞培养的化学现象化学物理环孢菌素类/化学柔红霉素/化学柔红霉素/药代动力学右旋糖酐类上皮细胞/代谢荧光素-5-异硫氰酸盐/类似物和衍生物基因 MDR/遗传学伊达比星/化学伊达比星/药代动力学模型生物学联机系统紧密连接部/代谢动物牛狗人类

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Prostanoid receptors in intestinal epithelium: selective expression, function, and change with inflammation

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PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS 2000年第4期63卷 223-235页

作者： Takafuji, V Cosme, R Lublin, D Lynch, K Roche, JK Univ Virginia Hlth Sci Ctr Dept Internal Med Charlottesville VA 22908 USA Univ Virginia Hlth Sci Ctr Dept Pharmacol Charlottesville VA 22908 USA

The tissue concentration of PGE(2) is heightened during mucosal inflammation. Nevertheless, the cellular targets of this prostanoid and its effects on epithelial cell physiology are incompletely understood. We used a panel of specific immunoglobulin and mRNA probes in order to localize and quantitate the four member EP family of prostanoid receptors for binding PGE(2) on cells of histologically normal and inflamed human colonic mucosa, and then examined the physiological consequences for the epithelial component of intestine, with special attention to its barrier function. Prostanoid receptors were selectively expressed on a limited number of human colonic mucosal cells, and differed markedly between normal and inflamed tissue, in non-inflamed mucosa, EP2 and EP3 were expressed on epithelia at the apex of crypts;while EP4 was expressed on surface and lateral crypt epithelia. Dual immunostaining and in situ hybridization with digoxygenin-labelled RNA probes largely confirmed the epithelial localization of EP4. On the other hand, during inflammation, lateral crypt (non-surface) epithelial cells newly and significantly expressed prostanoid receptors EP2 and EP3 (p < 0.05, by computer-assisted densitometry). Functionally, exogenous E series prostanoids applied to epithelial monolayers in nM concentrations brought about a 24% increase in the level of barrier function;an associated rise in intracellular cAMP (EC50 of 281);and protection of epithelium from the effects of T cell cytokines. A major perturbation in the number and distribution of functional eicosonoid receptors on epithelia occurs in chronic inflammation of human colonic mucosa. (C) 2000 Harcourt Publishers Ltd.

关键词：前列地尔/药理学抗体/免疫学抗体特异性共同培养技术环AMP/代谢地诺前列酮/药理学电生理学上皮细胞/细胞学上皮细胞/药物作用上皮细胞/代谢上皮细胞/病理学免疫组织化学原位杂交炎症/遗传学炎症/代谢干扰素Ⅱ型/药理学肠黏膜/细胞学肠黏膜/药物作用肠黏膜/代谢肠黏膜/病理学 RNA 信使/遗传学 RNA 信使/代谢受体前列腺素E/分类受体前列腺素E/遗传学受体前列腺素E/免疫学受体前列腺素E/代谢 T淋巴细胞/代谢紧密连接部/药物作用紧密连接部/代谢紧密连接部/病理学人类

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Tight junctions: Guardians of the paracellular pathway

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KIDNEY INTERNATIONAL 2000年第6期57卷 2652-2653页

作者： Brown, D Massachusetts Gen Hosp E Renal Unit Charlestown MA 02129 USA

Editorial. Focuses on the contribution of tight junction to the establishment and maintenance of epithelial cell polarity. Variability of tight junction in the urinary tubule; Molecular components of tight junction in relationship between junctional complexity and transepithelial resistance; Factors regulating tight junction assembly.

关键词：电阻抗肾小管/代谢肾小管/生理学膜蛋白质类/代谢通透性紧密连接部/代谢紧密连接部/生理学人类

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Structure-activity relationships for enhancement of paracellular permeability by 2-alkoxy-3-alkylamidopropylphosphocholines across Caco-2 cell monolayers

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第11期88卷 1169-1174页

作者： Liu, DZ Morris-Natschke, SL Kucera, LS Ishaq, KS Thakker, DR Univ N Carolina Sch Pharm Div Drug Delivery & Disposit Chapel Hill NC 27599 USA Univ N Carolina Sch Pharm Div Med Chem & Nat Prod Chapel Hill NC 27599 USA Wake Forest Univ Sch Med Dept Microbiol & Immunol Winston Salem NC 27103 USA

The oral route is the preferred route of delivery for a large number of drug molecules. However, the intestinal epithelium presents a formidable barrier for delivery of drugs into systemic circulation. Phospholipids are among compounds that enhance the absorption of drugs across the intestinal epithelium. In this paper, we describe structure-activity relationships for phospholipid derivatives as enhancers of paracellular permeability across Caco-2 cell monolayers. in a series of 2-alkoxy-3-alkylamidopropylphosphocholine derivatives, compounds with a long chain at C-3 (R-3) and short chain at C-2 (R-2) were potent in causing a decrease in transepithelial electrical resistance (TEER) and an increase in mannitol transport, but also showed significant cytotoxicity. Compounds with 9-11 carbons at C-3 and 6-10 carbons at C-2 provided good separation (up to 2.7-fold) between activity and cytotoxicity. Notably, a good correlation (r(2) = 0.93) was observed between EC50 (TEER) [concentration that caused a drop in TEER to 50% of its control (untreated) value] and EC10X (mannitol) [concentration that caused 10-fold increase in mannitol transport over the control (untreated) value], confirming that a decrease in TEER is associated with enhanced permeability of the hydrophilic compounds across Caco-2 cell monolayers. Compounds with medium to long carbon chains at C-2 and C-3, and the total carbons in the alkyl chains > 20, showed poor activity and no cytotoxicity.

