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Naoyuki Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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loss of core fucosylation reduces low density lipoprotein receptor expression in hepatocytes by inducing pcsk9 production
Biochemical and Biophysical Research Communications, 2020Co-Authors: Yoshihiro Kamada, Akiko Yamamoto, Anna Fujiyoshi, Masahiro Koseki, Koichi Morishita, Tatsuya Asuka, Shinji Takamatsu, Yasushi Sakata, Tetsuo Takehara, Naoyuki TaniguchiAbstract:Fucosylation is a type of glycosylation, a form of post-transcriptional regulation of proteins, involved in cancer and inflammation. It involves the attachment of a fucose residue to N-glycans, O-glycans, and glycolipids, which is catalyzed by a family of enzymes called fucosyltransferases (Futs). Among the many Futs, α-1,6-fucosyltransferase (FUT8) is the only enzyme that produces α-1,6-fucosylated oligosaccharides (core fucose). In the human liver, the expression and activity of FUT8 are frequently elevated during progression of chronic liver diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-known negative regulator of the low-density lipoprotein receptor (LDLR). Here, we found that loss of core fucose in immortalized hepatocytes led to LDLR downregulation through a dramatic induction of PCSK9. We used the immortalized hepatocytes derived from FUT8 knockout mice or a FUT8 knockdown AML12 hepatocyte cell line. Using these cells, we investigated the effects of FUT8 on hepatocyte cholesterol influx. Both cell lines had reduced LDLR protein levels, resulting from marked increases in PCSK9 expression. Intracellular cholesterol levels were significantly lower and LDL cholesterol uptake was suppressed in FUT8-KO cells. Hepatocyte nuclear factor 1α accumulated in nuclei of FUT8-KO hepatocytes, which mediated increases in PCSK9 mRNA expression. Our findings demonstrated that loss of core fucosylation promoted degradation of LDLR and impaired cholesterol uptake, which is a novel mechanism that regulates cholesterol influx, suggesting that FUT8 might be a novel causative gene for familial hypercholesterolemia.
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loss of α1 6 fucosyltransferase suppressed liver regeneration implication of core fucose in the regulation of growth factor receptor mediated cellular signaling
Scientific Reports, 2015Co-Authors: Yuqin Wang, Naoyuki Taniguchi, Tomoya Isaji, Yoshihiro Kamada, Tomohiko Fukuda, Hohsun Lee, Yasuhito Ohkubo, Eiji MiyoshiAbstract:Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (FUT8). Increased expression of FUT8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of FUT8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that FUT8 is also critical for the regeneration of liver. Interestingly, we show that the FUT8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking FUT8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of FUT8−/− mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the FUT8−/− mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of FUT8+/− mice. Overall, our study provides the first direct evidence for the involvement of FUT8 in liver regeneration.
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Deletion of Core Fucosylation on α3β1 Integrin Down-regulates Its Functions
The Journal of biological chemistry, 2006Co-Authors: Yanyang Zhao, Xiangchun Wang, Eiji Miyoshi, Satsuki Itoh, Tomoya Isaji, Yoshinobu Kariya, Kaoru Miyazaki, Nana Kawasaki, Naoyuki TaniguchiAbstract:The core fucosylation (alpha1,6-fucosylation) of glycoprotein is widely distributed in mammalian tissues. Recently alpha1,6-fucosylation has been further reported to be very crucial by the study of alpha1,6-fucosyltransferase (FUT8)-knock-out mice, which shows the phenotype of emphysema-like changes in the lung and severe growth retardation. In this study, we extensively investigated the effect of core fucosylation on alpha3beta1 integrin and found for the first time that FUT8 makes an important contribution to the functions of this integrin. The role of core fucosylation in alpha3beta1 integrin-mediated events has been studied by using FUT8(+/+) and FUT8(-/-) embryonic fibroblasts, respectively. We found that the core fucosylation of alpha3beta1 integrin, the major receptor for laminin 5, was abundant in FUT8(+/+) cells but was totally abolished in FUT8(-/-) cells, which was associated with the deficient migration mediated by alpha3beta1 integrin in FUT8(-/-) cells. Moreover integrin-mediated cell signaling was reduced in FUT8(-/-) cells. The reintroduction of FUT8 potentially restored laminin 5-induced migration and intracellular signaling. Collectively, these results suggested that core fucosylation is essential for the functions of alpha3beta1 integrin.
