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  1 / 1903 MEDLINE  
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[PMID]:29352318
[Au] Autor:William D; Walther M; Schneider B; Linnebacher M; Classen CF
[Ad] Endereço:University Children's and Adolescents' Hospital, University Medicine of Rostock, Rostock, Germany.
[Ti] Título:Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma.
[So] Source:PLoS One;13(1):e0191511, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment.
[Mh] Termos MeSH primário: Antineoplásicos Alquilantes/efeitos adversos
Neoplasias Encefálicas/tratamento farmacológico
Neoplasias Encefálicas/patologia
Dacarbazina/análogos & derivados
Glioblastoma/tratamento farmacológico
Glioblastoma/patologia
[Mh] Termos MeSH secundário: Antibacterianos/administração & dosagem
Antineoplásicos Alquilantes/administração & dosagem
Biomarcadores Tumorais/metabolismo
Neoplasias Encefálicas/metabolismo
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Metilases de Modificação do DNA/genética
Enzimas Reparadoras do DNA/genética
Dacarbazina/administração & dosagem
Dacarbazina/efeitos adversos
Doxiciclina/administração & dosagem
Resistência a Medicamentos Antineoplásicos
Fucosiltransferases/metabolismo
Glioblastoma/metabolismo
Seres Humanos
Antígeno Lewis X/metabolismo
Mitocôndrias/efeitos dos fármacos
Células-Tronco Neoplásicas/efeitos dos fármacos
Células-Tronco Neoplásicas/metabolismo
Células-Tronco Neoplásicas/patologia
Nestina/metabolismo
Ensaio Tumoral de Célula-Tronco
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antineoplastic Agents, Alkylating); 0 (Biomarkers, Tumor); 0 (Lewis X Antigen); 0 (NES protein, human); 0 (Nestin); 0 (Tumor Suppressor Proteins); 7GR28W0FJI (Dacarbazine); EC 2.1.1.- (DNA Modification Methylases); EC 2.1.1.63 (MGMT protein, human); EC 2.4.1.- (FUT4 protein, human); EC 2.4.1.- (Fucosyltransferases); EC 6.5.1.- (DNA Repair Enzymes); N12000U13O (Doxycycline); YF1K15M17Y (temozolomide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191511


  2 / 1903 MEDLINE  
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[PMID]:29339069
[Au] Autor:Liu H; Sui T; Liu D; Liu T; Chen M; Deng J; Xu Y; Li Z
[Ad] Endereço:Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China.
[Ti] Título:Multiple homologous genes knockout (KO) by CRISPR/Cas9 system in rabbit.
[So] Source:Gene;647:261-267, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The CRISPR/Cas9 system is a highly efficient and convenient genome editing tool, which has been widely used for single or multiple gene mutation in a variety of organisms. Disruption of multiple homologous genes, which have similar DNA sequences and gene function, is required for the study of the desired phenotype. In this study, to test whether the CRISPR/Cas9 system works on the mutation of multiple homologous genes, a single guide RNA (sgRNA) targeting three fucosyltransferases encoding genes (FUT1, FUT2 and SEC1) was designed. As expected, triple gene mutation of FUT1, FUT2 and SEC1 could be achieved simultaneously via a sgRNA mediated CRISPR/Cas9 system. Besides, significantly reduced serum fucosyltransferases enzymes activity was also determined in those triple gene mutation rabbits. Thus, we provide the first evidence that multiple homologous genes knockout (KO) could be achieved efficiently by a sgRNA mediated CRISPR/Cas9 system in mammals, which could facilitate the genotype to phenotype studies of homologous genes in future.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Mutação/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sequência de Bases
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética
Fucosiltransferases/genética
Técnicas de Inativação de Genes/métodos
Fenótipo
RNA Guia/genética
Coelhos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide); EC 2.4.1.- (Fucosyltransferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE


