Updated on 2022/03/10

写真a

 
TATSUKAWA Hideki
 
Organization
Graduate School of Pharmaceutical Sciences Department of Basic Medicinal Sciences Bioscience Assistant Professor
Graduate School
Graduate School of Pharmaceutical Sciences
Undergraduate School
School of Agricultural Sciences
Title
Assistant Professor
Contact information
メールアドレス
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Degree 3

  1. 博士(医学) ( 2009.3   東京医科歯科大学 ) 

  2. 修士(医科学) ( 2005.3   東京医科歯科大学 ) 

  3. 学士(理学) ( 2003.3   東京理科大学 ) 

Research Interests 10

  1. 分子生物学

  2. 生物系薬学

  3. ケミカルバイオロジー.薬理学一般

  4. 消化器内科学

  5. 分子生物学

  6. 農芸化学

  7. 生物系薬学

  8. 生化学

  9. 消化器内科学

  10. ケミカルバイオロジー.薬理学一般

Research Areas 5

  1. Others / Others  / Cellular Biochemistry

  2. Life Science / Molecular biology

  3. Life Science / Cell biology

  4. Life Science / Pathological biochemistry

  5. Life Science / Applied molecular and cellular biology

Current Research Project and SDGs 6

  1. 肝線維化の病態機序の解明

  2. 腎線維化の病態機序の解明

  3. FRETを用いたタンパク質架橋化酵素活性の生体内検出プローブの開発

  4. タンパク質架橋化酵素の網羅的な生体内発現分布の解析

  5. 非環式レチノイドによる肝臓癌特異的細胞死の経路解析に基づく新規抗癌剤の開発

  6. Role of Transglutaminase 2 in Liver Injury via Crosslinking and Silencing of Transcription Factor, Sp1

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Research History 4

  1. Nagoya University   Graduare School of Pharmaceutical Sciences   Assistant Professor

    2012.4

  2. Nagoya University   School of Agricultural Sciences   Assistant Professor

    2012.4

  3. Nagoya University   School of Agricultural Sciences

    2012.4

  4. 理化学研究所 特別研究員

    2009.4 - 2012.3

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    Country:Japan

Education 3

  1. Tokyo Medical and Dental University   Graduate School of Medical and Dental Sciences   Gerontology and Gerodontology

    2005.4 - 2009.3

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    Country: Japan

  2. Tokyo Medical and Dental University   Graduate School of Medical and Dental Sciences   Gerontology and Gerodontology

    2003.4 - 2005.3

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    Country: Japan

  3. Tokyo University of Science   Faculty of Science   Department of Chemistry

    1999.4 - 2003.3

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    Country: Japan

Professional Memberships 13

  1. 日本分子生物学会

    2003

  2. 日本生化学会

  3. 日本農芸化学会

  4. 日本肝臓学会

  5. 日本生化学会

    2003

  6. 日本癌学会

  7. ケミカルバイオロジー学会

  8. 日本肝臓学会

  9. 日本癌学会

  10. 日本免疫学会

  11. ケミカルバイオロジー学会

  12. 日本腎臓学会

  13. American Thoracic Society

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Committee Memberships 2

  1. Nature Research Publishing - Scientific reports -   Editorial board member  

    2019.6   

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    Committee type:Academic society

  2. 日本生化学会 中部支部   幹事  

    2017.9 - 2019.8   

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    Committee type:Academic society

Awards 8

  1. Young Investigator Travel Award

    2018.9   International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis  

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    Award type:Award from international society, conference, symposium, etc.  Country:Japan

  2. Young Investigator award

    2018.9   The 13th International Symposium on ALPD and Cirrhosis  

  3. Travel Award

    2011.10   International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis  

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    Country:Japan

  4. CHUGAI Award

    2010.10  

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    Country:Japan

  5. Travel Award

    2009.10   International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis  

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    Country:Japan

  6. Poster Award

    2009.10  

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    Country:Japan

  7. Best Poster Award

    2009.10  

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    Country:Japan

  8. Travel Award

    2007.10   International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis  

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    Country:Japan

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Papers 67

  1. Spatially Resolved Identification of Transglutaminase Substrates by Proteomics in Pulmonary Fibrosis. Reviewed International journal

    Taishu Takeuchi, Hideki Tatsukawa, Yoshiki Shinoda, Keiko Kuwata, Miyuki Nishiga, Hiroshi Takahashi, Naoki Hase, Kiyotaka Hitomi

    American journal of respiratory cell and molecular biology   Vol. 65 ( 3 ) page: 319 - 330   2021.9

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Idiopathic pulmonary fibrosis (IPF) is characterized by the invariably progressive deposition of fibrotic tissue in the lungs and overall poor prognosis. TG2 (transglutaminase 2) is an enzyme that crosslinks glutamine and lysine residues and is involved in IPF pathogenesis. Despite the accumulating evidence implicating TG2 as a critical enzyme, the causative function and direct target of TG2 relating to this pathogenesis remain unelucidated. Here, we clarified the distributions of TG2 protein/activity and conducted quantitative proteomics analyses of possible substrates crosslinked by TG2 on unfixed lung sections in a mouse pulmonary fibrosis model. We identified 126 possible substrates as markedly TG2-dependently increased in fibrotic lung. Gene ontology analysis revealed that these identified proteins were mostly enriched in the lipid metabolic process, immune system process, and protein transport. In addition, these proteins were enriched in 21 pathways, including phagosome, lipid metabolism, several immune responses, and protein processing in endoplasmic reticulum. Furthermore, the network analyses screened out the six clusters and top 20 hub proteins with higher scores, which are related to endoplasmic reticulum stress and peroxisome proliferator-activated receptor signals. Several enriched pathways and categories were identified, some of which were the same terms based on transcription analysis in IPF. Our results provide novel pathological molecular networks driven by protein crosslinking via TG2, which can lead to the development of new therapeutic targets for IPF.

    DOI: 10.1165/rcmb.2021-0012OC

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    PubMed

  2. Isozyme-specific comprehensive characterization of transglutaminase-crosslinked substrates in kidney fibrosis. Reviewed International journal

    Hideki Tatsukawa, Risa Otsu, Yuji Tani, Ryosuke Wakita, Kiyotaka Hitomi

    Scientific reports   Vol. 8 ( 1 ) page: 7306 - 7306   2018.5

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    Authorship:Lead author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-β1. Despite the accumulating evidences indicating that TG2 is a key enzyme in fibrosis, genetic knockout of TG2 reduced by only 50% the elevated protein crosslinking and fibrous protein in renal fibrosis model, whereas treatment with TG inhibitor almost completely reduced these levels. Here, we also clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific crosslinked substrates for both TG1 and TG2 in fibrotic kidney. We found that TG1 activity was markedly enhanced in renal tubular epithelium and interstitial areas, whereas TG2 activity increased only in the extracellular space. In total, 47 and 67 possible candidates were identified as TG1 and TG2 substrates, respectively, only in fibrotic kidney. Among them, several possible substrates related to renal disease and fibrosis were identified. These findings provide novel insights into the mechanisms of renal fibrosis through the targeting of isozyme-specific TG substrates.

    DOI: 10.1038/s41598-018-25674-4

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  3. Global identification and analysis of isozyme-specific possible substrates crosslinked by transglutaminases using substrate peptides in mouse liver fibrosis. Reviewed International journal

    Hideki Tatsukawa, Yuji Tani, Risa Otsu, Haruka Nakagawa, Kiyotaka Hitomi

    Scientific reports   Vol. 7   page: 45049 - 45049   2017.3

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    Authorship:Lead author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    The transglutaminase (TG) family comprises eight isozymes that form the isopeptide bonds between glutamine and lysine residues and contribute to the fibrotic diseases via crosslinking-mediated stabilization of ECM and the activation of TGF-β in several tissues. However, despite a growing body of evidence implicating TG2 as a key enzyme in fibrosis, the causative role of TG2 and the involvement of the other isozymes have not yet been fully elucidated. Therefore, here we clarified the distributions of TG isozymes and their in situ activities and identified the isozyme-specific possible substrates for both TG1 and TG2 using their substrate peptides in mouse fibrotic liver. We found that TG1 activity was markedly enhanced intracellularly over a widespread area, whereas TG2 activity increased in the extracellular space. In total, 43 and 42 possible substrates were identified for TG1 and TG2, respectively, as involved in chromatin organization and cellular component morphogenesis. These included keratin 18, a biomarker for hepatic injury, which was accumulated in the fibrotic liver and showed the partly similar distribution with TG1 activity. These findings suggest that TG1 activity may be involved in the functional modification of intracellular proteins, whereas TG2 activity contributes to the stabilization of extracellular proteins during liver fibrosis.

    DOI: 10.1038/srep45049

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  4. 臓器の線維化を誘導するタンパク質架橋酵素の網羅的な分子標的解析 Invited

    辰川英樹, 人見清隆

    バイオサイエンスとインダストリー   Vol. 80 ( 2 ) page: 1 - 5   2022.3

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    Authorship:Lead author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

  5. Investigation of mouse amniotic fluid for stimulating ability of keratinocyte differentiation depending on the fetal stage. International journal

    Miki Kuribayashi, Yusuke Kawaguchi, Hirofumi Teshima, Hisateru Yamaguchi, Hideki Tatsukawa, Kiyotaka Hitomi

    Archives of biochemistry and biophysics   Vol. 711   page: 109003 - 109003   2021.10

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    During fetal development, the barrier function of the fetal skin is developed under specific conditions for epidermis formation. In keratinocyte differentiation, the well-orchestrated production and modification of various structural proteins are induced. We assessed the epidermal barrier function in different fetal stages by evaluating the enzymatic activity of cross-linking proteins, transglutaminases, and the permeation of fluorescence dye in the stained epidermal sections. During days 15.5-17.5 in gestation, the enzymatic activities in the epidermis appeared to increase significantly; meanwhile, dye permeation was substantially decreased, suggesting the formation of a protective barrier. For the fetal epidermis formation in the earlier stage, unclarified stimulating factors in the amniotic fluid (AF) are possible to promote barrier function by stimulating keratinocyte differentiation. Thus, we performed proteomic spectrometric (MS) analysis on the components in the AF at different fetal stages. Also, we investigated the promotive ability of the components using a cultured keratinocyte differentiation system. According to the MS analysis, the AF components appeared to exhibit stage-specific variations, where possible unique functions have been identified. We also found that adding the AF from each stage to the medium for cultured keratinocytes specifically enhanced the levels of the differentiation markers. These results provide information on the possible role of AF that contains regulatory factors on keratinocyte differentiation.