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down regulation of trypsinogen expression is associated with growth retardation in α1 6 fucosyltransferase deficient mice attenuation of proteinase activated receptor 2 activity
Glycobiology, 2006Co-Authors: Takatoshi Nakagawa, Xiangchun Wang, Eiji Miyoshi, Naoyuki Taniguchi, Nobuto Koyama, Jinhua Jin, Yoko Mizunohorikawa, Ikunoshin Kato, Koichi Honke, Akihiro KondoAbstract:Alpha1,6-fucosyltransferase (FUT8) plays important roles in physiological and pathological conditions. FUT8-deficient (FUT8-/-) mice exhibit growth retardation, earlier postnatal death, and emphysema-like phenotype. To investigate the underlying molecular mechanism by which growth retardation occurs, we examined the mRNA expression levels of FUT8-/- embryos (18.5 days postcoitum [dpc]) using a cDNA microarray. The DNA microarray and real-time polymerase chain reaction (PCR) analysis showed that a group of genes, including trypsinogens 4, 7, 8, 11, 16, and 20, were down-regulated in FUT8-/- embryos. Consistently, the expression of trypsinogen proteins was found to be lower in FUT8-/- mice in the duodenum, small intestine, and pancreas. Trypsin, an active form of trypsinogen, regulates cell growth through a G-protein-coupled receptor, the proteinase-activated receptor 2 (PAR-2). In a cell culture system, a FUT8 knockdown mouse pancreatic acinar cell carcinoma, TGP49-FUT8-KDs, showed decreased growth rate, similar to that seen in FUT8-/- mice, and the decreased growth rate was rescued by the application of the PAR-2-activating peptide (SLIGRL-NH2). Moreover, epidermal growth factor (EGF)-induced receptor phosphorylation was attenuated in TGP49-FUT8-KDs, which was highly associated with a reduction of trypsinogens mRNA levels. The addition of exogenous EGF recovered c-fos, c-jun, and trypsinogen mRNA expression in TGP49-FUT8-KDs. Again, the EGF-induced up-regulation of c-fos and c-jun mRNA expression was significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between FUT8 and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathway in controlling cell growth and that the EGFR-trypsin-PAR-2 pathway is suppressed in TGP49-FUT8-KDs as well as in FUT8-/- mice.
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Core Fucosylation Regulates Epidermal Growth Factor Receptor-mediated Intracellular Signaling
The Journal of biological chemistry, 2005Co-Authors: Xiangchun Wang, Eiji Miyoshi, Koichi Honke, Hideyuki Ihara, Naoyuki TaniguchiAbstract:alpha1,6-Fucosyltransferase (FUT8) catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an alpha1,6-linkage to form core fucosylation in mammals. We recently found that disruption of the FUT8 gene induces severe growth retardation and early postnatal death. To investigate the molecular mechanism involved, we have established embryonic fibroblasts of FUT8+/+ and FUT8-/-, derived from wild-type and FUT8-null mice, respectively. Interestingly, the epidermal growth factor (EGF)-induced phosphorylation levels of the EGF receptor (EGFR) were substantially blocked in FUT8-/- cells, compared with FUT8+/+ cells, while there are no significant changes in the total activities of tyrosine phosphatase for phosphorylated EGFR between two cells. The inhibition of EGFR phosphorylation was completely restored by re-introduction of the FUT8 gene to FUT8-/- cells. Consistent with this, EGFR-mediated JNK or ERK activation was significantly suppressed in FUT8-/- cells. Finally, we found that the core fucosylation of N-glycans is required for the binding of the EGF to its receptor, whereas no effect was observed for the expression levels of EGFR on the cell surface. Collectively, these results strongly suggest that core fucosylation is essential for EGF receptor-mediated biological functions.
Qiu Yan - One of the best experts on this subject based on the ideXlab platform.
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Role of fucosyltransferase IV in the migration and invasion of human melanoma cells.
IUBMB life, 2020Co-Authors: Xiu Shan, Qiu Yan, Weijie Dong, Li Zhang, Xin Cai, Yi Zhao, Qun Chen, Jiwei LiuAbstract:Malignant melanoma is one of the most aggressive human tumor types, mainly due to its high invasion capability, metastatic properties, and the absence of effective treatments. Glycosylation serves a pivotal role in the migration and invasion of melanoma. However, differences in glycosylation between high and low metastatic melanoma cells and how these regulate migration and invasion by altering the expression of fucosyltransferases (FUTs) remain unclear. In the present study, matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) analysis revealed that the composition profiling of fucosylated N-glycans differed between high metastatic C8161 and low metastatic A375P cells. Further analysis revealed that FUT4 expression was significantly increased in C8161 cells. Melanoma tissue arrays further demonstrated that FUT4 was overexpressed in metastatic samples. Altered FUT4 expression was accompanied by a change in the migration and invasion capacity of the cells. In addition, the migration and invasion potential of melanoma cells were decreased in C8161 and increased in A375P cells upon altering FUT4 expression levels by small interfering RNA or complementary DNA transfection. Furthermore, regulating FUT4 expression markedly modulated the activity of the phosphoinositide-3-kinase/Akt (PI3K/Akt) signaling pathway, which affected melanoma cell migration and invasion. In conclusion, FUT4 is a novel biomarker and regulator of the migration and invasion of melanoma cells and may serve as a therapeutic target for melanoma.
