Details of a Researcher - KOJIMA Takashi

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Gap and tight junctions

KOJIMA Takashi, MURATA Masaki, SAWADA Norimasa

kenbikyo ( The Japanese Society of Microscopy ) 39 ( 2 ) 110 - 115 2004.07

DOI CiNii

Expression profiles and functional implications of p53-like transcription factors in thymic epithelial cell subtypes

T Kikuchi, S Ichimiya, T Kojima, L Crisa, S Koshiba, A Tonooka, N Kondo, PT van der Saag, S Yokoyama, N Sato

INTERNATIONAL IMMUNOLOGY ( OXFORD UNIV PRESS ) 16 ( 6 ) 831 - 841 2004.06

In this study, we investigated the localization and functional significance of p53 tumor suppressor-like molecules, p63 and p73, in human thymic epithelial cells (TECs). Immunohistochemical studies showed particular distribution profiles of p63 and p73 in thymic epithelium, in which cortical TECs preferentially expressed p63 in their nuclei whereas subcapsular and medullary TECs expressed both p63 and p73 in their nuclei. The wide distribution of p63 in TECs was further suggested by studies using TECs of primary culture. In vitro studies using two human TEC lines demonstrated that p63 was capable of up-regulating intercellular adhesion molecule-1 (ICAM-1) and enhancing the production of IL-6 and IL-8. Moreover, in vitro studies also indicated that p73, but not p63, had the capacity to induce granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) in the TEC lines. These findings suggest that p63 would regulate the cell adhesive property through ICAM-1/LFA-1 interaction and the production of IL-6 and IL-8, probably in all TEC subtypes. p73 in subcapslar and medullary TECs was suggested to play a role in the regulation of the production of GM-CSF and G-CSF, which might stimulate other stromal cells such as dendritic cells, macrophages and endothelial cells around these regions.

DOI PubMed CiNii

ヒト鼻粘膜上皮及び咽頭扁桃上皮おけるタイト結合関連蛋白の発現とバリア機能

高野賢一, 小島隆, 郷充, 村田雅樹, 千葉英樹, 氷見徹夫, 澤田典均

日本病理学会会誌 ( (一社)日本病理学会 ) 93 ( 1 ) 369 - 369 2004.05

The sinaling transduction pathways of TGF-beta plus EGF induced EMT in primary cultures of adult rat hepatocytes

Ken-ichi Takano, Takashi Kojima, Mitsuru Go, Masaki Murata, Hideki Chiba, Norimasa Sawada

CELL STRUCTURE AND FUNCTION ( JAPAN SOC CELL BIOLOGY ) 29 48 - 48 2004.05

Research paper, summary (international conference)

p38 MAP-kinase regulates function of gap and tight junctions during regeneration of rat hepatocytes

Takashi Kojima, Toshinobu Yamamoto, Masaki Murata, Ken-ichi Takano, Mitsuru Go, Hideki Chiba, Norimasa Sawada

CELL STRUCTURE AND FUNCTION ( JAPAN SOC CELL BIOLOGY ) 29 49 - 49 2004.05

Research paper, summary (international conference)

Is occludin transducer for survival signal?

Masaki Murata, Takashi Kojima, Toshinobu Yamamoto, Kenichi Takano, Mitsuru Go, Hideki Chiba, Norimasa Sawada

CELL STRUCTURE AND FUNCTION ( JAPAN SOC CELL BIOLOGY ) 29 49 - 49 2004.05

Research paper, summary (international conference)

Thr(203) of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions

M Fujibe, H Chiba, T Kojima, T Soma, T Wada, T Yamashita, N Sawada

EXPERIMENTAL CELL RESEARCH ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 295 ( 1 ) 36 - 47 2004.04