    DOI: 10.1016/j.abb.2021.109003

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  6. Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis. Invited Reviewed International journal

    Hideki Tatsukawa, Kiyotaka Hitomi

    Cells   Vol. 10 ( 7 )   2021.7

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslinking between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open conformation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial roles of TG2, focusing on cell death/survival and fibrosis.

    DOI: 10.3390/cells10071842

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  7. タンパク質架橋化酵素トランスグルタミナーゼの糸球体炎症進展への役割解明

    伊藤 辰将, 辰川 英樹, 梅田 良祐, 横江 優貴, 高橋 和男, 湯澤 由紀夫, 人見 清隆, 坪井 直毅

    日本腎臓学会誌   Vol. 63 ( 4 ) page: 519 - 519   2021.6

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  8. Thrombin-deficient mutant of medaka, a model fish, displays serious retardation in blood coagulation. Reviewed

    doi: 10.1093/bbb/zbaa098.

    Biosci Biotechnol Biochem     2021.2

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    DOI: 10.1093/bbb/zbaa098.

  9. Thrombin-deficient mutant of medaka, a model fish, displays serious retardation in blood coagulation. International journal

    Yuko Watanabe, Rina Oguri, Risa Suzuki, Qi Meng, Yuta Ishikawa, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi

    Bioscience, biotechnology, and biochemistry   Vol. 85 ( 4 ) page: 824 - 833   2021

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    At the last stage of the blood coagulation cascade, thrombin plays a central role in the processing of fibrinogen for the polymerization and in the additional activation of Factor XIII for the stable cross-linking of fibrin. In addition, thrombin carries out possible multiple roles via processing or interaction with various functional proteins. Several studies conducted in order to elucidate additional physiological significance are ongoing. To clarify further significance of thrombin and to establish an associated disease model, we characterized the orthologue gene for medaka (Oryzias latipes), a research model fish. Tissue distribution of medaka prothrombin has been immunotechnically analyzed. Furthermore, thrombin-deficient medaka mutants were viably established by utilizing a genome-editing method. The established gene-deficient mutants exhibited retarded blood coagulation even in the heterozygous fish. Taking advantage of their ease of handling, this specific model is useful for further investigation in medical research areas on human coagulation diseases.

    DOI: 10.1093/bbb/zbaa098

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  10. Identification and characterization of substrates crosslinked by transglutaminases in liver and kidney fibrosis. Reviewed International journal

    Hideki Tatsukawa, Taishu Takeuchi, Yoshiki Shinoda, Kiyotaka Hitomi

    Analytical biochemistry   Vol. 604   page: 113629 - 113629   2020.9

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    Authorship:Lead author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    The transglutaminase (TGase) family consists of eight isozymes that catalyze Ca2+-dependent crosslink formation between glutamine and lysine residues of proteins. In the pathogenesis of various chronic diseases, among the TGase isozymes, TG2 in particular is upregulated and contributes to a critical role in fibrosis development and progression via the stabilization of extracellular matrix proteins and activation of TGF-β. Although TG2 has been considered a key enzyme in fibrosis, the causative role of TG2 and involvement of other isozymes remain unclear. We have recently developed a comprehensive analysis method targeting the isozyme-specific substrates of TGase in liver and kidney fibrosis. In this review article, we introduce a previously developed method for determining the activity and tissue distribution of TGase and for the detecting and identification of TGase substrates in an isozyme-specific manner. Using our comprehensive analysis method, we newly characterized the overlapping profile data regarding potential substrates of TG1 and TG2 that have been identified in liver and kidney fibrosis to date. Our results obtained by comparing the specificity and similarity of potential TGase substrates between different tissue fibrosis models provide a deeper understanding regarding the specific and common pathways in disease pathogenesis and progression.

    DOI: 10.1016/j.ab.2020.113629

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  11. Transglutaminase orthologues in medaka fish - biochemical characterization and establishment of gene-deficient mutants. Reviewed International journal

    Qi Meng, Yuko Watanabe, Risa Suzuki, Rina Oguri, Hideki Tatsukawa, Kiyotaka Hitomi

    Analytical biochemistry   Vol. 604   page: 113610 - 113610   2020.9

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    By genome analysis, seven homologous genes (orthologues) of human transglutaminases (TGases) have been identified in medaka fish (Oryzias latipes), some of which clearly corresponded to the Factor XIII, TG1, and TG2. The enzymatically active-recombinant proteins for these medaka TGases has been successfully produced in bacteria or baculovirus-infected insect cell systems. Specific antibodies have been prepared and used in immunohistochemical analyses to reveal tissue distribution. Furthermore, gene-deficient medaka mutants for the genes encoding Factor XIII and TG1 have been established with analysis of their phenotypes. Retarded cross-linking of fibrin and higher sensitivity to osmolality are observed in which each gene had been knock-out. In this review, we summarize these biochemical features and the phenotypes of these gene-deficient fish.

    DOI: 10.1016/j.ab.2020.113610

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  12. Gene disruption of medaka (Oryzias latipes) orthologue for mammalian tissue-type transglutaminase (TG2) causes movement retardation. Reviewed International journal

    Yuko Watanabe, Kazuho Okuya, Yuki Takada, Masato Kinoshita, Saori Yokoi, Shinichi Chisada, Yasuhiro Kamei, Hideki Tatsukawa, Naoyuki Yamamoto, Hideki Abe, Hisashi Hashimoto, Kiyotaka Hitomi

    Journal of biochemistry   Vol. 168 ( 3 ) page: 213 - 222   2020.9

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    Transglutaminases (TGases) are an enzyme family that catalyzes protein cross-linking essential for several biological functions. In the previous studies, we characterized the orthologues of the mammalian TGase family in medaka (Oryzias latipes), an established fish model. Among the human isozymes, tissue-type transglutaminase (TG2) has multiple functions that are involved in several biological phenomena. In this study, we established medaka mutants deficient for the orthologue of human TG2 (OlTGT) using the CRISPR/Cas9 and TALEN systems. Although apparent morphological changes in the phenotype were not observed, movement retardation was found in the mutant fish when evaluated by a tank diving test. Furthermore, comparative immunohistochemistry analysis using in this fish model revealed that OlTGT was expressed at the periventricular layer of the optic tectum. Our findings provide novel insight for the relationship between tissue-type TGase and the nervous system and the associated behavior.

    DOI: 10.1093/jb/mvaa038

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  13. Analysis of the expression of transglutaminases in the reconstructed human epidermis using a three-dimensional cell culture. Reviewed International journal

    Hirofumi Teshima, Manami Kato, Hideki Tatsukawa, Kiyotaka Hitomi

    Analytical biochemistry   Vol. 603   page: 113606 - 113606   2020.8

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    The skin epidermis functions as a barrier to various external stresses. In the outermost layer, the terminally differentiated keratinocytes result in cornification with tough structure by formation of cornified envelope beneath the plasma membrane. To complete the formation of the cornified envelope, several structural proteins are cross-linked via the catalytic action of transglutaminases (TG1, TG3, TG5, and TG6). The expression and activation of these enzymes are regulated in a tightly coordinated manner during keratinocyte differentiation. We here show the system detecting the activity of the TGases using specific glutamine-donor substrate peptides in a three-dimensional culture system of keratinocytes. In this review, we summarize the roles of the epidermal enzymes and introduce a detection method that will provide a system for evaluating the skin barrier function.

    DOI: 10.1016/j.ab.2020.113606

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  14. 抗体型糸球体腎炎におけるタンパク質架橋化酵素トランスグルタミナーゼの機能

    伊藤 辰将, 辰川 英樹, 横江 優貴, 高橋 和男, 丸山 彰一, 湯澤 由紀夫, 人見 清隆, 坪井 直毅

    日本腎臓学会誌   Vol. 62 ( 4 ) page: 270 - 270   2020.7

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  15. タンパク質架橋酵素を介した上皮細胞の間葉転換機構の解析 Invited Reviewed

    辰川英樹, 篠田祥希, 竹内大修, 人見清隆

    日本応用酵素協会誌   Vol. 55   page: 1 - 9   2020

  16. タンパク質の架橋による翻訳後修飾反応を介した組織線維化の分子メカニズムの解析

    辰川 英樹, 竹内 大修, 伊藤 辰将, 人見 清隆

    日本生化学会大会プログラム・講演要旨集   Vol. 92回   page: [3T09m - 04]   2019.9

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  17. タンパク質の架橋による翻訳後修飾反応を介した組織線維化の分子メカニズムの解析

    辰川 英樹, 竹内 大修, 伊藤 辰将, 人見 清隆

    日本生化学会大会プログラム・講演要旨集   Vol. 92回   page: [3T09m - 04]   2019.9

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  18. Studies on differentiation-dependent expression and activity of distinct transglutaminases by specific substrate peptides using three-dimensional reconstituted epidermis. Reviewed International journal

    Yuki Tanabe, Miki Yamane, Manami Kato, Hirofumi Teshima, Miki Kuribayashi, Hideki Tatsukawa, Hiroyuki Takama, Masashi Akiyama, Kiyotaka Hitomi

    The FEBS journal   Vol. 286 ( 13 ) page: 2536 - 2548   2019.7

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    During skin formation, particularly during differentiation of keratinocytes, unique post-translational modifications play a role in forming a proteinaceous supermolecule called the cornified envelope (CE), which is necessary for barrier function. Transglutaminases (TGs) are essential enzymes involved in the cross-linking of various keratinocyte structural proteins to complete CE formation. The TG family consists of eight isozymes, with two members, TG1 and TG3, located mainly in the epidermis. In an in vitro three-dimensional (3D) culture system, reconstruction of the epidermis allows cornification of the terminally differentiated keratinocytes. In this study, using isozyme-specific substrate peptides that enable detection of TG activity, we investigated the expression and the activation pattern of each isozyme during differentiation in this culture system. In the differentiating cells, the protein levels, enzymatic activities, as well as localization of TG1 and TG3 exhibited distinct patterns. Specific knockdown of these enzymes by siRNA revealed less cornification, suggesting that each TG contributes to the epidermal formation. In conclusion, we demonstrate the efficiency of the 3D system for studying differentiation-dependent expression and activity of distinct TGs by specific substrate peptides. ENZYME: Transglutaminase, EC2.3.2.13.