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Novel function of pregnancy-associated plasma protein A: promotes endometrium receptivity by up-regulating N-fucosylation
Scientific reports, 2017Co-Authors: Jiao Wang, Shuai Liu, Xiaoqi Wang, Qiu YanAbstract:Glycosylation of uterine endometrial cells plays important roles to determine their receptive function to blastocysts. Trophoblast-derived pregnancy-associated plasma protein A (PAPPA) is specifically elevated in pregnant women serum, and is known to promote trophoblast cell proliferation and adhesion. However, the relationship between PAPPA and endometrium receptivity, as well as the regulation of N-fucosylation remains unclear. We found that rhPAPPA and PAPPA in the serum samples from pregnant women or conditioned medium of trophoblast cells promoted endometrium receptivity in vitro. Moreover, rhPAPPA increased α1,2-, α1,3- and α1,6-fucosylation levels by up-regulating N-fucosyltransferases FUT1, FUT4 and FUT8 expression, respectively, through IGF-1R/PI3K/Akt signaling pathway in human endometrial cells. Additionally, α1,2-, α1,3- and α1,6-fucosylation of integrin αVβ3, a critical endometrium receptivity biomarker, was up-regulated by PAPPA, thereby enhanced its adhesive functions. Furthermore, PAPPA blockage with antibody inhibited embryo implantation in vivo, mouse embryo adhesion and spreading in vitro, as well as N-fucosylation level of the endometrium in pregnant mice. In summary, this study suggests that PAPPA is essential to maintain a receptive endometrium by up-regulating N-fucosylation, which is a potential useful biomarker to evaluate the receptive functions of the endometrium.
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suppression of fut1 fut4 expression by sirna inhibits tumor growth
Biochimica et Biophysica Acta, 2008Co-Authors: Zhenbo Zhang, Xiaoqi Wang, Ping Sun, Jiwei Liu, Jie Yan, Yuejian Liu, Qiu YanAbstract:Lewis Y (LeY) antigen is highly expressed in a variety of human carcinomas of epithelial cell origin. Recent studies suggest functional blockade of LeY may provide a novel therapeutic approach for the treatment of cancers. However, suppressing LeY expression by genetic manipulation and its impact on neoplastic cell proliferation has not been investigated. We report here that different fucosyltransferases (FUTs) were expressed with the greatest expression of fucosyltransferase I or IV (FUT1/4), the two key enzymes for the synthesis of LeY in human epidermoid carcinoma A431 cells. Knocking down FUT1/4 expression by short interfering RNA technique dramatically reduced the expression of FUT1/4 and LeY and inhibited cell proliferation through decreasing epidermal growth factor receptor (EGFR) signaling pathway. Treatment of A431 cells that were inoculated into the nude mice with FUT1 siRNA or FUT4 siRNA greatly impeded tumor growth. Suppressing FUT1/4 expression also blocked EGF-induced tyrosine phosphorylation of EGFR and mitogen-activated protein kinases. In conclusion, suppressing the expression of FUT1/4 by RNAi technology reduces the synthesis of LeY and inhibits cancer growth. It may serve as a potential methodology for the treatment of cancers that express LeY glycoconjugates.
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Suppression of FUT1/FUT4 expression by siRNA inhibits tumor growth.
Biochimica et biophysica acta, 2007Co-Authors: Zhenbo Zhang, Xiaoqi Wang, Ping Sun, Jiwei Liu, Jie Yan, Yuejian Liu, Qiu YanAbstract:Lewis Y (LeY) antigen is highly expressed in a variety of human carcinomas of epithelial cell origin. Recent studies suggest functional blockade of LeY may provide a novel therapeutic approach for the treatment of cancers. However, suppressing LeY expression by genetic manipulation and its impact on neoplastic cell proliferation has not been investigated. We report here that different fucosyltransferases (FUTs) were expressed with the greatest expression of fucosyltransferase I or IV (FUT1/4), the two key enzymes for the synthesis of LeY in human epidermoid carcinoma A431 cells. Knocking down FUT1/4 expression by short interfering RNA technique dramatically reduced the expression of FUT1/4 and LeY and inhibited cell proliferation through decreasing epidermal growth factor receptor (EGFR) signaling pathway. Treatment of A431 cells that were inoculated into the nude mice with FUT1 siRNA or FUT4 siRNA greatly impeded tumor growth. Suppressing FUT1/4 expression also blocked EGF-induced tyrosine phosphorylation of EGFR and mitogen-activated protein kinases. In conclusion, suppressing the expression of FUT1/4 by RNAi technology reduces the synthesis of LeY and inhibits cancer growth. It may serve as a potential methodology for the treatment of cancers that express LeY glycoconjugates.
