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Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis

Hideki Tatsukawa, Kiyotaka Hitomi
2021 Cells  
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
more » ... pair, 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 pmid:34360011 pmcid:PMC8307792 fatcat:6mmypachibaixh6orzlbvipgiq


2013 Farumashia  
doi:10.14894/faruawpsj.49.7_701 fatcat:djqllssekrdqjjgngxeasqlx3a

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

Yuko Watanabe, Rina Oguri, Risa Suzuki, Qi Meng, Yuta Ishikawa, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi
2021 Bioscience, biotechnology and biochemistry  
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
more » ... ablish 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 pmid:33589932 fatcat:ybjkrx5phjblpkzcsfoovo7vg4

Tissue Distribution of Heavy Metals in Loggerhead Turtles (Caretta caretta)
アカウミガメ(Caretta caretta)における重金属類の体内分布

1996 Journal of Environmental Chemistry  
Iron, manganese, zinc, copper, lead, nickel, cadmium, cobalt, and mercury were determined in 23 tissues and organs of loggerhead turtles (6 females and 1 male), in order to understand fundamental information for heavy metal monitoring in sea turtle species. These heavy metal concentrations and burdens were high in liver, kidney, pancreas, and hard tissues, while low in brain and fat tissue. However, markedly high zinc concentration was found in fat tissue. Zinc concentration in fat was about
more » ... times higher than in fat of marine mammals and seabirds species previously reported. Furthermore, total burden of zinc in fat comprised more than 10% of the whole body burden. More than 10% of copper burdens to whole body burden were found in eggs and ovary, suggesting that copper may be easily transfered to reproductive organs.
doi:10.5985/jec.6.27 fatcat:w3l2kf7ogbdc3p6y4phhnoudfq

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

Hideki Tatsukawa, Yuji Tani, Risa Otsu, Haruka Nakagawa, Kiyotaka Hitomi
2017 Scientific Reports  
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
more » ... s 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. Transglutaminases (TGs) are crosslinking enzymes that catalyze the formation of covalent bonds between glutamine (Gln) and lysine (Lys) residues in substrate proteins via Ca 2+ -dependent posttranslational modifying reactions 1-5 . The TG family comprises eight isozymes designated as factor XIIIa (FXIIIa) and TG1-7, which are widely distributed and involved in multiple biological processes, including blood coagulation, epidermis formation, transcriptional regulation, and extracellular matrix stabilization. In addition to these physiological functions, these is strong evidence that TGs are involved in a number of pathologies, including liver and skin diseases, cancer, inflammation, and neurodegeneration. Several previous studies have investigated the involvement of TGs in liver disease, which have shown that only TG2 appears to play a role. However, although TG2 expression and activity significantly increased in a number of in vitro and in vivo models for liver injury and was involved in the progression of hepatic apoptosis and liver fibrosis 6-10 , the opposite effects have also been reported, even in the same model 11-13 , likely owing to the different cell types and animal backgrounds used 5 . Therefore, further detailed studies on the distributions of TG expressions and activities as well as on the identification of disease-specific substrates for each TG isozyme are required. We previously characterized the preferred Gln-donor substrate sequences with a unique reaction tendency for each TG isozyme, using a random peptide library 14,15 . These peptide sequences appeared to act as substrates with high reactivity and isozyme specificity, even in the peptide form (12 amino acid residues). In addition, we developed a method for detecting isozyme-specific activities by incorporating a fluorescence-labeled substrate peptide into the Lys residues of proteins 16 . This revealed that the expressions and activities of both TG1 and TG2 were markedly higher in the liver than in the other internal organs 16 . Previous studies have shown that TG1 is
doi:10.1038/srep45049 pmid:28327670 pmcid:PMC5361200 fatcat:6gnzt5sc4ngnladxtvhoqxa3va

Distribution of Rare Earth Elements in Non-cultivated Soil in Western Part of Shikoku Island, Japan

Hideki ICHIHASHI, Hideyoshi MORITA, Katsuhisa HONDA, Ryo TATSUKAWA
1991 Chikyukagaku  
doi:10.14934/chikyukagaku.24.115 fatcat:sixyac43mfd2fcjmol74fdybli

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

Hideki Tatsukawa, Tetsuro Sano, Yayoi Fukaya, Naoto Ishibashi, Makiko Watanabe, Masataka Okuno, Hisataka Moriwaki, Soichi Kojima
2011 Molecular Cancer  
Tatsukawa et al. Molecular Cancer 2011, 10:4  ... 
doi:10.1186/1476-4598-10-4 pmid:21214951 pmcid:PMC3024303 fatcat:r7ldmvd3y5difkrko7ffr4qqfa

Pituitary Adenylate Cyclase-activating Polypeptide Type 1 Receptor (PAC1) Gene Is Suppressed by Transglutaminase 2 Activation