  3 / 1903 MEDLINE  
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[PMID]:29178652
[Au] Autor:Modi BP; Teves ME; Pearson LN; Parikh HI; Haymond-Thornburg H; Tucker JL; Chaemsaithong P; Gomez-Lopez N; York TP; Romero R; Strauss JF
[Ad] Endereço:Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.
[Ti] Título:Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM).
[So] Source:Mol Genet Genomic Med;5(6):720-729, 2017 11.
[Is] ISSN:2324-9269
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Twin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM. METHODS: We carried out whole exome sequencing (WES) of genomic DNA from neonates born of African-American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies (N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes. Targeted genotyping of mutations in the candidates discovered by WES was conducted on an additional 188 PPROM cases and 175 controls. RESULTS: We identified rare heterozygous nonsense and frameshift mutations in several of the candidate genes, including CARD6, CARD8, DEFB1, FUT2, MBL2, NLP10, NLRP12, and NOD2. We discovered that some mutations (CARD6, DEFB1, FUT2, MBL2, NLRP10, NOD2) were present only in PPROM cases. CONCLUSIONS: We conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in African-Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.
[Mh] Termos MeSH primário: Ruptura Prematura de Membranas Fetais/diagnóstico
Imunidade Inata/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Sinalização CARD/genética
Estudos de Casos e Controles
Códon sem Sentido
DNA/química
DNA/isolamento & purificação
DNA/metabolismo
Feminino
Ruptura Prematura de Membranas Fetais/etiologia
Ruptura Prematura de Membranas Fetais/genética
Mutação da Fase de Leitura
Fucosiltransferases/genética
Seres Humanos
Recém-Nascido
Gravidez
Risco
Análise de Sequência de DNA
Sequenciamento Completo do Exoma
beta-Defensinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (CARD Signaling Adaptor Proteins); 0 (CARD6 protein, human); 0 (Codon, Nonsense); 0 (DEFB1 protein, human); 0 (beta-Defensins); 9007-49-2 (DNA); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.69 (galactoside 2-alpha-L-fucosyltransferase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1002/mgg3.330


  4 / 1903 MEDLINE  
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[PMID]:27773385
[Au] Autor:Mueller TM; Yates SD; Haroutunian V; Meador-Woodruff JH
[Ad] Endereço:Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: tonimueller@uabmc.edu.
[Ti] Título:Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia.
[So] Source:Schizophr Res;182:66-73, 2017 04.
[Is] ISSN:1573-2509
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Glycosylation is a post-translational modification that is an essential element in cell signaling and neurodevelopmental pathway regulation. Glycan attachment can influence the tertiary structure and molecular interactions of glycosylated substrates, adding an additional layer of regulatory complexity to functional mechanisms underlying central cell biological processes. One type of enzyme-mediated glycan attachment, fucosylation, can mediate glycoprotein and glycolipid cell surface expression, trafficking, secretion, and quality control to modulate a variety of inter- and intracellular signaling cascades. Building on prior reports of glycosylation abnormalities and evidence of dysregulated glycosylation enzyme expression in schizophrenia, we examined the protein expression of 5 key fucose-modifying enzymes: GDP-fucose:protein O-fucosyltransferase 1 (POFUT1), GDP-fucose:protein O-fucosyltransferase 2 (POFUT2), fucosyltransferase 8 (FUT8), fucosyltransferase 11 (FUT11), and plasma α-l-fucosidase (FUCA2) in postmortem superior temporal gyrus of schizophrenia (N=16) and comparison (N=14) subjects. We also used the fucose binding protein, Aleuria aurantia lectin (AAL), to assess α-1,6-fucosylated N-glycoprotein abundance in the same subjects. In schizophrenia, we found increased expression of POFUT2, a fucosyltransferase uniquely responsible for O-fucosylation of thrombospondin-like repeat domains that is involved in a non-canonical endoplasmic reticulum quality control pathway. We also found decreased expression of FUT8 in schizophrenia. Given that FUT8 is the only α-1,6-fucosyltransferase expressed in mammals, the concurrent decrease in AAL binding in schizophrenia, particularly evident for N-glycoproteins in the ~52-58kDa and ~60-70kDa molecular mass ranges, likely reflects a consequence of abnormal FUT8 expression in the disorder. Dysregulated FUT8 and POFUT2 expression could potentially explain a variety of molecular abnormalities in schizophrenia.
[Mh] Termos MeSH primário: Fucosiltransferases/metabolismo
Esquizofrenia/patologia
Lobo Temporal/enzimologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Análise de Variância
Animais
Antipsicóticos/farmacologia
Diagnóstico
Feminino
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/fisiologia
Seres Humanos
Lectinas/farmacocinética
Masculino
Meia-Idade
Ratos
Ratos Sprague-Dawley
Esquizofrenia/metabolismo
Lobo Temporal/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Lectins); 0 (lectin, Aleuria aurantia); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.221 (POFUT2 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180113
[Lr] Data última revisão:
180113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  5 / 1903 MEDLINE  
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[PMID]:29176671
[Au] Autor:Schneider M; Kumar V; Nordstrøm LU; Feng L; Takeuchi H; Hao H; Luca VC; Garcia KC; Stanley P; Wu P; Haltiwanger RS
[Ad] Endereço:Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
[Ti] Título:Inhibition of Delta-induced Notch signaling using fucose analogs.
[So] Source:Nat Chem Biol;14(1):65-71, 2018 Jan.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Notch is a cell-surface receptor that controls cell-fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools that inhibit Notch activity are being developed as cancer therapeutics. To this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1.
[Mh] Termos MeSH primário: Família de Proteínas EGF/metabolismo
Fucose/análogos & derivados
Fucose/farmacologia
Fucosiltransferases/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/metabolismo
Receptores Notch/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Fucose/química
Fucose/genética
Fucosiltransferases/genética
Células HEK293
Seres Humanos
Ligantes
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EGF Family of Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Ligands); 0 (Membrane Proteins); 0 (Receptors, Notch); 0 (delta protein); 28RYY2IV3F (Fucose); EC 2.4.1.- (Fucosyltransferases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171225
[Lr] Data última revisão:
171225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2520


