Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.99.7 (sialyltransferase)
1,534 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian cDNA encoding alpha (1,3)-fucosyltransferase (alpha (1,3)Fuc-T) termed ELAM-1 ligand fucosyltransferase (ELFT) or Fuc-TIV was previously cloned by three groups who reported different results from transfection studies Goelz et al. (Goelz, S. E., Hession, C., Goff, D., Griffiths, B., Tizard, R., Newman, B., Chi-Rosso, G., and Lobb, R. (1990) Cell 63, 1349-1356) found that Chinese hamster ovary (CHO) cells expressing the ELFT cDNA had alpha (1,3)Fuc-T activity and were able to bind to E-selectin. In contrast, Lowe et al. (Lowe, J. B., Kukowska-Latallo, J. F., Nair, R. P., Larsen, R. D., Marks, R. M., Macher, B. A., Kelly, R. J., and Ernst, L. K. (1991) J. Biol. Chem. 266, 17467-17477) and Kumar et al. (Kumar, R., Potvin, B., Muller, W. A., and Stanley, P. (1991) J. Biol. Chem. 266, 21777-21783) found no binding to E-selectin of CHO transfectants expressing the same alpha (1,3)Fuc-T gene; nor did the latter transfectants synthesize a known E-selectin ligand, sialylated Lex (SLex), although they had substantial alpha (1,3)Fuc-T activity. We now show that these discrepant results were due to a difference between the parental CHO cell lines. Following transfection of ELFT cDNA into Pro-5 or dihydrofolate reductase (DHFR)- CHO cells, only the DHFR- transfectants expressed SLex and bound to E-selectin. Indirect evidence from monoclonal antibody and lectin binding studies indicates that the range of carbohydrate structures synthesized by the Pro-5 and DHFR- CHO cell lines differs. Since DHFR-/ELFT transfectants expressed cell surface SLex but transferred fucose poorly to sialylated substrates in vitro, ELFT may be able to fucosylate a complex carbohydrate missing from Pro-5 cells. Alternatively, either CHO line may have an activity (such as an alpha (2,3)-sialyltransferase), that modifies alpha (1,3)-fucosylated lactosamines.
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PMID:Differential expression of an E-selectin ligand (SLex) by two Chinese hamster ovary cell lines transfected with the same alpha (1,3)-fucosyltransferase gene (ELFT). 750 3

Sialyl Lewis a/sialyl Lewis x antigens, which panels of monoclonal antibodies can recognize, are synthesized by a series of glycosyltransferases. Especially, alpha (1,3)/(1,4) fucosyltransferases and/or alpha(2,3)sialyltransferases regulate expression patterns temporally and spatially, such as in epithelium of digestive systems or in leukocytes. The carbohydrate ligands of P-selectin and E-selectin have been identified as sialyl Lewis x expressed on granulocytes, monocytes, and natural killer cells. Expression of sialyl Lewis x on these cells is mainly determined by Fuc-TVII, but as for the counterparts of sialyl-transferases, there remains much uncertainty. P-selectin-dependent adhesion of tumor cells and E-selectin-dependent adhesion of tumor cells to endothelial cells play some role for tumor cell aggregation leading to microembolism and hematogenous metastasis of cancers. We have found expression of some fucosyltransferases (Fuc-TIII, VI, VII) and a sialyltransferase (ST3O) are increased in colon cancer tissues coincidentally with sialyl Lewis a antigens, with which E-selectin can interact. As already started in many laboratories, genetic manipulation of glycosylation pathways in gene-targeted animals has an outstanding potential to yield clues to oligosaccharide function.
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PMID:[Structures, synthesis and functions of sialyl Le(a)/sialyl Le(x) antigens]. 763 14

Sialyl-Lewisx (NeuAc alpha 2-->3Gal beta 1-->4[Fuc alpha 1-->3]GlcNAc] has been identified as a ligand for E-selectin, P-selectin and recently also for L-selectin. We have synthesized the sialyl-Lewisx tetrasaccharide by total enzymatic synthesis from N-acetyllactosamine using a placental alpha 2-->3-sialyltransferase specific for type-2 chain acceptors, followed by a cloned human alpha 1-->3-fucosyltransferase (FucTV, the 'plasma-type' enzyme). This procedure resulted in the tetrasaccharide in a 61% overall yield.
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PMID:Efficient enzymatic synthesis of the sialyl-Lewisx tetrasaccharide. A ligand for selectin-type adhesion molecules. 769 Jul 13