Rosella Mollicone - One of the best experts on this subject based on the ideXlab platform.
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FUT4 and FUT9 genes are expressed early in human embryogenesis.
Glycobiology, 2000Co-Authors: Anne Cailleau-thomas, Rafael Oriol, Philippe Coullin, Jean-jacques Candelier, Luis Balanzino, Benoît Mennesson, Rosella MolliconeAbstract:The Le(x) oligosaccharide is expressed in organ buds progressing in mesenchyma, during human embryogenesis. Myeloid-like alpha3-fucosyltransferases are good candidates to synthesize this oligosaccharide. We investigated by Northern analysis all the alpha3-fucosyltransferase gene transcripts and only FUT4 and FUT9 were detected. The enzymes encoded by the FUT4 and FUT9 genes are the first alpha3-fucosyltransferases strongly expressed during the first two months of embryogenesis. The Northern profile of expression of the embryo FUT4 transcripts is similar in size and sequence to the known FUT4 transcripts of 6 kb, 3 kb, and 2.3 kb, but a new FUT9 transcript of 2501 bp, different from the known mouse (2170 bp) and human (3019 bp) transcripts was cloned. FUT3, FUT5, FUT6, and FUT7 were not detected by Northern blot. The FUT3 and FUT6 transcripts start to appear at this stage, but are only detected by reverse transcriptase-PCR analysis. The expression of FUT5 is weaker than FUT3 and FUT6 and the RT-PCR signal is faint and irregular. FUT7 is not detected at all. Using mRNA from 40- to 65-day-old embryos, we have prepared different hexamer and oligo-dT cDNA libraries and cloned, by rapid amplification cDNA ends-PCR, FUT4 and FUT9 alpha3-fucosyltransferase transcripts. The tissue expression of the embryonic FUT9 transcript is closer to that observed for the mouse (brain), than to the known human (stomach) transcripts. The acceptor specificity and the kinetics of the alpha3-fucosyltransferase encoded by this FUT9 transcript are similar to the FUT4 enzyme, except for the utilization of the lac-di-NAc acceptor which is not efficiently transformed by the FUT9 enzyme. Like FUT4, this embryonic FUT9 is N-ethylmaleimide and heat resistant and the corresponding gene was confirmed to be localized in the chromosome band 6q16. Finally, this FUT9 transcript has a single expressed exon as has been observed for most of the other vertebrate alpha2- and alpha3-fucosyltransferases.
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Evolution of fucosyltransferase genes in vertebrates.
The Journal of biological chemistry, 1997Co-Authors: Marieta Costache, Rafael Oriol, Anne Cailleau, Pol-andré Apoil, Anders Elmgren, Göran Larson, Stephen Henry, Antoine Blancher, Dana Iordachescu, Rosella MolliconeAbstract:Abstract Cloning and expression of chimpanzee FUT3, FUT5, and FUT6 genes confirmed the hypothesis that the gene duplications at the origin of the present human cluster of genes occurred between: (i) the great mammalian radiation 80 million years ago and (ii) the separation of man and chimpanzee 10 million years ago. The phylogeny of fucosyltransferase genes was completed by the addition of the FUT8 family of α(1,6)fucosyltransferase genes, which are the oldest genes of the fucosyltransferase family. By analysis of data banks, a newFUT8 alternative splice expressed in human retina was identified, which allowed mapping the human FUT8 gene to 14q23. The results suggest that the fucosyltransferase genes have evolved by successive duplications, followed by translocations, and divergent evolution from a single ancestral gene.
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A Missense Mutation in the FUT6 Gene Results in Total Absence of α3-Fucosylation of Human α1-Acid Glycoprotein
The Journal of biological chemistry, 1996Co-Authors: Els C.m. Brinkman-van Der Linden, Rosella Mollicone, Rafael Oriol, Göran Larson, Dirk H. Van Den Eijnden, Willem Van DijkAbstract:The major α3-fucosyltransferase activity in human plasma is encoded by the gene for fucosyltransferase VI (FUT6). A missense mutation (Gly-739 → Ala) in this gene is responsible for deficiency of enzyme activity in plasma. To examine whether this fucosyltransferase is the sole enzyme responsible for the α3-fucosylation of serum glycoproteins in the liver, we studied the fucosylation of three glycoproteins in sera of individuals with or without inactivated FUT3 and/or FUT6 gene(s) but with a functional FUT5 gene. α1-Acid glycoprotein was used as the principal reporter protein for liver α3-fucosyltransferase activity, because of its high fucose content. In all individuals with the FUT6 missense mutation Gly-739 → Ala in double dose, no fucosylation of α1-acid glycoprotein was found. This α1-acid glycoprotein was not intrinsically resistant to fucosylation, since it was susceptible to in vitro fucosylation using an α3/4-fucosyltransferase isolated from human milk. The same result was found for α1-antichymotrypsin and α1-protease inhibitor. On the other hand in all individuals with α3-fucosyltransferase activity in plasma, α3-fucosylated glycoforms of the glycoproteins studied were found. The degree of fucosylation of α1-acid glycoprotein was correlated with α3-fucosyltransferase activity (Rs = 0.82). These data indicate that the product of FUT6, but not of FUT3 or of FUT5, is responsible for the α3-fucosylation of glycoproteins produced in liver and suggest that this organ is a major source of α3-fucosyltransferase activity in plasma.