Mitogen-activated protein kinase (MAPK) modulates the barrier function of tight junctions. We identified a putative phosphorylation site for MAPK at around Thr(203) (PK-PTP) in claudin-1, and determined the biological significance of this site. To this end, using the rat lung endothelial cell line RLE, we generated cells expressing doxycycline (Dox)-inducible wild-type claudin-1 and its mutant with substitution of Thr(203) to Ala, and named them RLE:rtTA:CL1 and RLE:rtTA:CLIT203A, respectively. We herein show, by measurement of transendothelial electrical resistance and paracellular flux of mannitol and inulin, that functional tight junctions were reconstituted in both cells by Dox-induced expression of claudin-1. Interestingly, the barrier functions of tight junctions were less developed in RLE:rtTA:CL1T203A cells compared with RLE:rtTA:CLl cells. Consistently, levels of both detergent-insoluble claudin-1 protein and its threonine-phosphorylation after Dox treatment were low in RLE:rtTA:CLIT203A cells compared to RLE:rtTA:CLl cells. Furthermore, pretreatment with the MAPK inhibitor PD98059 markedly suppressed the barrier function and amount of detergent-insoluble claudin-1 in Dox-exposed RLE:rtTA:CL1 cells, whereas it marginally influenced those in RLE:rtTA:CLIT203A cells. These findings indicate that Thr(203) of claudin-1 is required to enhance the barrier function of claudin-1-based tight junctions, probably via its phosphorylation and subsequent integration into tight junctions. (C) 2004 Elsevier Inc. All rights reserved.

DOI PubMed CiNii

Inhibition of MAP kinase activity moderates changes in expression and function of Cx32 but not claudin-1 during DNA synthesis in primary cultures of rat hepatocytes

Takashi Kojima, Toshinobu Yamamoto, Mengdong Lan, Masaki Murata, Ken-Ichi Takano, Mitsuru Go, Shingo Ichimiya, Hideki Chiba, Norimasa Sawada

Medical Electron Microscopy ( Springer Japan ) 37 ( 2 ) 101 - 113 2004

The signal transduction pathways and activation of the MAP kinase or PI3 kinase signaling cascade regulate a variety of cellular processes, including proliferation and differentiation in hepatocytes. To elucidate the mechanisms of signal transmission required for the regulation of gap and tight junctions during DNA synthesis in rat hepatocytes, we determined changes of expression and function of gap and tight junctions of cells grown in primary culture, using inhibitors of signaling pathways for MAP kinase (PD98059) and PI3 kinase (LY294002). During the stimulation of DNA synthesis induced by epidermal growth factor (EGF), immunoreactivity and mRNAs of gap junction protein Cx32 and of tight junction protein claudin-1 markedly decreased with reduction of gap junctional intercellular communication (GJIC) and the fence function of tight junctions. In Western blots, whole-cell lysate of claudin-1 protein decreased and phosphorylated Cx32 protein in the insoluble fraction of Triton X-100 increased during the stimulation of DNA synthesis. During reinhibition of DNA synthesis, the changes of Cx32 and claudin-1 returned to control levels, as did both functions. In treatment with the inhibitors before DNA synthesis, PD98059 inhibited the changes of expression and function of Cx32, but not claudin-1, without inhibition of cell growth, whereas LY294002 completely inhibited cell growth. These findings indicate that the PI3 kinase pathway rather than the MAP kinase pathway plays an important role for EGF-induced proliferation of rat hepatocytes, and that changes of Cx32 in hepatocytes during the stimulation of DNA synthesis may be in part controlled through MAP kinase. Furthermore, Cx32, but not claudin-1, protein may be a target of activated MAP kinase in hepatocytes.

DOI PubMed

Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP.

Exp Cell Res 15 201 - 12 2004

Tight junction protein MAGI-1 is up-regulated by transfection with connexin 32 in an immortalized mouse hepatic cell line: cDNA microarray analysis.