Sialic acids decorating blood and cell surface proteins can play important roles in various biological processes. The inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1, as well as bacterial lipopolysaccharide, can activate vascular endothelium, increasing expression of several surface glycoproteins. Here we show that treatment of cultured human endothelial cells (HEC) with TNF-alpha, interleukin-1, or lipopolysaccharide causes increased expression of the enzyme beta-galactoside alpha-2,6-sialytransferase (alpha 2-6STN). TNF-alpha was most effective, inducing a 3.5-fold enhancement of cell-associated sialytransferase activity by 72 h. In addition, activated HEC secreted a large portion of the induced sialyltransferase activity into the medium. Analysis of labeled HEC showed both a relative and an absolute increase of alpha 2,6-linked sialic acid on N-linked oligosaccharides after TNF-alpha stimulation. This coincided with increased expression of endothelial glycoproteins bearing N-linked glycans with alpha 2,6-linked sialic acid detected by the lectin Sambucus nigra agglutinin. The cytokine-inducible endothelial cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 are among these glycoprotein substrates for alpha 2-6STN. These changes also correlated with a substantial increase in binding sites for CD22 beta, a mammalian lectin known to recognize oligosaccharides carrying multiple copies of alpha 2,6-linked sialic acid. Northern analysis revealed increased levels of mRNA encoding alpha 2-6STN. Thus, activation of endothelial cells during inflammatory and immunological processes may induce alpha 2-6STN, which can participate in sialylation of other activation-dependent molecules.
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PMID:Cytokine-induced beta-galactoside alpha-2,6-sialyltransferase in human endothelial cells mediates alpha 2,6-sialylation of adhesion molecules and CD22 ligands. 814 53

The adhesion of circulating cancer cells to vascular endothelium is an important step in the hematogenous metastasis of cancer. Until recently, it has been believed that carbohydrate antigens are expressed on cancer cells, and E-selectin is expressed on endothelial cells to effect this adhesion. We investigated the gene expression of fucosyl-transferase (Fuc-T) and sialyltransferase (ST), which are involved in the synthesis of sialyl Lewisx (s-Lex) in breast cancer by using Northern blot analysis. The concentration of s-Lex in the cancerous portion was increased, compared to that in the adjacent non-cancerous portion. A correlation was found between the concentration of s-Lex and the amount of Fuc-T VI message in 9 cases of breast cancer tissue. Expression of the Fuc-T III message was found in only one case who expressed s-Lea. No expression of the Fuc-T V or VII message was observed. There was no relationship between the concentration of s-Lex and the amount of ST3N and ST4 transcripts. Similar findings were obtained from an analysis using cell lines derived from human breast cancer. When Fuc-T VI gene was transfected to MCF-7 cells, the expression of s-Lex was markedly induced on MCF-7 cells, and the attachment of cancer cells to endothelial cells was enhanced. These findings suggest that Fuc-T VI is chiefly involved in the synthesis of s-Lex on breast cancer cells.
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PMID:Gene expression of fucosyl- and sialyl-transferases which synthesize sialyl Lewisx, the carbohydrate ligands for E-selectin, in human breast cancer. 953 43

Sialyl-Lex (sLex) antigen expression recognized by KM93 monoclonal antibody was significantly down-regulated during differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human pre-B lymphocytic leukemia cell line KM3. The sLex determinants were almost exclusively expressed on O-linked oligosaccharide chains of an O-glycosylated 150-kDa glycoprotein (gp150). A low shear force cell adhesion assay showed that TPA treatment significantly inhibited E-selectin-mediated cell adhesion. Transcript and/or enzyme activity levels of alpha1-->3-fucosyltransferase, alpha2-->3-sialyltransferase, beta1-->4-galactosyltransferase, and elongation beta1-->3-N-acetylglucosaminyltransferase did not correlate with sLex expression levels. However, transcript and enzyme activity levels of core 2 GlcNAc-transferase (C2GnT) were significantly down-regulated during TPA treatment. Following transfection and constitutive expression of full-length exogenous C2GnT transcript, C2GnT enzyme activities were maintained at high levels even after TPA treatment and down-regulation of cell surface sLex antigen expression by TPA was completely abolished. Furthermore, in the transfected cells, the KM93 reactivity of gp150 was not reduced by TPA treatment, and the inhibition of cell adhesion by TPA was also blocked. These results suggest that sLex expression is critically regulated by a single glycosyltransferase, C2GnT, during differentiation of KM3 cells.
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PMID:Single glycosyltransferase, core 2 beta1-->6-N-acetylglucosaminyltransferase, regulates cell surface sialyl-Lex expression level in human pre-B lymphocytic leukemia cell line KM3 treated with phorbolester. 975 22