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Fucosyltransferase genes are dispersed in the genome: FUT7 is located on 9q34.3 distal to D9S1830.
Comptes rendus de l'Academie des sciences. Serie III Sciences de la vie, 1996Co-Authors: I. Reguigne-arnould, Rosella Mollicone, Rafael Oriol, Wolfe J, Hornigold N, S. Faure, Philippe CoullinAbstract:La synthese des antigenes tissulaires A, B, H, Lewis et apparentes est catalysee par differentes fucosyltransferases. La specificite d'accepteurs enzymatiques et l'expression tissulaire permettent de definir 2 types d'α-2-fucosyltransferases et 5 types d'α-3-fucosyltransferases, codes par des genes specifiques denommes FUT1 a FUT7. Nous avons precedemment assigne FUT4 a la region llq21, le groupe FUTI-FUT2 a la bande 19q13.3 et le groupe FUT6-FUT3-FUT5 a l'intervalle 19p13.3. Le dernier gene cloue (FUT7) code une α-3-fucosyltransferase, exprimee dans les leucocytes, qui synthetise l'antigene sialyl Le x , un ligand des selectines. A l'aide d'hybrides somatiques cellulaires porteurs d'un chromosome 9 remanie et caracterises par rapport a la carte genetique des microsatellites, puis en criblant une banque de cosmides, nous avons localise FUT7 au sein de la bande chromosomique 9q34.3, dans la portion telomerique par rapport a D9S1830 et proche des genes ABC2 et C8G.
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Molecular genetics of H, Se, Lewis and other fucosyltransferase genes.
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine, 1995Co-Authors: Rosella Mollicone, Anne Cailleau, Rafael OriolAbstract:Seven human fucosyltransferase genes have been cloned and registered in the Genome Data Base (GDB) as FUT1 to FUT7. According to their acceptor specificity, two main groups of enzymes can be distinguished. The alpha-2-fucosyltransferases: FUT1 (H) of red cells and vascular endothelium and FUT2 (Se) of exocrine secretions. The alpha-3-fucosyltransferases: FUT3 (Lewis) of exocrine secretions; FUT4 (myeloid) of white cells and brain; FUT5 whose tissue distribution has not been defined as yet; FUT6 (plasma) present in plasma, renal proximal tubules and hepatocytes; FUT7 (leukocyte) found in neutrophils. A high DNA sequence homology has been detected among the genes within each of these two groups, while no homology has been detected between the genes of the two groups. Point mutations responsible of inactivating genetic polymorphisms have been found for FUT1, FUT2, FUT3 and FUT6, while FUT4 and FUT7 seem to be genetically monomorphic. FUT4 has been detected in all tissues of 5 to 10 weeks old human embryos suggesting that it may play a role in development. FUT7 is a candidate for the control of the synthesis of the receptors of selectin mediated cell adhesion.
Rafael Oriol - One of the best experts on this subject based on the ideXlab platform.
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FUT4 and FUT9 genes are expressed early in human embryogenesis.
Glycobiology, 2000Co-Authors: Anne Cailleau-thomas, Rafael Oriol, Philippe Coullin, Jean-jacques Candelier, Luis Balanzino, Benoît Mennesson, Rosella MolliconeAbstract:The Le(x) oligosaccharide is expressed in organ buds progressing in mesenchyma, during human embryogenesis. Myeloid-like alpha3-fucosyltransferases are good candidates to synthesize this oligosaccharide. We investigated by Northern analysis all the alpha3-fucosyltransferase gene transcripts and only FUT4 and FUT9 were detected. The enzymes encoded by the FUT4 and FUT9 genes are the first alpha3-fucosyltransferases strongly expressed during the first two months of embryogenesis. The Northern profile of expression of the embryo FUT4 transcripts is similar in size and sequence to the known FUT4 transcripts of 6 kb, 3 kb, and 2.3 kb, but a new FUT9 transcript of 2501 bp, different from the known mouse (2170 bp) and human (3019 bp) transcripts was cloned. FUT3, FUT5, FUT6, and FUT7 were not detected by Northern blot. The FUT3 and FUT6 transcripts start to appear at this stage, but are only detected by reverse transcriptase-PCR analysis. The expression of FUT5 is weaker than FUT3 and FUT6 and the RT-PCR signal is faint and irregular. FUT7 is not detected at all. Using mRNA from 40- to 65-day-old embryos, we have prepared different hexamer and oligo-dT cDNA libraries and cloned, by rapid amplification cDNA ends-PCR, FUT4 and FUT9 alpha3-fucosyltransferase transcripts. The tissue expression of the embryonic FUT9 transcript is closer to that observed for the mouse (brain), than to the known human (stomach) transcripts. The acceptor specificity and the kinetics of the alpha3-fucosyltransferase encoded by this FUT9 transcript are similar to the FUT4 enzyme, except for the utilization of the lac-di-NAc acceptor which is not efficiently transformed by the FUT9 enzyme. Like FUT4, this embryonic FUT9 is N-ethylmaleimide and heat resistant and the corresponding gene was confirmed to be localized in the chromosome band 6q16. Finally, this FUT9 transcript has a single expressed exon as has been observed for most of the other vertebrate alpha2- and alpha3-fucosyltransferases.