  6 / 1903 MEDLINE  
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Suzuki, Akemi
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[PMID]:27773703
[Au] Autor:Hirano M; Totani K; Fukuda T; Gu J; Suzuki A
[Ad] Endereço:Institute of Glycoscience, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan; Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kichijoji-kita, Musashino, Tokyo 180-8633, Japan. Electronic address: mhirano@st.seikei.ac.jp.
[Ti] Título:N-Glycoform-dependent interactions of megalin with its ligands.
[So] Source:Biochim Biophys Acta;1861(1 Pt A):3106-3118, 2017 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Megalin is a 600-kDa single-spanning transmembrane glycoprotein and functions as an endocytic receptor, distributed not only in the kidney but also in other tissues. Structurally and functionally distinct ligands for megalin have been identified. Megalin has 30 potential N-glycosylation sites in its extracellular domain. We found that megalin interacts with its ligands in a glycoform-dependent manner. METHODS: Distribution of megalin and glycans was histochemically analyzed in mouse kidneys. Kidney absorption of Cy5-labeled ligands was examined in vivo. Megalin-ligand interactions were analyzed using ligand blotting and ELISA. RESULTS: Megalins expressed on renal proximal convoluted tubules (PCTs) and proximal straight tubules (PSTs) have different N-glycans. PCT megalin stained with Lens culinaris agglutinin (LCA), which recognizes core-fucosyl N-glycans catalyzed by α1,6-fucosyltransferase (Fut8). In contrast, PST megalin stained with wheat germ agglutinin (WGA), which recognizes hybrid-type N-glycans. Retinol-binding protein-Cy5 (RBP-Cy5) was endocytosed by megalin on PCTs but minimally endocytosed by PSTs. BSA-Cy5 was endocytosed nearly equally by both tubules. The purified LCA-positive glycoform megalin had higher binding activity for RBP and vitamin D-binding protein than did WGA-positive glycoform megalin. Both glycoforms had nearly the same BSA- and kanamycin-binding activities. RBP-binding analysis of megalin lacking core fucose, in Fut8 mouse kidneys, had significantly decreased binding activity. CONCLUSIONS: N-Glycosylation of megalin can modulate its ligand-binding activity. Core fucosylation, in particular, is a modification crucial for megalin-RBP interactions. GENERAL SIGNIFICANCE: Cell type-specific glycoforms of megalin exist in the proximal tubular cells and modulate ligand absorption capacity.
[Mh] Termos MeSH primário: Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Polissacarídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Carbocianinas/metabolismo
Cromatografia de Afinidade
Feminino
Fucosiltransferases/deficiência
Fucosiltransferases/metabolismo
Glicosilação
Rim/metabolismo
Túbulos Renais Proximais/citologia
Túbulos Renais Proximais/metabolismo
Ligantes
Camundongos Endogâmicos C57BL
Camundongos Knockout
Especificidade de Órgãos
Lectinas de Plantas/metabolismo
Ligação Proteica
Proteínas de Ligação ao Retinol/metabolismo
Aglutininas do Germe de Trigo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carbocyanines); 0 (Ligands); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 0 (Plant Lectins); 0 (Polysaccharides); 0 (Retinol-Binding Proteins); 0 (Wheat Germ Agglutinins); 0 (cyanine dye 5); 0 (lentil lectin); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.68 (Glycoprotein 6-alpha-L-fucosyltransferase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171224
[Lr] Data última revisão:
171224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