E-selectin is a cytokine-inducible, calcium-dependent endothelial cell adhesion molecule that plays a critical role in the leucocyte-endothelium interaction during inflammation and is thought to contribute to the metastatic dissemination of tumour cells. Like the other selectins, E-selectin binds to ligands carrying the tetrasaccharide sialyl-Lewis x (NeuAcalpha2,3Galbeta1,4[Fucalpha1, 3]GlcNAc)1 or its isomer sialyl-Lewis a (NeuAcalpha2, 3Galbeta1, 3[Fucalpha1,4]GlcNAc). We examined the effect of expressing the H-type alpha(1,2)-fucosyltransferase or the alpha(2, 6)-sialyltransferase on the synthesis of sialyl-Lewis x by alpha(1, 3)fucosyltransferase. We found that H-type alpha(1, 2)-fucosyltransferase but not alpha(2,6)-sialyltransferase, strongly inhibited sialyl-Lewis x expression and E-selectin adhesion. We assume that H-type alpha(1,2)-fucosyltransferase competes with the endogenous alpha(2,3)-sialyltransferase for the N-acetyllactosamine structures assigned to further serve as acceptors for alpha(1, 3)fucosyltransferase.
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PMID:alpha(1,2)-fucosylation prevents sialyl Lewis x expression and E-selectin-mediated adhesion of fucosyltransferase VII-transfected cells. 1060 50

The expression of alpha(1,2) fucosyltransferases that catalyze the fucose transfer to galactose of the N-acetyl(iso)lactosamine chain is decreased in human metastatic pancreatic cancer cells. alpha(2,3) Sialyltransferases catalyze the transfer of sialic acid to the same substrate to form, with alpha(1,3/1,4) fucosyltransferases, sialyl-Lewis a and sialyl-Lewis x determinants on cell surface that are involved in pancreatic metastatic invasion. The aim of this study was to determine whether this decrease of alpha(1,2) fucosyltransferase expression can favor the alpha(2,3) sialyltransferase activity to form metastatic sialyl-Lewis antigens. Restoration of alpha(1,2) fucosyltransferase activity in the human pancreatic cancer cell line BxPC-3 was obtained by selecting stable transfectants expressing FUT1. Overexpression of FUTI in BxPC-3 cells resulted in a substantial reduction of sialyl-Lewis antigen expression that correlated with an increase of expression of Lewis y and H-type antigens on cell surface. The modified oligosaccharide structures were preferentially restricted to three major glycoproteins, which could in part be related to mucin-type glycoproteins. The reduction of sialyl-Lewis antigen expression was associated with an inhibition of adhesive properties to E-selectin and a decrease of gastrointestinal metastatic power of BxPC-3 cells after xenograft transplantation into nude mice. This study provides evidence that the expression level of alpha(1,2) fucosyltransferase may regulate the expression of sialyl-Lewis a and sialyl-Lewis x antigens and consequently could play an important role in metastatic properties of human pancreatic cancer cells.
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PMID:Restoration of alpha(1,2) fucosyltransferase activity decreases adhesive and metastatic properties of human pancreatic cancer cells. 1072 12

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.
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PMID:Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates. 1514 Oct 79

Recombinant soluble human complement receptor type 1 (sCR1) is a highly glycosylated glycoprotein intended for use as a drug to treat ischemia-reperfusion injury and other complement-mediated diseases and injuries. sCR1-sLe(x) produced in the FT-VI-expressing mutant CHO cell line LEC11 exists as a heterogeneous mixture of glycoforms, a fraction of which include structures with one or more antennae terminated by the sialyl Lewis X (sLe(x)) [Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc]) epitope. Such multivalent presentation of sLe(x) was shown previously to effectively target sCR1 to activated endothelial cells expressing E-selectin. Here, we describe the use of the soluble, recombinant alpha2-3 sialyltransferase ST3Gal-III and the alpha1-3 fucosyltransferase FT-VI in vitro to introduce sLe(x) moieties onto the N-glycan chains of sCR1 overexpressed in standard CHO cell lines. The product (sCR1-S/F) of these in vitro enzymatic glycan remodeling reactions performed at the 10-g scale has approximately 14 N-glycan chains per sCR1 molecule, comprised of biantennary (90%), triantennary (8.5%), and tetraantennary (1.5%) structures, nearly all of whose antennae terminate with sLe(x) moieties. sCR1-S/F retained complement inhibitory activity and, in comparison with sCR1-sLe(x) produced in the LEC11 cell line, contained twice the number of sLe(x) moieties per mole glycoprotein, exhibited a twofold increase in area under the intravenous clearance curve in a rat pharmacokinetic model, and exhibited a 10-fold increase in affinity for E-selectin in an in vitro binding assay. These results demonstrate that in vitro glycosylation of the sCR1 drug product reduces heterogeneity of the glycan profile, improves pharmacokinetics, and enhances carbohydrate-mediated binding to E-selectin.
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PMID:Production of a complement inhibitor possessing sialyl Lewis X moieties by in vitro glycosylation technology. 1519 8


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