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Evolution of fucosyltransferase genes in vertebrates.
The Journal of biological chemistry, 1997Co-Authors: Marieta Costache, Rafael Oriol, Anne Cailleau, Pol-andré Apoil, Anders Elmgren, Göran Larson, Stephen Henry, Antoine Blancher, Dana Iordachescu, Rosella MolliconeAbstract:Abstract Cloning and expression of chimpanzee FUT3, FUT5, and FUT6 genes confirmed the hypothesis that the gene duplications at the origin of the present human cluster of genes occurred between: (i) the great mammalian radiation 80 million years ago and (ii) the separation of man and chimpanzee 10 million years ago. The phylogeny of fucosyltransferase genes was completed by the addition of the FUT8 family of α(1,6)fucosyltransferase genes, which are the oldest genes of the fucosyltransferase family. By analysis of data banks, a newFUT8 alternative splice expressed in human retina was identified, which allowed mapping the human FUT8 gene to 14q23. The results suggest that the fucosyltransferase genes have evolved by successive duplications, followed by translocations, and divergent evolution from a single ancestral gene.
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A Missense Mutation in the FUT6 Gene Results in Total Absence of α3-Fucosylation of Human α1-Acid Glycoprotein
The Journal of biological chemistry, 1996Co-Authors: Els C.m. Brinkman-van Der Linden, Rosella Mollicone, Rafael Oriol, Göran Larson, Dirk H. Van Den Eijnden, Willem Van DijkAbstract:The major α3-fucosyltransferase activity in human plasma is encoded by the gene for fucosyltransferase VI (FUT6). A missense mutation (Gly-739 → Ala) in this gene is responsible for deficiency of enzyme activity in plasma. To examine whether this fucosyltransferase is the sole enzyme responsible for the α3-fucosylation of serum glycoproteins in the liver, we studied the fucosylation of three glycoproteins in sera of individuals with or without inactivated FUT3 and/or FUT6 gene(s) but with a functional FUT5 gene. α1-Acid glycoprotein was used as the principal reporter protein for liver α3-fucosyltransferase activity, because of its high fucose content. In all individuals with the FUT6 missense mutation Gly-739 → Ala in double dose, no fucosylation of α1-acid glycoprotein was found. This α1-acid glycoprotein was not intrinsically resistant to fucosylation, since it was susceptible to in vitro fucosylation using an α3/4-fucosyltransferase isolated from human milk. The same result was found for α1-antichymotrypsin and α1-protease inhibitor. On the other hand in all individuals with α3-fucosyltransferase activity in plasma, α3-fucosylated glycoforms of the glycoproteins studied were found. The degree of fucosylation of α1-acid glycoprotein was correlated with α3-fucosyltransferase activity (Rs = 0.82). These data indicate that the product of FUT6, but not of FUT3 or of FUT5, is responsible for the α3-fucosylation of glycoproteins produced in liver and suggest that this organ is a major source of α3-fucosyltransferase activity in plasma.
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Fucosyltransferase genes are dispersed in the genome: FUT7 is located on 9q34.3 distal to D9S1830.
Comptes rendus de l'Academie des sciences. Serie III Sciences de la vie, 1996Co-Authors: I. Reguigne-arnould, Rosella Mollicone, Rafael Oriol, Wolfe J, Hornigold N, S. Faure, Philippe CoullinAbstract:La synthese des antigenes tissulaires A, B, H, Lewis et apparentes est catalysee par differentes fucosyltransferases. La specificite d'accepteurs enzymatiques et l'expression tissulaire permettent de definir 2 types d'α-2-fucosyltransferases et 5 types d'α-3-fucosyltransferases, codes par des genes specifiques denommes FUT1 a FUT7. Nous avons precedemment assigne FUT4 a la region llq21, le groupe FUTI-FUT2 a la bande 19q13.3 et le groupe FUT6-FUT3-FUT5 a l'intervalle 19p13.3. Le dernier gene cloue (FUT7) code une α-3-fucosyltransferase, exprimee dans les leucocytes, qui synthetise l'antigene sialyl Le x , un ligand des selectines. A l'aide d'hybrides somatiques cellulaires porteurs d'un chromosome 9 remanie et caracterises par rapport a la carte genetique des microsatellites, puis en criblant une banque de cosmides, nous avons localise FUT7 au sein de la bande chromosomique 9q34.3, dans la portion telomerique par rapport a D9S1830 et proche des genes ABC2 et C8G.