    DOI: 10.1111/febs.14832

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  19. Detection and identification of potential transglutaminase 2 substrates in the mouse renal glomeruli. Reviewed International journal

    Yoshimasa Ito, Hideki Tatsukawa, Hisateru Yamaguchi, Kazuo Takahashi, Kiyotaka Hitomi, Yukio Yuzawa

    Archives of biochemistry and biophysics   Vol. 660   page: 11 - 19   2018.12

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    The glomerulus primarily comprises mesangial cells, glomerular microvascular endothelial cells, and podocytes. IgA nephropathy is the most common primary glomerulonephritis worldwide and has a risk of progression to end-stage renal disease. IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangial area, where TG2 is significantly enhanced. Therefore, identification of glomerular TG2 substrates is the first step in elucidating the role of TG2 as a crosslinking enzyme during disease progression. To clarify potential glomerular TG2 substrates, and to establish a procedure for substrate identification, we attempted to identify those molecules using normal mouse glomeruli. Extracts from mouse glomerular and non-glomerular fractions were treated with our established biotin-labeled substrate peptide, which specifically crosslinks to the lysine-donor substrates depending on TG2 activity. Peptide-incorporated proteins were then purified using avidin resin and identified via mass spectrometry. In parallel, we performed the identification using corresponding samples from TG2 knockout mice. Consequently, potential TG2 substrates were separately identified in glomerular and non-glomerular fractions. They were mainly identified as novel TG2 substrates and partly include the well-known substrates. These results potentially provide novel insights into the mechanism underlying IgA nephropathy and may help elucidate the physiological functions of TG2.

    DOI: 10.1016/j.abb.2018.10.001

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  20. Tschimganine and its derivatives extend the chronological life span of yeast via activation of the Sty1 pathway. Reviewed International journal

    Takahide Hibi, Hokuto Ohtsuka, Takafumi Shimasaki, Shougo Inui, Masatoshi Shibuya, Hideki Tatsukawa, Kei Kanie, Yoshihiko Yamamoto, Hirofumi Aiba

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 23 ( 8 ) page: 620 - 637   2018.8

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    Most antiaging factors or life span extenders are associated with calorie restriction (CR). Very few of these factors function independently of, or additively with, CR. In this study, we focused on tschimganine, a compound that was reported to extend chronological life span (CLS). Although tschimganine led to the extension of CLS, it also inhibited yeast cell growth. We acquired a Schizosaccharomyces pombe mutant with a tolerance for tschimganine due to the gene crm1. The resulting Crm1 protein appears to export the stress-activated protein kinase Sty1 from the nucleus to the cytosol even under stressful conditions. Furthermore, we synthesized two derivative compounds of tschimganine, α-hibitakanine and β-hibitakanine; these derivatives did not inhibit cell growth, as seen with tschimganine. α-hibitakanine extended the CLS, not only in S. pombe but also in Saccharomyces cerevisiae, indicating the possibility that life span regulation by tschimganine derivative may be conserved across various yeast species. We found that the longevity induced by tschimganine was dependent on the Sty1 pathway. Based on our results, we propose that tschimganine and its derivatives extend CLS by activating the Sty1 pathway in fission yeast, and CR extends CLS via two distinct pathways, one Sty1-dependent and the other Sty1-independent. These findings provide the potential for creating an additive life span extension effect when combined with CR, as well as a better understanding of the mechanism of CLS.

    DOI: 10.1111/gtc.12604

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  21. Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia. Reviewed International journal

    Ivana Mižíková, Tilman Pfeffer, Claudio Nardiello, David E Surate Solaligue, Heiko Steenbock, Hideki Tatsukawa, Diogo M Silva, István Vadász, Susanne Herold, Richard J Pease, Siiri E Iismaa, Kiyotaka Hitomi, Werner Seeger, Jürgen Brinckmann, Rory E Morty

    The FEBS journal   Vol. 285 ( 16 ) page: 3056 - 3076   2018.8

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    The generation, maturation and remodelling of the extracellular matrix (ECM) are essential for the formation of alveoli during lung development. Alveoli formation is disturbed in preterm infants that develop bronchopulmonary dysplasia (BPD), where collagen fibres are malformed, and perturbations to lung ECM structures may underlie BPD pathogenesis. Malformed ECM structures might result from abnormal protein cross-linking, in part attributable to the increased expression and activity of transglutaminase 2 (TGM2) that have been noted in affected patient lungs, as well as in hyperoxia-based BPD animal models. The objective of the present study was to assess whether TGM2 plays a causal role in normal and aberrant lung alveolarization. Targeted deletion of Tgm2 in C57BL/6J mice increased septal thickness and reduced gas-exchange surface area in otherwise normally developing lungs. During aberrant lung alveolarization that occurred under hyperoxic conditions, collagen structures in Tgm2-/- mice were partially protected from the impact of hyperoxia, where normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance was restored; however, the lung alveolar architecture remained abnormal. Inhibition of transglutaminases (including TGM2) with cysteamine appreciably reduced transglutaminase activity in vivo, as assessed by Nε -(γ-l-glutamyl)-l-lysine abundance and TGM catalytic activity, and restored normal dihydroxylysinonorleucine and hydroxylysylpiridinoline collagen cross-link abundance under pathological conditions. Furthermore, a moderate improvement in alveoli size and gas-exchange surface density was noted in cysteamine-treated mouse lungs in which BPD was modelled. These data indicate that TGM2 plays a role in normal lung alveolarization, and contributes to the formation of aberrant ECM structures during disordered lung alveolarization.

    DOI: 10.1111/febs.14596

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  22. ISOZYME-SPECIFIC IDENTIFICATION AND CHARACTERIZATION OF SUBSTRATES CROSSLINKED BY TRANSGLUTAMINASES IN LIVER FIBROSIS

    Tatsukawa H., Nakagawa H., Hitomi K.

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   Vol. 42   page: 33A-33A   2018.8

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  23. Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid. Reviewed International journal

    Xian-Yang Qin, Harukazu Suzuki, Masao Honda, Hikari Okada, Shuichi Kaneko, Ikuyo Inoue, Etsuko Ebisui, Kosuke Hashimoto, Piero Carninci, Keita Kanki, Hideki Tatsukawa, Naoto Ishibashi, Takahiro Masaki, Tomokazu Matsuura, Hiroyuki Kagechika, Kan Toriguchi, Etsuro Hatano, Yohei Shirakami, Goshi Shiota, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 115 ( 19 ) page: 4969 - 4974   2018.5

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    Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix-loop-helix-zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/β-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM- cells. In a long-term (>10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.

    DOI: 10.1073/pnas.1802279115

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  24. 糖尿病モデルマウスにおけるキヌレニン経路代謝物の腎組織イメージング質量分析

    松下 祥子, 高橋 和男, 伊藤 辰将, 山本 康子, 藤垣 英嗣, 毛利 彰宏, 中嶋 和紀, 尾之内 高慶, 辰川 英樹, 釘田 雅則, 長尾 静子, 人見 清隆, 齋藤 邦明, 瀬藤 光利, 湯澤 由紀夫

    日本腎臓学会誌   Vol. 60 ( 3 ) page: 403 - 403   2018.4

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  25. 組織の線維化に伴い架橋される基質タンパク質群の網羅的同定・解析 Invited

    辰川英樹, 人見清隆

    日本応用酵素協会   Vol. 52   page: 1-10   2018.3

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  26. 組織の線維化に伴い架橋される基質タンパク質群の網羅的同定・解析 Invited

    辰川英樹, 人見清隆

    日本応用酵素協会   Vol. 52   page: 1-10   2018.3

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  27. Higher susceptibility to osmolality of the medaka (Oryzias latipes) mutants in orthologue genes of mammalian skin transglutaminases. Reviewed International journal

    Yuko Watanabe, Eri Furukawa, Hideki Tatsukawa, Hisashi Hashimoto, Yasuhiro Kamei, Yoshihito Taniguchi, Kiyotaka Hitomi

    Bioscience, biotechnology, and biochemistry   Vol. 82 ( 7 ) page: 1165 - 1168   2018

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    Transglutaminase (TG) is an essential enzyme to catalyze cross-linking reactions of epidermal proteins. Recently, we biochemically characterized human skin TG orthologues for medaka (Oryzias latipes), a model fish. By genome editing, gene-modified fishes for the two orthologues were obtained, both of which lack the ordinal enzymes. These fish appeared to exhibit higher susceptibility to osmolality at the period of larvae.

    DOI: 10.1080/09168451.2018.1453294

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  28. Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes. Reviewed International journal

    Xian-Yang Qin, Mitsuko Hara, Erik Arner, Yoshikuni Kawaguchi, Ikuyo Inoue, Hideki Tatsukawa, Yutaka Furutani, Keisuke Nagatsuma, Tomokazu Matsuura, Feifei Wei, Jun Kikuchi, Hideko Sone, Carsten Daub, Hideya Kawaji, Timo Lassmann, Masayoshi Itoh, Harukazu Suzuki, Piero Carninci, Yoshihide Hayashizaki, Norihiro Kokudo, Alistair R R Forrest, Soichi Kojima

    EBioMedicine   Vol. 24   page: 257 - 266   2017.10

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    The acute phase protein orosomucoid-1 (Orm1) is mainly expressed by hepatocytes (HPCs) under stress conditions. However, its specific function is not fully understood. Here, we report a role of Orm1 as an executer of HPC proliferation. Increases in serum levels of Orm1 were observed in patients after surgical resection for liver cancer and in mice undergone partial hepatectomy (PH). Transcriptome study showed that Orm1 became the most abundant in HPCs isolated from regenerating mouse liver tissues after PH. Both in vitro and in vivo siRNA-induced knockdown of Orm1 suppressed proliferation of mouse regenerating HPCs and human hepatic cells. Microarray analysis in regenerating mouse livers revealed that the signaling pathways controlling chromatin replication, especially the minichromosome maintenance protein complex genes were uniformly down-regulated following Orm1 knockdown. These data suggest that Orm1 is induced in response to hepatic injury and executes liver regeneration by activating cell cycle progression in HPCs.