  7 / 1903 MEDLINE  
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[PMID]:28988527
[Au] Autor:Kononova SV
[Ad] Endereço:Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. skonon23@gmail.com.
[Ti] Título:How Fucose of Blood Group Glycotopes Programs Human Gut Microbiota.
[So] Source:Biochemistry (Mosc);82(9):973-989, 2017 Sep.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Formation of appropriate gut microbiota is essential for human health. The first two years of life is the critical period for this process. Selection of mutualistic microorganisms of the intestinal microbiota is controlled by the FUT2 and FUT3 genes that encode fucosyltransferases, enzymes responsible for the synthesis of fucosylated glycan structures of mucins and milk oligosaccharides. In this review, the mechanisms of the selection and maintenance of intestinal microorganisms that involve fucosylated oligosaccharides of breast milk and mucins of the newborn's intestine are described. Possible reasons for the use of fucose, and not sialic acid, as the major biological signal for the selection are also discussed.
[Mh] Termos MeSH primário: Antígenos de Grupos Sanguíneos
Fucose
Microbioma Gastrointestinal
Leite Humano/química
[Mh] Termos MeSH secundário: Feminino
Fucosiltransferases/fisiologia
Seres Humanos
Lactente
Recém-Nascido
Leite Humano/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Blood Group Antigens); 28RYY2IV3F (Fucose); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.65 (3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase); EC 2.4.1.69 (galactoside 2-alpha-L-fucosyltransferase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171010
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917090012


  8 / 1903 MEDLINE  
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[PMID]:28729422
[Au] Autor:Takeuchi H; Yu H; Hao H; Takeuchi M; Ito A; Li H; Haltiwanger RS
[Ad] Endereço:From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
[Ti] Título:-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking.
[So] Source:J Biol Chem;292(38):15964-15973, 2017 Sep 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein -fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be -glycosylated by several ER-localized enzymes, including protein -glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of and in an additive manner. unfolding assays reveal that addition of -glucose or -fucose stabilizes a single EGF repeat and that addition of both -glucose and -fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full -glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that -fucose and -glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.
[Mh] Termos MeSH primário: Fator de Crescimento Epidérmico/química
Oxigênio/metabolismo
Receptores Notch/química
Receptores Notch/metabolismo
Sequências Repetitivas de Aminoácidos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Fucosiltransferases/deficiência
Fucosiltransferases/genética
Regulação da Expressão Gênica
Técnicas de Inativação de Genes
Glucose/metabolismo
Glucosiltransferases/deficiência
Glucosiltransferases/genética
Glicosilação
Células HEK293
Seres Humanos
Camundongos
Modelos Moleculares
Conformação Proteica
Transporte Proteico
Receptor Notch1/química
Receptor Notch1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Notch1); 0 (Receptors, Notch); 62229-50-9 (Epidermal Growth Factor); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.- (Glucosyltransferases); EC 2.4.1.- (POGLUT1 protein, human); EC 2.4.1.221 (polypeptide fucosyltransferase); IY9XDZ35W2 (Glucose); S88TT14065 (Oxygen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.800102