Ayako Miura, Yuki Kambe, Kazuhiko Inoue, Hideki Tatsukawa, Takashi Kurihara, Martin Griffin, Soichi Kojima, Atsuro Miyata
2013 Journal of Biological Chemistry  
The expression of PAC1, a specific receptor for PACAP, is decreased in brain ischemia. Results: PAC1 expression was attenuated by inactivation of Sp1 through cross-linking by transglutaminase 2 (TG2) activated by ER stress. Conclusion: TG2 is involved in negative regulation of PAC1 gene expression. Significance: Suppression of PAC1 by TG2 might be involved in neuronal damage from brain ischemia. . 2 The abbreviations used are: PAC1, PACAP type 1 receptor; CLSp1, crosslinked Sp1; ER, endoplasmic
more » ... reticulum; OGD, oxygen-glucose deprivation; PACAP, pituitary adenylate cyclase-activating polypeptide; PERK, protein kinase RNA-like endoplasmic reticulum kinase; TG2, transglutaminase 2; TM, tunicamycin.
doi:10.1074/jbc.m113.452706 pmid:24045949 pmcid:PMC3820906 fatcat:aqru2hr7nbdcbkoso46zbldrgm

A Novel Repressor of the ica Locus Discovered in Clinically Isolated Super-Biofilm-Elaborating Staphylococcus aureus

Liansheng Yu, Junzo Hisatsune, Ikue Hayashi, Nobuyuki Tatsukawa, Yusuke Sato'o, Emiri Mizumachi, Fuminori Kato, Hideki Hirakawa, Gerald B. Pier, Motoyuki Sugai, Steven J. Projan
2017 mBio  
Staphylococcus aureus TF2758 is a clinical isolate from an atheroma and a super-biofilm-elaborating/polysaccharide intercellular adhesin (PIA)/poly- N -acetylglucosamine (PNAG)-overproducing strain (L. Shrestha et al., Microbiol Immunol 60:148–159, 2016, ). A microarray analysis and DNA genome sequencing were performed to identify the mechanism underlying biofilm overproduction by TF2758. We found high transcriptional expression levels of a 7-gene cluster
more » ... ( satf2580 to satf2586 ) and the ica operon in TF2758. Within the 7-gene cluster, a putative transcriptional regulator gene designated rob had a nonsense mutation that caused the truncation of the protein. The complementation of TF2758 with rob from FK300, an rsbU -repaired derivative of S. aureus strain NCTC8325-4, significantly decreased biofilm elaboration, suggesting a role for rob in this process. The deletion of rob in non-biofilm-producing FK300 significantly increased biofilm elaboration and PIA/PNAG production. In the search for a gene(s) in the 7-gene cluster for biofilm elaboration controlled by rob , we identified open reading frame (ORF) SAOUHSC_2898 ( satf2584 ). Our results suggest that ORF SAOUHSC_2898 ( satf2584 ) and icaADBC are required for enhanced biofilm elaboration and PIA/PNAG production in the rob deletion mutant. Rob bound to a palindromic sequence within its own promoter region. Furthermore, Rob recognized the TATTT motif within the icaR-icaA intergenic region and bound to a 25-bp DNA stretch containing this motif, which is a critically important short sequence regulating biofilm elaboration in S. aureus . Our results strongly suggest that Rob is a long-sought repressor that recognizes and binds to the TATTT motif and is an important regulator of biofilm elaboration through its control of SAOUHSC_2898 (SATF2584) and Ica protein expression in S. aureus . IMPORTANCE During the search for molecular mechanisms underlying biofilm overproduction of Staphylococcus aureus TF2758, we found a putative transcriptional regulator gene designated rob within a 7-gene cluster showing a high transcriptional expression level by microarray analysis. The deletion of rob in non-biofilm-producing FK300, an rsbU -repaired derivative of NCTC8325-4, significantly increased biofilm elaboration and PIA/PNAG production. The search for a gene(s) in the 7-gene cluster for biofilm elaboration controlled by rob identified ORF SAOUHSC_2898. Besides binding to its own promoter region to control ORF SAOUHSC_2898 expression, Rob recognized the TATTT motif within the icaR-icaA intergenic region and bound to a 25-bp DNA stretch containing this motif, which is a critically important short sequence regulating biofilm elaboration in S. aureus . Our results strongly suggest that Rob is a long-sought repressor that recognizes and binds to the TATTT motif and is a new important regulator of biofilm elaboration through its control of SAOUHSC_2898 and Ica protein expression in S. aureus .
doi:10.1128/mbio.02282-16 pmid:28143981 pmcid:PMC5285506 fatcat:cdoyrhovhjb5fbpv3kzcj6jgba

Variations in Both TG1 and TG2 Isozyme-specific In Situ Activities and Protein Expressions during Mouse Embryonic Development

Miho Itoh, Hideki Tatsukawa, Lee Eun-Seo, Kiyofumi Yamanishi, Soichi Kojima, Kiyotaka Hitomi
2013 Journal of Histochemistry and Cytochemistry  
by its post-translational modifications of extracellular matrix proteins, transcription factors, and signaling molecules (Fesus and Piacentini 2002; Beninati and Piacentini 2004; Mehta et al. 2006; Tatsukawa  ... 
doi:10.1369/0022155413501676 pmid:23896968 pmcid:PMC3808576 fatcat:f2cn2ucwhzg43ityp2ucl7nq2i