    DOI: 10.1016/j.ebiom.2017.09.008

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  29. Global identification and analysis of isozyme-specific substrates crosslinked by transglutaminases in mouse liver fibrosis

    Tatsukawa Hideki, Nakagawa Haruka, Kiyotaka Hitomi

    HEPATOLOGY   Vol. 66   page: 222A-222A   2017.10

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  30. Biochemical characterization of a medaka (Oryzias latipes) orthologue for mammalian Factor XIII and establishment of a gene-edited mutant. Reviewed International journal

    Rima Horimizu, Ryota Ogawa, Yuko Watanabe, Hideki Tatsukawa, Masato Kinoshita, Hisashi Hashimoto, Kiyotaka Hitomi

    The FEBS journal   Vol. 284 ( 17 ) page: 2843 - 2855   2017.9

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    In the final process of blood coagulation, fibrin molecules are stabilized via a catalytic reaction by Factor XIIIA (FXIIIA), a member of the transglutaminase (TGase) family that catalyzes protein cross-linking reactions. In this study, we characterized the orthologue of this enzyme in medaka (Oryzias latipes), an established model fish in which a coagulation system is also preserved. The recombinant protein of this orthologue enzyme was produced in baculovirus-infected insect cells and used for analysis of its biochemical properties including activation by thrombin proteolysis and calcium dependence of the TGase enzymatic activity. Immunostaining and immunoblotting revealed that medaka FXIIIA is expressed in the kidney, bone, and esophagus in addition to blood cells. Furthermore, a gene-mutant fish was established using the CRISPR/Cas9 system. The loss of FXIIIA expression was validated in the mutants, and phenotypes, such as absence of fibrin cross-linking, were investigated in the established mutant fish.

    DOI: 10.1111/febs.14153

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  31. FANTOM5 CAGE profiles of human and mouse samples. Reviewed International journal

    Shuhei Noguchi, Takahiro Arakawa, Shiro Fukuda, Masaaki Furuno, Akira Hasegawa, Fumi Hori, Sachi Ishikawa-Kato, Kaoru Kaida, Ai Kaiho, Mutsumi Kanamori-Katayama, Tsugumi Kawashima, Miki Kojima, Atsutaka Kubosaki, Ri-Ichiroh Manabe, Mitsuyoshi Murata, Sayaka Nagao-Sato, Kenichi Nakazato, Noriko Ninomiya, Hiromi Nishiyori-Sueki, Shohei Noma, Eri Saijyo, Akiko Saka, Mizuho Sakai, Christophe Simon, Naoko Suzuki, Michihira Tagami, Shoko Watanabe, Shigehiro Yoshida, Peter Arner, Richard A Axton, Magda Babina, J Kenneth Baillie, Timothy C Barnett, Anthony G Beckhouse, Antje Blumenthal, Beatrice Bodega, Alessandro Bonetti, James Briggs, Frank Brombacher, Ailsa J Carlisle, Hans C Clevers, Carrie A Davis, Michael Detmar, Taeko Dohi, Albert S B Edge, Matthias Edinger, Anna Ehrlund, Karl Ekwall, Mitsuhiro Endoh, Hideki Enomoto, Afsaneh Eslami, Michela Fagiolini, Lynsey Fairbairn, Mary C Farach-Carson, Geoffrey J Faulkner, Carmelo Ferrai, Malcolm E Fisher, Lesley M Forrester, Rie Fujita, Jun-Ichi Furusawa, Teunis B Geijtenbeek, Thomas Gingeras, Daniel Goldowitz, Sven Guhl, Reto Guler, Stefano Gustincich, Thomas J Ha, Masahide Hamaguchi, Mitsuko Hara, Yuki Hasegawa, Meenhard Herlyn, Peter Heutink, Kelly J Hitchens, David A Hume, Tomokatsu Ikawa, Yuri Ishizu, Chieko Kai, Hiroshi Kawamoto, Yuki I Kawamura, Judith S Kempfle, Tony J Kenna, Juha Kere, Levon M Khachigian, Toshio Kitamura, Sarah Klein, S Peter Klinken, Alan J Knox, Soichi Kojima, Haruhiko Koseki, Shigeo Koyasu, Weonju Lee, Andreas Lennartsson, Alan Mackay-Sim, Niklas Mejhert, Yosuke Mizuno, Hiromasa Morikawa, Mitsuru Morimoto, Kazuyo Moro, Kelly J Morris, Hozumi Motohashi, Christine L Mummery, Yutaka Nakachi, Fumio Nakahara, Toshiyuki Nakamura, Yukio Nakamura, Tadasuke Nozaki, Soichi Ogishima, Naganari Ohkura, Hiroshi Ohno, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Yasushi Okazaki, Valerio Orlando, Dmitry A Ovchinnikov, Robert Passier, Margaret Patrikakis, Ana Pombo, Swati Pradhan-Bhatt, Xian-Yang Qin, Michael Rehli, Patrizia Rizzu, Sugata Roy, Antti Sajantila, Shimon Sakaguchi, Hiroki Sato, Hironori Satoh, Suzana Savvi, Alka Saxena, Christian Schmidl, Claudio Schneider, Gundula G Schulze-Tanzil, Anita Schwegmann, Guojun Sheng, Jay W Shin, Daisuke Sugiyama, Takaaki Sugiyama, Kim M Summers, Naoko Takahashi, Jun Takai, Hiroshi Tanaka, Hideki Tatsukawa, Andru Tomoiu, Hiroo Toyoda, Marc van de Wetering, Linda M van den Berg, Roberto Verardo, Dipti Vijayan, Christine A Wells, Louise N Winteringham, Ernst Wolvetang, Yoko Yamaguchi, Masayuki Yamamoto, Chiyo Yanagi-Mizuochi, Misako Yoneda, Yohei Yonekura, Peter G Zhang, Silvia Zucchelli, Imad Abugessaisa, Erik Arner, Jayson Harshbarger, Atsushi Kondo, Timo Lassmann, Marina Lizio, Serkan Sahin, Thierry Sengstag, Jessica Severin, Hisashi Shimoji, Masanori Suzuki, Harukazu Suzuki, Jun Kawai, Naoto Kondo, Masayoshi Itoh, Carsten O Daub, Takeya Kasukawa, Hideya Kawaji, Piero Carninci, Alistair R R Forrest, Yoshihide Hayashizaki

    Scientific data   Vol. 4   page: 170112 - 170112   2017.8

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    In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.

    DOI: 10.1038/sdata.2017.112

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  32. FRET-based detection of isozyme-specific activities of transglutaminases. Reviewed

    Tatsukawa H, Liu HH, Oba S, Kamiya N, Nakanishi Y, Hitomi K.

    Amino Acids   Vol. 49 ( 3 ) page: 615-623   2017.3

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    DOI: 10.1007/s00726-016-2322-0.

  33. FRET-based detection of isozyme-specific activities of transglutaminases. Reviewed International journal

    Hideki Tatsukawa, Hong Hong Liu, Shota Oba, Noriho Kamiya, Yoichi Nakanishi, Kiyotaka Hitomi

    Amino acids   Vol. 49 ( 3 ) page: 615 - 623   2017.3

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    Transglutaminases (TGs) comprise a protein family in which the members catalyze the formation of isopeptide bonds between glutamine and lysine residues in various proteins. Expression studies on its three major members, FXIII, TG1, and TG2, have been performed in a relatively large number of mammalian tissues in comparison with those on the other isozymes. We previously identified a highly reactive substrate peptide, including glutamine, for each isozyme from a phage display library and developed a method for detecting isozyme-specific activities by incorporating a labeled substrate peptide into lysine residues of proteins. Here, we describe genetically encoded Förster resonance energy transfer (FRET)-based probes composed of each fluorescence protein (Cerulean and EVenus) fused with substrate peptides. The probe pairs, designated as Trac-MTG (His-CerΔ11-LQ/EV-K-His) containing linker and substrate peptide sequence for microbial TG (MTG), increased the EVenus:Cerulean fluorescence intensity ratio by more than 1.5-fold. Furthermore, we demonstrated that Trac-TG1 (His-CerΔ11-K5) and Trac-TG2 (His-CerΔ11-T26) containing substrate peptide sequence for mammalian TGs successfully detected the isozyme-specific activity of TG1 and TG2, respectively. In this study, we developed a rapid and convenient experimental system for measuring the isozyme-specific activity of TGs. The application of these probes for analyses in cells and tissues will be helpful for elucidating the physiological and pathological functions of TGs.

    DOI: 10.1007/s00726-016-2322-0

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  34. Biochemical characterization of the medaka (Oryzias latipes) orthologue for mammalian tissue-type transglutaminase (TG2). Reviewed International journal

    Yuki Takada, Yuko Watanabe, Kazuho Okuya, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi

    Bioscience, biotechnology, and biochemistry   Vol. 81 ( 3 ) page: 469 - 474   2017.3

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    Transglutaminase is an enzyme family responsible for post-translational modification such as protein cross-linking and the attachment of primary amine and/or deamidation of glutamine-residue in proteins. Medaka (Oryzias latipes), a recently established model fish, has similar functional proteins to those characterized in mammals. Previously, we found the apparent orthologues that correspond to human transglutaminases in medaka. In this study, regarding the medaka orthologue of human tissue-type transglutaminase (OlTGT), recombinant protein was expressed in an active form in bacteria cultured at low temperature. Using the recombinant protein, we biochemically characterized the enzymatic activity and also obtained a monoclonal antibody that specifically recognized OlTGT. Immunochemical analysis revealed that OlTGT was not expressed ubiquitously, unlike its mammalian orthologue, but in primarily limited tissues such as the eye, brain, spinal cord, and gas gland.

    DOI: 10.1080/09168451.2016.1256757

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  35. Analysis on transglutaminase 1 and its substrates using specific substrate peptide in cultured keratinocytes.

    Yamane M, Sugimura K, Kawasaki H, Tatsukawa H, Hitomi K.

    Biochem Biophys Res Commun   Vol. 478 ( 1 ) page: 343-348   2016.9

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    DOI: 10.1016/j.bbrc.2016.07.051.