关键词： Caco-2细胞/细胞学 Caco-2细胞/药物作用 Caco-2细胞/代谢细胞膜通透性/药物作用依地酸/药理学电阻抗甘露醇/药代动力学磷脂酰胆碱类/化学合成磷脂酰胆碱类/化学磷脂酰胆碱类/药理学磷脂酰胆碱类/毒性构效关系紧密连接部/药物作用紧密连接部/代谢紧密连接部/生理学人类

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huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第13期97卷 7284-7289页

作者： Nakamura, T Blechman, J Tada, S Rozovskaia, T Itoyama, T Bullrich, F Mazo, A Croce, CM Geiger, B Canaani, E Thomas Jefferson Univ Jefferson Med Coll Kimmel Canc Ctr Philadelphia PA 19107 USA Weizmann Inst Sci Dept Mol Cell Biol IL-76100 Rehovot Israel

During animal development, regions of the embryo become committed to position-specific: identities, which are determined by spatially restricted expression of Hox/homeotic genes. This expression pattern is initially established by the activity of the segmentation genes and is subsequently maintained during the proliferative stage through the action of transcription factors encoded by the trithorax (trx) and Polycomb (Pc) groups of genes. trithorax (trx) and ash1 (absent, small, or homeotic 1) are members of the Drosophila trx group. Their products are associated with chromosomes and are believed to activate transcription of target genes through chromatin remodeling. Recently, we reported molecular studies indicating that TRX and ASH1 proteins act in concert to bind simultaneously to response elements located at close proximity within the same set of target genes. Extension of these and other studies to mammalian systems required identification and cloning of the mammalian homologue of ash1 (the mammalian homologue of trx, ALL-1, was previously cloned). We have identified a human expressed sequence tag (EST) clone with similarity to the SET domain of Drosophila ASH1, and used it to clone the human gene. huASH1 resides at chromosomal band 1q21. The gene is expressed in multiple tissues as an approximate to 10.5-kb transcript and encodes a protein of 2962 residues. The protein contains a SET domain, a PHD finger, four AT hooks, and a region with homology to the bromodomain. The last region is not present in Drosophila ASH1, and as such might confer to the human protein a unique additional function, Using several anti-huASH1 Ab for immunostaining of cultured cells, we found that the protein is distributed in intranuclear speckles, and unexpectedly also in intercellular junctions. Double-immunofluorescence labeling of huASH1 and several junctional proteins localized the huASH1 protein into tight junctions. The significance of huASH1 dual location is discussed. In particu

关键词：氨基酸序列细胞核/遗传学细胞核/代谢染色体图 DNA结合蛋白质类果蝇属果蝇蛋白质类分子序列数据器官特异性序列比对序列同源性氨基酸紧密连接部/遗传学紧密连接部/代谢转录因子/遗传学转录因子/代谢锌指动物人类

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CNS myelin and Sertoli cell tight junction strands are absent in Osp/Claudin-11 null mice

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CELL 1999年第6期99卷 649-659页

作者： Gow, A Southwood, CM Li, JS Pariali, M Riordan, GP Brodie, SE Danias, J Bronstein, JM Kachar, B Lazzarini, RA CUNY Mt Sinai Med Ctr Brookdale Ctr Dev & Mol Biol New York NY 10029 USA CUNY Mt Sinai Med Ctr Dept Ophthalmol New York NY 10029 USA NICHHD Sect Struct Cell Biol NIH Bethesda MD 20892 USA Univ Calif Los Angeles Sch Med Dept Neurol Los Angeles CA 90095 USA

Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function. Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile. Freeze fracture reveals that tight junction intramembranous strands are absent in CNS myelin and between Sertoli cells of mutant mice. Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions. These novel results provide direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function.

关键词：脑/细胞学脑/代谢冷冻断裂基因表达调控发育期类人猿亚目后肢/生长和发育不育男(雄)性/代谢不育男(雄)性/病理学膜蛋白质类/遗传学膜蛋白质类/代谢小鼠基因敲除显微镜检查共焦显微镜检查电子髓鞘/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢少突神经胶质/细胞学少突神经胶质/代谢塞尔托利细胞/代谢塞尔托利细胞/超微结构睾丸/病理学紧密连接部/代谢紧密连接部/超微结构动物男(雄)性小鼠大鼠

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Paracellular channels!

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Science (New York, N.Y.) 1999年第5424期285卷 62页

作者： V Wong D A Goodenough Department of Cell Biology Harvard Medical School Boston MA 02115 USA.

Simon et al report that a new member of the claudin protein family, paracellin-1, regulates the paracellular transport of magnesium ions in the kidney tubule.

关键词：钙通道/代谢细胞膜/代谢细胞膜/超微结构紧密连接蛋白质类克隆分子离子通道离子转运肾疾病/遗传学肾疾病/代谢肾小管/代谢肾小管/超微结构脂双层/代谢镁/血液镁/代谢镁缺乏/遗传学镁缺乏/代谢膜蛋白质类/遗传学膜蛋白质类/生理学突变紧密连接部/代谢人类

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