Cell Tissue Res 19 0-0 2004

Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways

T Ishizaki, H Chiba, T Kojima, M Fujibe, T Soma, H Miyajima, K Nagasawa, Wada, I, N Sawada

EXPERIMENTAL CELL RESEARCH ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 290 ( 2 ) 275 - 288 2003.11

Cyclic AMP (cAMP) promotes functions of tight junctions in endothelial cells, although its target remains unknown. We showed here that cAMP increased gene expression of claudin-5 and decreased that of claudin-1 in porcine blood-brain-barrier endothelial cells via protein kinase A (PKA)-independent and -dependent pathways, respectively. cAMP also enhanced immunoreactivity of claudin-5 along cell borders and in the cytoplasm, reorganized actin filaments, and altered signals of claudin-5, occludin, ZO-1, and ZO-2 along cell boundaries from zipperlike to linear patterns. In contrast, claudin-1 was detected only in the cytoplasm in a dotlike pattern, and its immunolabeling was reduced by cAMP. Interestingly, 31- and 62-kDa claudin-5 immunoprecipitates in the NP-40-soluble and -insoluble fractions, respectively, were highly phosphorylated on threonine residue(s) upon cAMP treatment. All these changes induced by cAMP, except for claudin-5 expression and its signals in the cytoplasm, were reversed by an inhibitor of PKA, H-89. We also demonstrated that cAMP elevated the barrier function of tight junctions in porcine blood-brain-barrier endothelial cells in PKA-dependent and -independent manners. These findings indicate that both PKA-induced phosphorylation of claudin-5 immunoprecipitates and cAMP-dependent but PKA-independent induction of claudin-5 expression could be involved in promotion of tight-junction function in endothelial cells. (C) 2003 Elsevier Inc. All rights reserved.

DOI PubMed CiNii

Regulation of the blood-biliary barrier: Interaction between gap and tight junctions in hepatocytes

Takashi Kojima, Toshinobu Yamamoto, Masaki Murata, Hideki Chiba, Yasuo Kokai, Norimasa Sawada

Medical Electron Microscopy 36 ( 3 ) 157 - 164 2003.09

Book review, literature introduction, etc.

Hepatocytes tightly connect with each other by intercellular junctions to form liver cell plates. The junctions composed of gap, tight, and adherens junctions and desmosomes concentrate around bile canaliculi. In particular, tight junctions serve as a barrier to keep bile in bile canaliculi away from the blood circulation. Thus, it is very reasonable to call tight junctions of hepatocytes the blood-biliary barrier. On the other hand, gap junctions of hepatocytes are considered to enable ordered contraction of bile canaculi from centrizonal to periportal hepatocytes by their function of intercellular communication. Gap and tight junctions may thus play a crucial role in bile secretion, one of the most differentiated functions of the liver. In intrahepatic cholestasis, a common pathological condition of the liver, downregulation of gap and tight junctional functions is seen, which results in impaired intercellular communication and in leaky tight junctions. Although the changes in gap and tight junctions had been considered to be independent of each other, recent findings that the tight junction-associated proteins ZO-1 and occludin bind to connexins indicate the possibility of either coordinate or reciprocal regulation of macromolecular complexes containing gap- and tight-junction proteins. In this review, we introduce the interaction and regulation between gap and tight junctions of hepatocytes in vitro and discuss the regulatory mechanisms of the "blood-biliary barrier" to study the molecular pathogenesis of cholestasis.

DOI PubMed CiNii

Tight junctions and human diseases

Norimasa Sawada, Masaki Murata, Keisuke Kikuchi, Makoto Osanai, Hirotoshi Tobioka, Takashi Kojima, Hideki Chiba

Medical Electron Microscopy 36 ( 3 ) 147 - 156 2003.09

Book review, literature introduction, etc.

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.

DOI PubMed CiNii

Role of the p38 MAP-kinase signaling pathway for Cx32 and claudin-1 in the rat liver

T Kojima, T Yamamoto, M Murata, M Lan, KI Takano, M Go, S Ichimiya, H Chiba, N Sawada