  36. Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death.

    Tatsukawa H, Furutani Y, Hitomi K, Kojima S.

    Cell Death and Disease   Vol. 7 ( 6 ) page: e2244   2016.6

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    DOI: 10.1038/cddis.2016.150.

  37. Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model.

    Qin XY, Tatsukawa H, Hitomi K, Shirakami Y, Ishibashi N, Shimizu M, Moriwaki H, Kojima S.

    Cancer Prevention Research     2016.3

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    DOI: 10.1158/1940-6207.CAPR-15-0326.

  38. Biochemical Characterization of Medaka (Oryzias latipes) Transglutaminases, OlTGK1 and OlTGK2, as Orthologues of Human Keratinocyte-Type Transglutaminase.

    Kikuta A, Furukawa E, Ogawa R, Suganuma N, Saitoh M, Nishimaki T, Katsumura T, Oota H, Kawamoto T, Tatsukawa H, Hashimoto H, Hitomi K.

    PLoS One     2015.12

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    DOI: doi: 10.1371/journal.pone.0144194.

  39. The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

    Hurst LD, Ghanbarian AT, Forrest AR; FANTOM consortium (Tatsukawa H), Huminiecki L.

    PLoS Biology     2015.12

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    DOI: doi: 10.1371/journal.pbio.1002315.

  40. Application of Gene Expression Trajectories Initiated from ErbB Receptor Activation Highlights the Dynamics of Divergent Promoter Usage.

    Carbajo D, Magi S, Itoh M, Kawaji H, Lassmann T, Arner E, Forrest AR, Carninci P, Hayashizaki Y, Daub CO; FANTOM consortium (Tatsukawa H), Okada-Hatakeyama M, Mar JC.

    PLoS One     2015.12

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    DOI: doi: 10.1371/journal.pone.0144176.

  41. Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells. Reviewed

    Shrestha R, Tatsukawa H, Shrestha R, Ishibashi N, Matsuura T, Kagechika H, Kose S, Hitomi K, Imamoto N, Kojima S.

    Cell Death & Disease     2015.12

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    DOI: doi: 10.1038/cddis.2015.339.

  42. Distribution of transglutaminase family members in mouse whole body sections. Reviewed

    Tatsukawa H, Abe N, Ohashi S, Hitomi K

    Biochem Biophys Res Commun     2015.10

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    DOI: 10.1016/j.bbrc.2015.10.001.

  43. Early response as shown by enhancement of transglutaminase 1 expression after cisplatin-induced acute kidney injury Reviewed

    Furukawa K, Yamane M, Tatsukawa H, Hitomi K

    Arch Biochem Biophys   Vol. 586   page: 27-32   2015.9

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  44. Discovery of molecular markers to discriminate corneal endothelial cells in the human body Reviewed

    Yoshihara M, Ohmiya H, Hara S, Kawasaki S; FANTOM consortium (Tatsukawa H), Hayashizaki Y, Itoh M, Kawaji H, Tsujikawa M, Nishida K.

    PLoS One   Vol. 10   page: e0117581   2015.3

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  45. The statistical geometry of transcriptome divergence in cell-type evolution and cancer Reviewed

    Liang C; FANTOM Consortium (Tatsukawa H), Forrest AR, Wagner GP.

    Nat Commun   Vol. 6   page: 6066   2015.1

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  46. CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes Reviewed

    Hasegawa Y, Tang D, Takahashi N, Hayashizaki Y, Forrest AR; FANTOM Consortium (Tatsukawa H), Suzuki H.

    Sci Rep   Vol. 4   page: 5228   2014.6

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  47. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation Reviewed

    Morikawa H, Ohkura N, Vandenbon A, Itoh M, Nagao-Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest AR, Standley DM, Date H, Sakaguchi S; FANTOM Consortium (Tatsukawa H).

    Proc Natl Acad Sci U S A   Vol. 111 ( 14 ) page: 5289-5294   2014.4

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  48. An atlas of active enhancers across human cell types and tissues Reviewed

    Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F; FANTOM Consortium (Tatsukawa H), Forrest AR, Carninci P, Rehli M, Sandelin A.

    Nature   Vol. 507 ( 7493 ) page: 455-461   2014.3

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  49. Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells Reviewed

    Arner E, Forrest AR, Ehrlund A, Mejhert N, Itoh M, Kawaji H, Lassmann T, Laurencikiene J, Rydén M, Arner P; FANTOM Consortium (Tatsukawa H).

    PLoS One   Vol. 9 ( 3 ) page: e80274   2014.3

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    Language:English   Publishing type:Research paper (scientific journal)  

  50. A promoter-level mammalian expression atlas Reviewed

    FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassman T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jørgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drabløs F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, 't Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, Hayashizaki Y

    Nature   Vol. 507 ( 7493 ) page: 462-470   2014.3

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  51. Variations in Both TG1 and TG2 Isozyme-specific in situ Activities and Protein Expressions during Mouse Embryonic Development Reviewed

    Itoh M, Tatsukawa H, Eun-Seo L, Yamanishi K, Kojima S and Hitomi K

    J Histochem Cytochem   Vol. 61 ( 11 ) page: 793-801   2013.11

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  52. Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation Reviewed

    Miura A, Kambe Y, Inoue K, Tatsukawa H, Kurihara T, Griffin M, Kojima S and Miyata A

    J Biol Chem   Vol. 288 ( 45 ) page: 32720-32730   2013.11

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  53. Phage-displayed peptide library screening for preferred human substrate peptide sequences for transglutaminase 7 Reviewed

    Kuramoto K, Yamasaki R, Shimizu Y, Tatsukawa H and Hitomi K

    Arch Biochem Biophys   Vol. 537 ( 1 ) page: 138-143   2013.9

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  54. 異常な細胞増殖・代謝にかかわるタンパク質の糖鎖修飾 Invited Reviewed

    辰川英樹

    ファルマシア   Vol. 49 ( 7 ) page: 701   2013.7

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  55. Regulation of transglutaminase-mediated hepatic cell death in alcoholic steatohepatitis and non-alcoholic steatohepatitis

    Kojima S, Kuo TF and Tatsukawa H

    J Gastroenterol Hepatol   Vol. 27   page: 52-57   2012.3

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    DOI: doi:10.1111/j.1440-1746.2011.07009.x

  56. Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways

    Kuo TF, Tatsukawa H, Matsuura T, Nagatsuma K, Hirose S and Kojima S

    J Cell Physiol   Vol. 227 ( 3 ) page: 1130-1137   2012.3

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    DOI: 10.1002/jcp.22833

  57. New insights into the functions and localization of nuclear transglutaminase 2

    Kuo TF, Tatsukawa H and Kojima S

    FEBS J   Vol. 278   page: 4756-4767   2011.12

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  58. Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells Reviewed

    Tatsukawa H, Sano T, Fukaya Y, Ishibashi N, Watanabe M, Okuno M, Moriwaki H and Kojima S

    Mol Cancer   Vol. 10   page: 4 (11 pages)   2011.1

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  59. Brain infarction correlates more closely with acrolein than with reactive oxygen species

    Saiki R, Park H, Ishii I, Yoshida M, Nishimura K, Toida T, Tatsukawa H, Kojima S, Ikeguchi Y, Pegg AE, Kashiwagi K and Igarashi K

    Biochem Biophys Res Commun   Vol. 404 ( 4 ) page: 1044-1049   2011.1

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  60. In situ detection of active transglutaminases for keratinocyte type (TGase 1) and tissue type (TGase 2) using fluorescence-labeled highly reactive substrate peptides

    Itoh M, Kawamoto T, Tatsukawa H, Kojima S, Yamanishi K and Hitomi K

    J Histochem Cytochem   Vol. 59   page: 180-187   2010.9

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    DOI: 10.1369/jhc.2010.957225

  61. Recent Advances in the Understanding of Roles of Transglutaminase 2 in Alcoholic Steatohepatitis

    Tatsukawa H and Kojima S

    Cell Biology International   Vol. 34   page: 325-334   2010.3

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  62. Induction of Cross-Linking and Silencing of Sp1 by Transglutaminase during Liver Injury in ASH and NASH via Different ER Stress Pathways

    Kojima S, Kuo TF, Tatsukawa H and Hirose S

    Digestive Diseases   Vol. 28   page: 715-721   2010

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  63. 生きた細胞でのヒストンアセチル化をリアルタイムで観察

    辰川英樹

      Vol. 2 ( 3 ) page: 20   2009.12

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  64. アルコール性肝障害の新規肝細胞死誘導経路の発見

    辰川英樹, 小嶋聡一

    バイオサイエンスとインダストリー   Vol. 67 ( 8 ) page: 423-427   2009.11

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  65. Role of Transglutaminase 2 in Liver Injury via Crosslinking and Silencing of Transcription Factor, Sp1 Reviewed

    Tatsukawa H, Fukaya Y, Frampton G, Martinez-Fuentes A, Suzuki K, Kuo TF, Nagatsuma K, Shimokado K, Okuno M, Wu J, Iismaa S, Matsuura T, Tsukamoto H, Zern MA, Graham RM, and Kojima S

    Gastroenterology   Vol. 136 ( 5 ) page: 1502-1505   2009.5

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  66. アテローム性動脈硬化症発症過程における血漿トランスグルタミナーゼ(XIIIA因子)による単球のアンジオテンシンⅡ受容体(AT1受容体)架橋二量体の形成

    辰川英樹

    日本血栓止血学会   Vol. 16 ( 3 ) page: 339   2005.3

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  67. 生体内バイオハイブリッド反応-架橋多機能性酵素、トランスグルタミナーゼによるタンパク質の機能変換

    辰川英樹,小嶋聡一

    化学工業   Vol. 54   page: 908-915   2003.12

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Books 2

  1. Transglutaminase: Multiple Functional Modifiers and Targets for New Drug Discovery - Preferred Substrate Structure of Transglutaminases

    Hitomi K and Tatsukawa H( Role: Joint author)

    Springer  2016.3 

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    Language:English

  2. 肝疾患Review 2010~2011

    辰川英樹, 小嶋聡一( Role: Joint author)