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Molecular genetics of H, Se, Lewis and other fucosyltransferase genes.
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine, 1995Co-Authors: Rosella Mollicone, Anne Cailleau, Rafael OriolAbstract:Seven human fucosyltransferase genes have been cloned and registered in the Genome Data Base (GDB) as FUT1 to FUT7. According to their acceptor specificity, two main groups of enzymes can be distinguished. The alpha-2-fucosyltransferases: FUT1 (H) of red cells and vascular endothelium and FUT2 (Se) of exocrine secretions. The alpha-3-fucosyltransferases: FUT3 (Lewis) of exocrine secretions; FUT4 (myeloid) of white cells and brain; FUT5 whose tissue distribution has not been defined as yet; FUT6 (plasma) present in plasma, renal proximal tubules and hepatocytes; FUT7 (leukocyte) found in neutrophils. A high DNA sequence homology has been detected among the genes within each of these two groups, while no homology has been detected between the genes of the two groups. Point mutations responsible of inactivating genetic polymorphisms have been found for FUT1, FUT2, FUT3 and FUT6, while FUT4 and FUT7 seem to be genetically monomorphic. FUT4 has been detected in all tissues of 5 to 10 weeks old human embryos suggesting that it may play a role in development. FUT7 is a candidate for the control of the synthesis of the receptors of selectin mediated cell adhesion.
Eiji Miyoshi - One of the best experts on this subject based on the ideXlab platform.
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loss of α1 6 fucosyltransferase suppressed liver regeneration implication of core fucose in the regulation of growth factor receptor mediated cellular signaling
Scientific Reports, 2015Co-Authors: Yuqin Wang, Naoyuki Taniguchi, Tomoya Isaji, Yoshihiro Kamada, Tomohiko Fukuda, Hohsun Lee, Yasuhito Ohkubo, Eiji MiyoshiAbstract:Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (FUT8). Increased expression of FUT8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of FUT8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that FUT8 is also critical for the regeneration of liver. Interestingly, we show that the FUT8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking FUT8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of FUT8−/− mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the FUT8−/− mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of FUT8+/− mice. Overall, our study provides the first direct evidence for the involvement of FUT8 in liver regeneration.
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Deletion of Core Fucosylation on α3β1 Integrin Down-regulates Its Functions
The Journal of biological chemistry, 2006Co-Authors: Yanyang Zhao, Xiangchun Wang, Eiji Miyoshi, Satsuki Itoh, Tomoya Isaji, Yoshinobu Kariya, Kaoru Miyazaki, Nana Kawasaki, Naoyuki TaniguchiAbstract:The core fucosylation (alpha1,6-fucosylation) of glycoprotein is widely distributed in mammalian tissues. Recently alpha1,6-fucosylation has been further reported to be very crucial by the study of alpha1,6-fucosyltransferase (FUT8)-knock-out mice, which shows the phenotype of emphysema-like changes in the lung and severe growth retardation. In this study, we extensively investigated the effect of core fucosylation on alpha3beta1 integrin and found for the first time that FUT8 makes an important contribution to the functions of this integrin. The role of core fucosylation in alpha3beta1 integrin-mediated events has been studied by using FUT8(+/+) and FUT8(-/-) embryonic fibroblasts, respectively. We found that the core fucosylation of alpha3beta1 integrin, the major receptor for laminin 5, was abundant in FUT8(+/+) cells but was totally abolished in FUT8(-/-) cells, which was associated with the deficient migration mediated by alpha3beta1 integrin in FUT8(-/-) cells. Moreover integrin-mediated cell signaling was reduced in FUT8(-/-) cells. The reintroduction of FUT8 potentially restored laminin 5-induced migration and intracellular signaling. Collectively, these results suggested that core fucosylation is essential for the functions of alpha3beta1 integrin.