  9 / 1903 MEDLINE  
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[PMID]:28729420
[Au] Autor:Yang Q; Zhang R; Cai H; Wang LX
[Ad] Endereço:From the Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742.
[Ti] Título:Revisiting the substrate specificity of mammalian α1,6-fucosyltransferase reveals that it catalyzes core fucosylation of -glycans lacking α1,3-arm GlcNAc.
[So] Source:J Biol Chem;292(36):14796-14803, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mammalian α1,6-fucosyltransferase (FUT8) catalyzes the core fucosylation of -glycans in the biosynthesis of glycoproteins. Previously, intensive studies with crude extract or purified enzyme concluded that the attachment of a GlcNAc on the α1,3 mannose arm of -glycan is essential for FUT8-catalyzed core fucosylation. In contrast, we have recently shown that expression of erythropoietin in a GnTI knock-out, FUT8-overexpressing cell line results in the production of fully core-fucosylated glycoforms of the oligomannose substrate Man GlcNAc , suggesting that FUT8 can catalyze core fucosylation of -glycans lacking an α1,3-arm GlcNAc in cells. Here, we revisited the substrate specificity of FUT8 by examining its activity toward an array of selected -glycans, glycopeptides, and glycoproteins. Consistent with previous studies, we found that free -glycans lacking an unmasked α1,3-arm GlcNAc moiety are not FUT8 substrates. However, Man GlcNAc glycan could be efficiently core-fucosylated by FUT8 in an appropriate protein/peptide context, such as with the erythropoietin protein, a V3 polypeptide derived from HIV-1 gp120, or a simple 9-fluorenylmethyl chloroformate-protected Asn moiety. Interestingly, when placed in the V3 polypeptide context, a mature bi-antennary complex-type -glycan also could be core-fucosylated by FUT8, albeit at much lower efficiency than the Man GlcNAc peptide. This study represents the first report of FUT8-catalyzed core fucosylation of -glycans lacking the α1,3-arm GlcNAc moiety. Our results suggest that an appropriate polypeptide context or other adequate structural elements in the acceptor substrate could facilitate the core fucosylation by FUT8.
[Mh] Termos MeSH primário: Acetilglucosamina/deficiência
Biocatálise
Fucosiltransferases/metabolismo
Polissacarídeos/química
Polissacarídeos/metabolismo
[Mh] Termos MeSH secundário: Adipogenia
Configuração de Carboidratos
Glicosilação
Células HEK293
Seres Humanos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polysaccharides); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.68 (Glycoprotein 6-alpha-L-fucosyltransferase); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.804070


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[PMID]:28718379
[Au] Autor:Picot T; Aanei CM; Fayard A; Flandrin-Gresta P; Tondeur S; Gouttenoire M; Tavernier-Tardy E; Wattel E; Guyotat D; Campos L
[Ad] Endereço:1 Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint-Etienne, France.
[Ti] Título:Expression of embryonic stem cell markers in acute myeloid leukemia.
[So] Source:Tumour Biol;39(7):1010428317716629, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34 CD38 and CD34 CD38 ) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34 CD38 than in CD34 CD38 subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/biossíntese
Fucosiltransferases/biossíntese
Leucemia Mieloide Aguda/tratamento farmacológico
Antígeno Lewis X/biossíntese
Fator 3 de Transcrição de Octâmero/biossíntese
Fatores de Transcrição SOXB1/biossíntese
[Mh] Termos MeSH secundário: ADP-Ribosil Ciclase 1/genética
Adulto
Idoso
Antígenos CD34/genética
Células da Medula Óssea/metabolismo
Diferenciação Celular/genética
Células-Tronco Embrionárias/metabolismo
Células-Tronco Embrionárias/patologia
Feminino
Citometria de Fluxo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células-Tronco Hematopoéticas/efeitos dos fármacos
Células-Tronco Hematopoéticas/patologia
Seres Humanos
Imunofenotipagem
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/patologia
Masculino
Meia-Idade
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD34); 0 (Biomarkers, Tumor); 0 (Lewis X Antigen); 0 (Octamer Transcription Factor-3); 0 (POU5F1 protein, human); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors); EC 2.4.1.- (FUT4 protein, human); EC 2.4.1.- (Fucosyltransferases); EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317716629



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