    日本メディカルセンター出版  2010.5 

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    Language:Japanese

MISC 6

  1. 羊水中に存在する表皮細胞分化制御成分の性状解析

    栗林美樹, 手島裕文, 川口友輔, 川口友輔, 山口央輝, 辰川英樹, 人見清隆

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 43rd   2020

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  2. 糸球体腎炎に関わるタンパク質架橋化酵素の機能解明に向けた基礎的研究

    伊藤辰将, 辰川英樹, 山口央輝, 高橋和男, 人見清隆, 湯澤由紀夫

    日本腎臓学会誌   Vol. 61 ( 3 ) page: 340 - 340   2019.5

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    Language:Japanese  

    J-GLOBAL

  3. マウスの胎生進行に伴う表皮形成レベルと羊水成分の変動解析

    栗林美樹, 手島裕文, 加藤まなみ, 山口央輝, 辰川英樹, 人見清隆

    日本分子生物学会年会プログラム・要旨集(Web)   Vol. 42nd   2019

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  4. マウス腎糸球体内で架橋される組織型トランスグルタミナーゼ基質候補タンパク質の網羅的解析

    伊藤辰将, 伊藤辰将, 辰川英樹, 山口央輝, 高橋和男, 人見清隆, 湯澤由紀夫

    JSBMS Letters   Vol. 43 ( Supplement ) page: 104 - 104   2018.8

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    Language:Japanese   Publisher:(一社)日本医用マススペクトル学会  

    J-GLOBAL

  5. ISOZYME-SPECIFIC IDENTIFICATION AND CHARACTERIZATION OF SUBSTRATES CROSSLINKED BY TRANSGLUTAMINASES IN LIVER FIBROSIS

    Tatsukawa H, Nakagawa H, Hitomi K

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   Vol. 42   page: 33A-33A   2018.8

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

  6. Global identification and analysis of isozyme-specific substrates crosslinked by transglutaminases in mouse liver fibrosis

    Hideki Tatsukawa, Haruka Nakagawa, Hitomi Kiyotaka

    HEPATOLOGY   Vol. 66   page: 222A - 222A   2017.10

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:WILEY  

    Web of Science

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Presentations 69

  1. Isozyme-Specific Global Identification and Analysis of Transglutaminase Substrates in Fibrotic Diseases Invited

    Hideki Tatsukawa

    Gordon Research Conference on Transglutaminases in Human Disease Processes  2018.6.17 

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  2. Global identification and analysis of isozyme-specific substrates crosslinked by transglutaminase in mouse fibrosis model Invited International conference

    2017.12.6 

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  3. Characterization of substrates crosslinked by transglutaminase in fibrotic diseases Invited

    Hideki Tatsukawa, Taishu Takeuchi, Yoshiki Shinoda, Kiyotaka Hitomi

    Gordon Research Conference on Transglutaminases in Human Disease Processes  2020.6.16 

  4. Analysis of the mechanism of transglutaminase-mediated tissue fibrosis Invited

    Hideki Tatsukawa, Yoshiki Shinoda, Taishu Takeuchi, Suguru Niwa, Kiyotaka Hitomi

    2020.9.15 

  5. Isozyme-specific identification and characterization of substrates crosslinked by transglutaminases in liver fibrosis International conference

    Hideki Tatsukawa, Kiyotaka Hitomi

    The 13th International Symposium on ALPD and Cirrhosis 

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    Event date: 2018.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  6. Isozyme-Specific Global Identification and Analysis of Transglutaminase Substrates in Fibrotic Diseases Invited International conference

    Hideki Tatsukawa

    Gordon Research Conference on Transglutaminases in Human Disease Processes 

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    Event date: 2018.6

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  7. Global identification and analysis of isozyme-specific substrates crosslinked by transglutaminase in mouse fibrosis model Invited

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    Event date: 2017.12

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  8. Detections of Isozyme-specific activity and Substrate for Transglutaminase in Animal Models for Fibrotic Disease

    The 2nd Tokai Nephrology & Immunology Forum -Transglutaminases and Kidney Diseases-ase Processes - 

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    Event date: 2014.10

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  9. Detections of isozyme-specific activity and substrate for transglutaminase in animal models for fibrotic disease International conference

    Tatsukawa H, Tani Y, Hitomi K

    Gordon reserch conference - Transglutaminases in Human Disease Processes - 

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    Event date: 2014.6 - 2014.7

    Language:English   Presentation type:Oral presentation (general)  

    Country:Italy  

  10. Crosslinking and Silencing of A Transcription Factor Sp1 by Transglutaminase during Liver Injury in ASH and NASH

    Tatsukawa H

    The 1st International Symposium on Latent TGF-β Activation Reaction -Development of Novel Diagnosis, Prevention, and Therapy Targeting TGF-β Activation Reaction 

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    Event date: 2012.3

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  11. Trials to identify a target molecule of acyclic retinoid, suppressing recurrence of hepatocellular carcinoma International conference

    Tatsukawa H, Honda K, Kondoh Y, Dohmae N, Ishibashi N, Osada H and Kojima S

    RIKEN - Max Planck Joint Research Center for Systems Chemical Biology Kick Off Symposium 

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    Event date: 2012.3

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  12. 肝細胞癌再発抑制剤「非環式レチノイド」の作用標的分子同定の試み

    辰川 英樹,本田 香織,近藤 恭光,堂前 直,石橋 直人,長田 裕之,森脇 久隆,小嶋 聡一

    第34回日本分子生物学会年会 

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    Event date: 2011.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  13. リン酸化RXRα特異抗体の作製および非環式レチノイドの標的分子同定の試み

    辰川 英樹,清水 雅仁,本田 香織,近藤 恭光,堂前 直,石橋 直人,長田 裕之,森脇 久隆,小嶋 聡一

    第22回日本レチノイド研究会学術集会 

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    Event date: 2011.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  14. 非環式レチノイドによる肝癌細胞死誘導機構の解析

    辰川 英樹,石橋 直人,森脇 久隆,小嶋 聡一

    第70回日本癌学会学術総会 

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    Event date: 2011.10

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  15. 非環式レチノイドによる肝細胞癌の細胞死で見られたトランスグルタミナーゼ核局在の新機構

    辰川 英樹,石橋 直人,森脇 久隆,小嶋 聡一

    日本消化器関連学会機構(JDDW2011) 

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    Event date: 2011.10

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  16. Analysis of nuclear localization of transglutaminase and screening of its inhibitors International conference

    Tatsukawa H, Yoshioka Y and Kojima S

    The 6th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis 

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    Event date: 2011.10

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  17. 肝臓癌細胞死に伴うタンパク質架橋結合酵素トランスグルタミナーゼ核局在の分子機構

    辰川 英樹,石橋 直人,小瀬 真吾,今本 尚子,森脇 久隆,小嶋 聡一

    第84回日本生化学会大会 

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    Event date: 2011.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  18. 非環式レチノイドによるタンパク架橋結合酵素を介した肝癌細胞死の誘導機構

    辰川 英樹,石橋 直人,森脇 久隆,小嶋 聡一

    第18回肝細胞研究会 

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    Event date: 2011.6

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  19. 非環式レチノイドによる肝癌細胞死誘導に伴うタンパク質架橋結合酵素トランスグルタミナーゼ核局在の分子機構解明

    辰川 英樹,石橋 直人,小瀬 真吾,今本 尚子,森脇 久隆,小嶋 聡一

    平成23年度日本生化学会関東支部例会 

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    Event date: 2011.6

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  20. 非環式レチノイドによる肝癌細胞死誘導機構 International conference

    辰川 英樹,石橋 直人,森脇 久隆,小嶋 聡一

    第33回日本分子生物学会年会&第83回日本生化学会大会(BMB2010) 

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    Event date: 2010.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  21. 非環式レチノイドによる肝臓癌細胞死に寄与するトランスグルタミナーゼの核移行の解析

    辰川 英樹,石橋 直人,森脇 久隆,小嶋 聡一

    第21回 日本レチノイド研究会 

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    Event date: 2010.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  22. Novel apoptotic pathway via crosslinking enzyme, transglutaminase: Its discovery and regulation

    Tatsukawa H

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    Event date: 2010.10

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  23. 非環式レチノイドによる肝細胞癌治療におけるリン酸化阻害作用と標的分子同定の試み

    辰川英樹,石橋 直人,森脇 久隆,小嶋 聡一

    第14回日本がん分子標的治療学会学術集会 

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    Event date: 2010.7

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  24. Analysis of nuclear localization of transglutaminase and screening of its inhibitors regulating nuclear transglutaminase activity International conference

    Tatsukawa H, Kouyama M, Tsukamoto H, Kojima S

    Gordon Research Conference on Transglutaminase in Human Disease Processes 

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    Event date: 2010.7

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  25. アルコール vs 遊離脂肪酸による肝障害誘導機構の比較検討

    辰川 英樹,Kuo Ting-Fang,松浦 知和,塚本 秀和,小嶋 聡一

    第46回日本肝臓学会総会 

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    Event date: 2010.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  26. 転写因子の架橋反応を標的とした肝障害の誘導機構とその制御

    辰川英樹,高山弥緒,松浦知和,塚本秀和,小嶋聡一

    第5回日本ケミカルバイオロジー学会 

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    Event date: 2010.5

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  27. Mechanism of liver injury (hepatocyte cell death) via crosslinking of a transcription factor

    Tatsukawa H, Kojima S

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    Event date: 2010.2

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  28. タンパク質の架橋反応が細胞死を招き、アルコール性肝障害に- アルコール性障害の肝臓で繰り広げられる新しい肝細胞死のメカニズムを発見

    辰川 英樹,小嶋聡一

    第22回理化学研究所と産業界との交流会 

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    Event date: 2010.2

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  29. Detection and regulation of alcoholic liver injury via controlling protein crosslinking enzyme, transglutaminase

    Tatsukawa H, Kouyama M, Matsuura T, Tsukamoto H, Kojima S

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    Event date: 2010.2

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  30. 転写因子の架橋反応を介する肝障害(肝細胞死)の誘導機構

    辰川 英樹,松浦知和,塚本秀和,小嶋聡一

    第32回日本分子生物学会年会 

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    Event date: 2009.12

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Country:Japan  

  31. Screening of novel compounds to prevent alcoholic liver injury targeting transglutaminase International conference

    Tatsukawa H, Kouyama M, Tsukamoto H, Kojima S

    The 4th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis 

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    Event date: 2009.10

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  32. Novel Mechanism of Acyclic Retinoid-induced Apoptosis in Hepatocellular Carcinoma Cells - Dual Induction of Caspase 3- and Transglutaminase-dependent Apoptotic Pathways - International conference