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down regulation of trypsinogen expression is associated with growth retardation in α1 6 fucosyltransferase deficient mice attenuation of proteinase activated receptor 2 activity
Glycobiology, 2006Co-Authors: Takatoshi Nakagawa, Xiangchun Wang, Eiji Miyoshi, Naoyuki Taniguchi, Nobuto Koyama, Jinhua Jin, Yoko Mizunohorikawa, Ikunoshin Kato, Koichi Honke, Akihiro KondoAbstract:Alpha1,6-fucosyltransferase (FUT8) plays important roles in physiological and pathological conditions. FUT8-deficient (FUT8-/-) mice exhibit growth retardation, earlier postnatal death, and emphysema-like phenotype. To investigate the underlying molecular mechanism by which growth retardation occurs, we examined the mRNA expression levels of FUT8-/- embryos (18.5 days postcoitum [dpc]) using a cDNA microarray. The DNA microarray and real-time polymerase chain reaction (PCR) analysis showed that a group of genes, including trypsinogens 4, 7, 8, 11, 16, and 20, were down-regulated in FUT8-/- embryos. Consistently, the expression of trypsinogen proteins was found to be lower in FUT8-/- mice in the duodenum, small intestine, and pancreas. Trypsin, an active form of trypsinogen, regulates cell growth through a G-protein-coupled receptor, the proteinase-activated receptor 2 (PAR-2). In a cell culture system, a FUT8 knockdown mouse pancreatic acinar cell carcinoma, TGP49-FUT8-KDs, showed decreased growth rate, similar to that seen in FUT8-/- mice, and the decreased growth rate was rescued by the application of the PAR-2-activating peptide (SLIGRL-NH2). Moreover, epidermal growth factor (EGF)-induced receptor phosphorylation was attenuated in TGP49-FUT8-KDs, which was highly associated with a reduction of trypsinogens mRNA levels. The addition of exogenous EGF recovered c-fos, c-jun, and trypsinogen mRNA expression in TGP49-FUT8-KDs. Again, the EGF-induced up-regulation of c-fos and c-jun mRNA expression was significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between FUT8 and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathway in controlling cell growth and that the EGFR-trypsin-PAR-2 pathway is suppressed in TGP49-FUT8-KDs as well as in FUT8-/- mice.
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Core Fucosylation Regulates Epidermal Growth Factor Receptor-mediated Intracellular Signaling
The Journal of biological chemistry, 2005Co-Authors: Xiangchun Wang, Eiji Miyoshi, Koichi Honke, Hideyuki Ihara, Naoyuki TaniguchiAbstract:alpha1,6-Fucosyltransferase (FUT8) catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an alpha1,6-linkage to form core fucosylation in mammals. We recently found that disruption of the FUT8 gene induces severe growth retardation and early postnatal death. To investigate the molecular mechanism involved, we have established embryonic fibroblasts of FUT8+/+ and FUT8-/-, derived from wild-type and FUT8-null mice, respectively. Interestingly, the epidermal growth factor (EGF)-induced phosphorylation levels of the EGF receptor (EGFR) were substantially blocked in FUT8-/- cells, compared with FUT8+/+ cells, while there are no significant changes in the total activities of tyrosine phosphatase for phosphorylated EGFR between two cells. The inhibition of EGFR phosphorylation was completely restored by re-introduction of the FUT8 gene to FUT8-/- cells. Consistent with this, EGFR-mediated JNK or ERK activation was significantly suppressed in FUT8-/- cells. Finally, we found that the core fucosylation of N-glycans is required for the binding of the EGF to its receptor, whereas no effect was observed for the expression levels of EGFR on the cell surface. Collectively, these results strongly suggest that core fucosylation is essential for EGF receptor-mediated biological functions.
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α6-Fucosyltransferase (FUT8)
Handbook of Glycosyltransferases and Related Genes, 2002Co-Authors: Eiji Miyoshi, Naoyuki TaniguchiAbstract:GDP-L-FucN-acetyl-β-D-glucosaminide α1-6fucosyltransferase (FUT8) catalyzes the transfer of fucose from GDP-Fuc to N-linked-type complex glycoproteins, as shown in Fig. 1. The enzymatic products, α1,6-fucosylated (core fucosylated) N-glycans, are commonly observed in many glycoproteins, and are especially abundant in brain tissue. It is well known that the sugar chains in α-fetoprotein (AFP), a well-known tumor marker of hepatocellular carcinoma, are microheterogenous in nature to sugar chains. The oligosaccharide structures of transferrin as well as AFP, synthesized by hepatocellular carcinoma cells, are highly fucosylated (Champion et al. 1989). In contrast, FUT8 is released from platelets during blood clotting (Koscielak et al. 1987), suggesting that this enzyme might play a role in blood coagulation. An increase in fucosylated carbohydrates in pathological conditions has also been reported in other types of cancer cells (Tatsumura 1977). Open image in new window Fig. 1 Reaction pathway of FUT8. GlcNAc indicates N-acetylglucosamine, Man indicates mannose, Fuc indicates fucose, GDP-Fuc indicates guanosinediphosphofucopyranoside, and Asn indicates asparagine