Hepatitis B Virus Reactivation Induced by Infliximab Administration in a Patient with Crohn's Disease

Yuka Miyake, Aki Hasebe, Tetsuya Tanihira, Akiko Shiraishi, Yusuke Imai, Haruka Tatsukawa, Hiroka Yamago, Hiromasa Nakahara, Yuko Shimizu, Keiko Ninomiya, Atsushi Hiraoka, Hideki Miyata (+2 others)
2013 Case Reports in Hepatology  
A 47-year-old man diagnosed with Crohn's disease was treated with infliximab. He tested negative for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) but positive for anti-HB core antibody (anti-HBc). He tested positive for hepatitis B virus (HBV-) DNA 3 months after treatment and was administered entecavir. HBV-DNA test showed negative results 1 month later. ALT was persistently within the normal range, and HBV-DNA was persistently negative thereafter despite the
more » ... continuation of infliximab every 8 weeks. In our hospital, 14 patients with inflammatory bowel disease, who tested negative for HBsAg, were treated with infliximab; 2 of them tested positive for anti-HBs and/or anti-HBc, and HBV reactivation was observed in 1 patient (the present patient). The present case and these findings highlight that careful follow-up is needed in patients with inflammatory bowel disease treated with infliximab who test positive for anti-HBc and/or anti-HBs.
doi:10.1155/2013/461879 pmid:25374717 pmcid:PMC4208426 fatcat:ohj4xrgyhbhejlb6ehm6xdf7ba

Seasonal and Positional Changes of Elemental Concentrations in the Leaves of Muku- no-ki (Aphananthe aspera)

1985 Japanese Journal of Soil Science and Plant Nutrition  
doi:10.20710/dojo.56.3_238 fatcat:ufsokx6zujcp5fxw7juroipyfu

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

Ayaka Kikuta, Eri Furukawa, Ryota Ogawa, Natsuki Suganuma, Mai Saitoh, Toshiyuki Nishimaki, Takafumi Katsumura, Hiroki Oota, Tadafumi Kawamoto, Hideki Tatsukawa, Hisashi Hashimoto, Kiyotaka Hitomi (+1 others)
2015 PLoS ONE  
Calcium-dependent transglutaminases (TGs) are a family of enzymes that catalyze protein cross-linking and/or attachment of primary amines in a variety of organisms. Mammalian TGs are implicated in multiple biological events such as skin formation, blood coagulation, and extracellular matrix stabilization. Medaka (Oryzias latipes) has been used as a model fish to investigate the physiological functions of mammalian proteins. By analysis of the medaka genome, we found seven TGs orthologues, some
more » ... f which apparently corresponded to the mammalian TG isozymes, TG1, TG2, and Factor XIII. All orthologues had preserved amino acid residues essential for enzymatic activity in their deduced primary structures. In this study, we analyzed biochemical properties of two orthologues (OlTGK1 and OlTGK2) of mammalian epithelium-specific TG (TG1) that are significantly expressed at the transcriptional level. Using purified recombinant proteins for OlTGK1 and OlTGK2, we characterized their catalytic reactions. Furthermore, immunohistochemical analyses of fish sections revealed higher expression in the pancreas (OTGK1), intervertebral disk (OlTGK2) and pharyngeal teeth (OlTGK2) as well as in the skin epidermis.
doi:10.1371/journal.pone.0144194 pmid:26713442 pmcid:PMC4694659 fatcat:t52oul7oznh35oslxljssd22r4

In Situ Detection of Active Transglutaminases for Keratinocyte Type (TGase 1) and Tissue Type (TGase 2) Using Fluorescence-Labeled Highly Reactive Substrate Peptides

Miho Itoh, Tadafumi Kawamoto, Hideki Tatsukawa, Soichi Kojima, Kiyofumi Yamanishi, Kiyotaka Hitomi
2011 Journal of Histochemistry and Cytochemistry  
Hideki Shibata in our laboratory for providing valuable suggestions. The knockout mouse for TGase 2 was kindly provided by Dr. Robert Graham (Victor Chang Cardiac Institute, Australia).  ...  enzymatic modification of extracellular matrix proteins, transcription factors, and signaling molecules (Fesus and Piacentini 2002; Beninati and Piacentini 2004; Jeon and Kim 2006; Mehta et al. 2006; Tatsukawa  ... 
doi:10.1369/jhc.2010.957225 pmid:20876521 pmcid:PMC3201132 fatcat:f7wv6z5yzzddxn7n3vfou7r4g4

Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes

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 (+10 others)
2017 EBioMedicine  
Proliferation Assay Cell viability was determined using the Cell Counting Kit-8 (Dojindo Molecular Technologies, Tokyo, Japan) in a plate reader (ARVO MX, Perkin Elmer Inc.) at 450 nm as previously described (Tatsukawa  ... 
doi:10.1016/j.ebiom.2017.09.008 pmid:28927749 pmcid:PMC5652006 fatcat:6gibtg2rpzhbtfuvna2ryf3pm4
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