    Tatsukawa H, Sano T, Ishibashi N, Okuno M, Moriwaki H and Kojima S

    The 60th Annual meeting of the American Association for the Study of Liver Diseases 

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    Event date: 2009.10

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  33. “転写因子の架橋反応を標的とした肝障害(肝細胞死)の誘導機構とその制御

    辰川 英樹,高山 弥緒,松浦 知和,塚本 秀和,小嶋 聡一

    第82回日本生化学大会 

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    Event date: 2009.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  34. 転写因子の架橋反応を標的とした肝障害(肝細胞死)の誘導機構とその制御

    辰川 英樹,小嶋 聡一

    第3回トランスグルタミナーゼ研究会&ポリアミン研究会 合同学術集会 

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    Event date: 2009.10

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  35. 転写因子の架橋反応を標的とした肝障害(肝細胞死)の誘導機構とその制御

    第4回 トランスグルタミナーゼ研究会&日本ポリアミン学会合同学術集会

    辰川 英樹,小嶋 聡一 

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    Event date: 2009.10

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  36. Screening of novel compounds to prevent alcoholic liver injury

    The 25th Naito Conference on Chemical Biology [II] 

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    Event date: 2009.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  37. 非環式レチノイドによる肝癌細胞のアポトーシス誘導機構

    辰川 英樹,深谷 弥生,石橋 直人,佐野 哲朗,下門 顕太郎,森脇 久隆,小嶋 聡一

    第45回日本肝臓学会総会 

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    Event date: 2009.6

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Country:Japan  

  38. Role of Transglutaminase 2 in Liver Injury via Crosslinking and Silencing of Transcription Factor, Sp1

    Tatsukawa H, Tsukamoto H, Shimokado K, Zern MA, Graham RM, Kojima S

    RIEKN 2009 JOINT RETREAT 

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    Event date: 2009.1

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  39. 非環式レチノイドによる肝癌細胞のアポトーシス誘導に関する研究

    辰川 英樹,深谷 弥生,石橋 直人,佐野 哲朗,下門 顕太郎,森脇 久隆,小嶋 聡一

    BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会) 

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    Event date: 2008.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  40. 非環式レチノイドによる肝癌細胞のアポトーシス誘導機構

    辰川 英樹,深谷 弥生,石橋 直人,佐野 哲朗,下門 顕太郎,森脇 久隆,小嶋 聡一

    第19回 日本レチノイド研究会 

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    Event date: 2008.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  41. A novel hepatic apoptosis pathway in the injured liver via crosslinking and inactivation of transcription factor, Sp1 by tissue transglutaminase International conference

    Tatsukawa H, Tsukamoto H, Shimokado K, Zern MA, Graham RM, Kojima S

    The 59th Annual meeting of the American Association for the Study of Liver Diseases 

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    Event date: 2008.10

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  42. タンパク質架橋結合酵素トランスグルタミナーゼによるアポトーシス誘導の制御

    辰川 英樹、深谷 弥生、小嶋 聡一

    第1回理研ケミカルバイオロジー研究領域国際シンポジウム 

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    Event date: 2008.9

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  43. 非環式レチノイドによる肝癌細胞死の誘導機構

    辰川 英樹,深谷 弥生,石橋 直人,佐野 哲朗,下門 顕太郎,森脇 久隆,小嶋 聡一

    第3回日本ケミカルバイオロジー研究会 

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    Event date: 2008.5

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  44. 肝癌細胞のアポトーシス誘導に伴うタンパク質架橋結合酵素の核移行

    辰川英樹,下門 顕太郎,辻本雅文,小嶋 聡一

    第4回ケミカルバイオロジーシンポジウム 

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    Event date: 2008.2

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  45. トランスグルタミナーゼを介したアポトーシス誘導機構

    辰川英樹,下門顕太郎,小嶋聡一

    第10回TGase研究会 

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    Event date: 2007.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  46. 非環式レチノイドによる肝癌細胞死の分子機構

    辰川 英樹,深谷 弥生,石橋 直人,佐野 哲朗,下門 顕太郎,森脇 久隆,小嶋 聡一

    BMB2007(第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会) 

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    Event date: 2007.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  47. 非環式レチノイドによる肝癌細胞死の誘導機構

    辰川英樹,深谷弥生,石橋直人,森脇 久隆,下門 顕太郎,小嶋聡一

    第18回 日本レチノイド研究会 

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    Event date: 2007.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  48. Mechanism of a novel apoptotic pathway in the injured liver via crosslinking and inactivation of transcription factor, Sp1 International conference

    Tatsukawa H, Shimokado K, Kojima S

    The 2nd International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis 

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    Event date: 2007.10

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  49. MOLECULAR MECHANISM FOR SUPPRESSION OF HEPATOCELLULAR CARCINOMA BY ACYCLIC RETINOID International conference

    Tatsukawa H, Sano T, Ishibashi N, Shimokado K, Tsujimoto M, Kojima S

    9th International conference on transglutaminases and protein cross linking 

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    Event date: 2007.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  50. タンパク質架橋酵素トランスグルタミナーゼを介する細胞死の制御

    辰川英樹,深谷弥生,小嶋聡一

    バイオアーキテクトシンポジウム2007 

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    Event date: 2007.9

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  51. タンパク架橋結合酵素トランスグルタミナーゼを介した肝癌細胞死の誘導機構

    辰川英樹,深谷 弥生,佐野 哲朗,森脇 久隆,下門 顕太郎,小嶋 聡一

    日本レチノイド研究会 

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    Event date: 2006.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  52. 転写因子の架橋不活性化反応における転写因子の特異性に関する研究

    辰川英樹,深谷弥生,鈴木健司,下門顕太郎,小嶋聡一

    第5回「ポリアミンと核酸の共進化」合同シンポジウム 

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    Event date: 2006.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  53. タンパク質架橋酵素トランスグルタミナーゼを介した細胞死の制御

    辰川英樹,下門顕太郎,小嶋聡一

    第9回TGase研究会 

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    Event date: 2006.6

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  54. Analysis of mechanism of a novel apoptotic pathway via crosslinking and inactivation of the transcription factor, Sp1 International conference

    Tatsukawa H,Shimokado K,Kojima S

    20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress 

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    Event date: 2006.6

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  55. 非環式レチノイドによる核内トランスグルタミナーゼ誘導を介する肝癌細胞死

    辰川英樹,深谷 弥生,奥野 正隆,佐野 哲朗,森脇 久隆,下門 顕太郎,小嶋 聡一

    第1回 日本ケミカルバイオロジー研究会 

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    Event date: 2006.5

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  56. タンパク架橋結合酵素トランスグルタミナーゼを介する新規アポトーシス(グルネーシス)の検出

    辰川英樹,中野なおこ,下門顕太郎,小嶋聡一

    第78回日本生化学会大会 

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    Event date: 2005.10

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  57. 組織トランスグルタミナーゼを介したアポトーシス

    辰川英樹,小嶋聡一

    第1回 TGase研究会&ポリアミン研究会 合同学術集会 

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    Event date: 2005.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  58. Novel apoptosis induced by a protein crosslinking enzyme, transglutaminase (Glunasis)

    Tatsukawa H

    RIKEN JOINT RETREAT 

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    Event date: 2005.5

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  59. 架橋Sp1抗体を用いた新規アポトーシスの検出

    辰川英樹,深谷弥生,下門顕太郎,小嶋聡一

    第27回日本分子生物学会年会 

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    Event date: 2004.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  60. レチノイドによる血管新生の制御におけるトランスグルタミナーゼの役割 International conference

    辰川英樹,深谷弥生,下門顕太郎,小嶋聡一

    第77回日本生化学会大会 

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    Event date: 2004.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  61. レチノイドによる血管新生の調節におけるトランスグルタミナーゼの役割

    辰川英樹,下門顕太郎,小嶋聡一

    第8回TGase研究会 

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    Event date: 2004.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  62. A Role of Transglutaminase in the Regulation of Angiogenesis by Retinoid International conference

    Tatsukawa H, Fukaya Y, Shimokado K, and Kojima S

    10th Int. International Society of Hematology, Asian-Pacific Division 

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    Event date: 2004.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  63. トランスグルタミナーゼを介するアポトーシスの誘導

    辰川英樹,深谷弥生,奥野正隆,佐野哲朗,森脇久隆,下門顕太郎,小嶋聡一

    第3回「ポリアミンと核酸の共進化」合同シンポジウム 

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    Event date: 2004.6

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  64. トランスグルタミナーゼを介する肝細胞死の分子機構

    辰川英樹,Mark A. Zern,下門顕太郎,小嶋聡一

    第19回バイオハイブリッド研究 

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    Event date: 2004.5

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  65. アンチセンス高発現細胞株を用いたトランスグルタミナーゼ誘導を介する肝癌細胞死の証明

    辰川英樹,深谷弥生,奥野正隆,佐野哲朗,森脇久隆,下門顕太郎,小嶋聡一

    第26回日本分子生物学会年会 

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    Event date: 2003.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  66. トランスグルタミナーゼ誘導を介する肝癌細胞死の証明

    辰川英樹,深谷弥生,奥野正隆,佐野哲朗,森脇久隆,下門顕太郎,小嶋聡一

    辰川英樹,深谷弥生,奥野正隆,佐野哲朗,森脇久隆,下門顕太郎,小嶋聡一 

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    Event date: 2003.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  67. A Role of Tissue Transglutaminase in Hepatocyte Apoptosis

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    Event date: 2003.10

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  68. トランスグルタミナーゼ誘導を介する肝癌細胞死の分子機構解析

    辰川英樹,奥野正隆,佐野哲郎,森脇久隆,下仲基之,小嶋聡一

    第25回日本分子生物学会年会 

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    Event date: 2002.12

    Language:Japanese   Presentation type:Poster presentation  

    Country:Japan  

  69. Isozyme-specific identification and characterization of substrates crosslinked by transglutaminases in liver fibrosis