CELL COMMUNICATION AND ADHESION ( TAYLOR & FRANCIS LTD ) 10 ( 4-6 ) 437 - 443 2003.07

Liver regeneration and cholestasis are associated with adaptive changes in expression of gap and tight junctions through signal transduction. The roles of stress responsitive MAP-kinase, p38 MAP-kinase, in the signaling pathway for gap junction protein, Cx32, and tight junction protein, claudin-1, were examined in rat liver in vivo and in vitro , including regeneration following partial hepatectomy and cholestasis after common bile duct ligation. Changes in the expression and function of Cx32 and claudin-1 in hepatocytes in vivo were studied using the p38 MAP-kinase inhibitor SB203580. Following partial hepatectomy and common bile duct ligation, down-regulation of Cx32 protein was inhibited by SB203580 treatment. Up-regulation of claudin-1 protein was enhanced by SB203580 treatment after partial hepatectomy but not common bile duct ligation. However, no change of the Ki-67 labeling index (which is a marker for cell proliferation) in the livers treated with SB203580, was observed compared to that without SB203580 treatment. In primary cultures of rat hepatocytes, however, treatment with a p38 MAP-kinase activator, anisomycin, decreased Cx32 and claudin-1 protein levels. p38 MAP-kinase may be an important signaling pathway for regulation of gap and tight junctions in hepatocytes. Changes of gap and tight junctions during liver regeneration and cholestasis are shown to be in part controlled via the p38 MAP-kinase signaling pathway and are independent of cell growth.

DOI

Hepatocyte nuclear factor (HNF)-4 alpha triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells

H Chiba, T Gotoh, T Kojima, S Satohisa, K Kikuchi, M Osanai, N Sawada

EXPERIMENTAL CELL RESEARCH ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 286 ( 2 ) 288 - 297 2003.06

F9 murine embryonal carcinoma cells provide an attractive system for facilitating molecular mechanisms for epithelial morphogenesis, since they have the capability of differentiating into polarized epithelial cells bearing an apical junctional complexes. We previously showed that a specific retinoid X receptor-retinoic acid receptor heterodimer transduced retinoid signals for biogenesis of functional tight junctions in F9 cells (Exp. Cell Res. 263, (2001) 163). In the present study we generated F9 cells expressing doxycycline-inducible hepatocyte nuclear factor (HNF)-4alpha, a nuclear receptor. We herein show that induction of HNF-4alpha initiates differentiation of F9 cells to polarized epithelial cells, in which tight-junction proteins occludin, claudin-6, claudin-7, and ZO-1 are concentrated at the apical-most regions of lateral membranes. Expression of occludin, claudin-6, and claudin-7 was induced in the cells by doxycycline treatment in a dose- and time-dependent manner, in terms of the amount of HNF-4a. In contrast, expression levels of ZO-1, ZO-2, E-cadherin, and P-catenin were not altered by HNF-4a. We also demonstrate, by analysis of diffusion of labeled sphingomyelin, that the fence function of tight junctions is achieved by induction of HNF-4a. These findings indicate that HNF-4a triggers de novo formation of functional tight junctions and establishment of epithelial cell polarity. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI PubMed CiNii

細胞間の接着とシグナル Hepatocyte nuclear factor(HNF)-4αはタイト結合分子の発現を制御し,上皮の分化と極性形成を誘導する

千葉英樹, 郷久晴朗, 小島隆, 菊地慶介, 小山内誠, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 18 - 18 2003.05

高カリウム培地とouabainによるヒト気管支上皮細胞(Calu-3)のタイト結合の変化

郷充, 小島隆, 村田雅樹, 高野賢一, 山本敏誠, 千葉英樹, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 34 - 34 2003.05

IL-1βによる急性期反応時の肝ギャップ及びタイト結合の変化はMAP-,p38MAP-及びPI3-kinase経路を介して制御されている

山本敏誠, 小島隆, 高野賢一, 村田雅樹, 郷充, 千葉英樹, 小海康夫, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 32 - 32 2003.05

肝細胞のタイト結合における膜貫通タイト結合蛋白occludin分子の役割

村田雅樹, 小島隆, 山本敏誠, 高野賢一, 郷充, 千葉英樹, 小海康夫, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 33 - 33 2003.05

肝細胞におけるコネキシン32によるタイト結合誘導のメカニズム

小島隆, 村田雅樹, 山本敏誠, 郷充, 高野賢一, 千葉英樹, 澤田典均

日本細胞生物学会大会講演要旨集 ( (一社)日本細胞生物学会 ) 56回 33 - 33 2003.05

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