    Hideki Tatsukawa, Kiyotaka Hitomi

    The 13th International Symposium on ALPD and Cirrhosis  2018.9.9 

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    Language:English   Presentation type:Poster presentation  

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Research Project for Joint Research, Competitive Funding, etc. 9

  1. マクロファージの極性化を標的とした腎線維化の分子機構解明研究

    2021.8 - 2022.3

    研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

  2. タンパク質架橋酵素の新規活性検出プローブの作製と制御剤探索

    2021 - 2022

    酵素研究助成 奨励研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\600000

  3. タンパク質架橋酵素の局在依存的な基質架橋部位の網羅的同定・定量法の開発

    2021 - 2022

    応用酵素助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1000000

  4. タンパク質架橋酵素を標的とした腎線維化の分子機構解明

    2020.8 - 2021.3

    研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\200000

  5. マクロファージの極性化を制御するタンパク質架橋酵素の解析

    2020 - 2021

    応用酵素助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\500000

  6. 上皮細胞の形質転換におけるタンパク質架橋修飾反応の意義

    2019 - 2020

    研究助成 

    辰川英樹

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1500000

  7. 肝障害に伴い架橋されるサイトケラチンの機能および局在変化を介した疾患関連性の解析

    2018 - 2019

    応用酵素助成 

    辰川英樹

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\500000

  8. 線維化組織に介在する架橋タンパク質群の網羅的同定・解析

    2016.5 - 2017.5

  9. 研究奨励ファンド

    2009.4 - 2010.3

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KAKENHI (Grants-in-Aid for Scientific Research) 8

  1. 尿細管上皮の間葉転換を制御するタンパク質架橋修飾の役割

    2019.4 - 2022.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    辰川 英樹

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    Authorship:Principal investigator  Grant type:Competitive

  2. 尿細管上皮の間葉転換を制御するタンパク質架橋修飾の役割

    2019.4 - 2022.3

    科学研究費補助金  基盤研究(C)

    辰川 英樹

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    Authorship:Principal investigator 

  3. 尿細管上皮の間葉転換を制御するタンパク質架橋修飾の役割

    Grant number:19K08675  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    辰川 英樹

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    慢性腎臓病は日本国内で1,330万人(成人の8人に1人)が罹患する国民病である。慢性腎臓病が末期腎不全に至る共通の過程として線維化があり、線維化の程度は腎機能低下と相関する。腎線維化の直接の発症要因は筋線維芽細胞による細胞外基質の過剰産生であるが、近年この筋線維芽細胞の活性化に関わる炎症反応の起点として尿細管上皮細胞の上皮間葉転換(EMT)が重要視されている。申請者は最近、表皮型のタンパク質架橋酵素が腎尿細管上皮において活性化し、EMTに対して保護(抑制)的な作用を示すことを見出しており、これらの分子機構の解明を目的として研究を遂行する。
    腎線維化は細胞外基質が過剰蓄積し、組織の硬化に伴い腎機能が失われる疾患である。病態初期では、尿細管上皮細胞の細胞死および部分的な上皮間葉転換(EMT)の誘導が病態形成の起点として考えられている。これまでの研究により、皮膚型のタンパク質架橋酵素トランスグルタミナーゼ(TG1)が尿細管上皮細胞で顕著に活性化し、同酵素が細胞死や尿細管上皮細胞のEMTに関わることを見出した。これらの分子機構解明を目的として、本年度は以下の3つの点について実験を実施した。
    ① 尿細管上皮細胞株HK-2を播種し、TG1特異的なsiRNAを導入後にTGF-βもしくはH2O2処理を行い、EMTや細胞死の程度について検討した。TGF-β処理によりタイトジャンクション構成蛋白質のClaudin-1は有意に減少したが、TG1の発現抑制下ではその発現減少はより顕著に亢進した。TGF-β処理により発現増加するFibronectin やVimentinについては、TG1の発現抑制により発現量の抑制が見られた。一方、H2O2処理による細胞死誘導の程度は、TG1の発現抑制により低下した。
    ② TGF-βやH2O2処理したHK-2に架橋酵素のリジン残基側の基質であるビオチン標識一級アミンBPAを添加して、EMTや細胞死誘導時においてTG1活性により取り込まれるBPA修飾タンパク質の経時的な変化を検出した。期待していた処理時間依存的なBPA修飾タンパク質の顕著な増加は見られず、既報告の再現が得られなかった。
    ③昨年度作製したTG1f/fマウスをタモキシフェンにより制御可能なCreERT2もしくは尿細管特異的に発現するgGT-Creの変異マウスと掛け合わせを行い、両遺伝子変異マウスを作製した。タモキシフェン投与したTG1f/f:CreERT2マウスは予想に反して、投与後すぐに顕著な体重減少が確認され、1週間以内に死亡した。
    架橋酵素TG1の発現抑制はTGF-βによるE-cadherinおよびClaudin-1の発現低下を亢進し、尿細管上皮細胞の上皮としての性質を低下させ、EMTを促進することが分かったが、相反してTG1の発現抑制は上皮細胞でのFibronectin やVimentinの発現上昇を阻害し、EMTを抑制することが分かった。この作用はTG1の単独抑制では見られず、TGF-βのシグナル依存的な効果であることも併せて検証した。この矛盾はTGF-β処理下において、TG1が上皮細胞保護的な効果を示す一方、細胞外基質産生を介して障害を受けた上皮細胞の修復過程にも関わることを示唆している。ビオチン標識一級アミンBPAを添加した実験では、期待していた処理時間依存的なBPA修飾タンパク質の顕著な増加は見られず、既報告の再現が得られなかったが、この成果を考えて次年度は新たなアプローチでTG1の標的因子を探る。昨年度作製したTG1f/fマウスをさらに掛け合わせ、TG1f/f:CreERT2およびTG1f/f:gGT-Creマウスを作製し、TG1f/f:CreERT2については表現型解析まで進めたことから、当初の計画以上に実験が進展している。
    このことから全体の研究計画を鑑み、研究の進捗状況を「おおむね順調に進展している」と考えた。
    架橋酵素TG1の発現抑制により、なぜE-cadherinおよびClaudin-1の発現低下が誘導されるのか、その分子機構の解析を進める。また相反する現象としてFibronectin やVimentinの発現上昇を阻害することが分かり、これらの標的の上流のパスウェイについても調べていく。これに関する研究に関連して、肺の線維化に関わる上皮細胞では、別の架橋酵素アイソザイムのTG2の発現抑制は顕著にE-cadherinの発現を誘導することを見出している。TG2の発現抑制自体が、TG1の発現抑制を誘導する現象が見られたことから、このような他のアイソザイムの関連についても研究を進める。
    本年度に新たに作製したTG1f/f:CreERT2およびTG1f/f:gGT-Creマウスについて引き続き表現型解析を行う。タモキシフェン誘導性のTG1欠損マウス(TG1f/f:CreERT2)については、タモキシフェン投与1週間で死亡することから、投与量や投与方法を変えた検証を行うと共に、マウスが死亡する原因を探っていく。尿細管特異的TG1欠損マウス(TG1f/f:CreERT2)については、生理的な表現型解析を行うと共に、尿管結紮による腎線維化を誘導し、その線維化の程度について検証する。これにより、尿細管でのTG1欠損が腎線維化に及ぼす影響を解析できる。

  4. 組織線維化に寄与する架橋修飾因子の網羅的解析および線維化抑制剤の開発

    2016.4 - 2019.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    辰川英樹

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    Authorship:Principal investigator  Grant type:Competitive

  5. 組織線維化に寄与する架橋修飾因子の網羅的解析および線維化抑制剤の開発

    2016.4 - 2019.3

    科学研究費補助金  基盤研究(C)

    辰川英樹

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    Authorship:Principal investigator 

  6. Global identification of the substrates of protein crosslinking enzyme and the development of preventive drug in tissue fibrosis

    Grant number:16K09353  2016.4 - 2019.3

    TATSUKAWA Hideki

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    The transglutaminase (TG) family comprises eight isozymes that catalyze the crosslinking reaction between glutamine and lysine residues and contribute to the fibrotic diseases in several tissues. Despite the evidence implicating TG2 as a key enzyme in fibrosis, the causative role and involvement of the other isozymes have not yet been fully elucidated. Therefore, here we clarified the distributions and activities of TG isozymes, and identified the isozyme-specific substrates for both TG1 and TG2 using each substrate peptide. The possible substrates for each TG were successfully identified and these included keratin 18, a biomarker for hepatic injury, which was accumulated in the fibrotic liver. Our findings suggest that each TG was independently activated in a different tissue area during fibrotic induction, and played a potential role in the functional modification of keratin 18, which are relevant to liver fibrosis progression.

  7. タンパク質架橋化酵素を標的とした肝線維化の病態機序の解明および制御法の開発

    2014.4

    科学研究費補助金  若手研究(B)

    辰川英樹

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    Authorship:Principal investigator 

  8. 非環式レチノイドによる肝臓癌特異的細胞死の経路解析に基づく新規抗癌剤の開発

    2010.4 - 2013.3

    科学研究費補助金  若手研究(B)

    辰川英樹

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    Authorship:Principal investigator 

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Teaching Experience (On-campus) 8

  1. 応用生命科学科実験実習

    2020

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    農学部応用生命科学科実験実習の中の細胞生物学実習(10日間)を担当する。
    G30学生対応のための英語による実習講義を含む

  2. 応用生命科学科実験実習

    2016

  3. 創薬生物科学実験

    2016

  4. 創薬生物科学セミナーⅠB

    2016

  5. 創薬生物科学セミナーⅠA

    2016

  6. 多分野融合実践実習

    2016

  7. 多分野融合実践演習

    2016

  8. 情報リテラシー入門

    2014

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Media Coverage 3

  1. 肺線維症の分子標的の探索法開発および同定に成功 ~架橋修飾反応が関わる特発性肺線維症の発症機構の解明~

    名古屋大学プレスリリース  2021.7

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    Author:Myself 

  2. 特発性肺線維症(IPF)発症メカニズ ムの⼀端を解明 Internet

    難病・希少疾患 情報サイト RareS. (レアズ)  2021.7

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    Author:Other 

  3. 特発性肺線維症、病態発症メカニズムの⼀端を明らかに-名⼤ Internet

    医療ニュース QLifePro  2021.7

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    Author:Other