Sialyl Lewis x and sialyl Lewis a are oncodevelopmental antigens involved in the pathogenesis of colon adenocarcinoma. Biosynthesis of these glycans is controlled by alpha(1,3/1,4)fucosyltransferases. We report the disruption of sialyl Lewis x/a biosynthesis and inhibition of colon carcinoma cell proliferation by stable transfection of antisense sequences directed at the human Lewis alpha(1,3/1,4)fucosyltransferase gene, FUT3, and the plasma alpha(1,3)fucosyltransferase gene, FUT6. COLO-205 cells expressed high levels of sialyl Lewis x/a, alpha(1,3)fucosyltransferase activity, and FUT3/6 transcripts, but COLO205-derived antisense transfectant cell lines AS5C and AS7A did not. Sense transfectant S6G expressed higher levels of fucosyltransferase than parental COLO-205. Cellular proliferation assays showed marked correlative decreases in the growth of antisense lines and, conversely, increased growth of sense transfectants. Subcutaneous tumors created by injection of nude mice with antisense transfectant cell lines grew more slowly than those arising from control COLO-205 and sense transfectants. These results provide target validation for inhibition of carcinoma proliferation with antisense sequences directed at human fucosyltransferases.
. Salomaa V, Pankow J, Heiss G, Cakir B, Eckfeldt JH, Ellison RC, Myers RH, Hiller KM, Brantley KR, Morris TL, Weston BW (National Public Health Institute, Helsinki, Finland, University of North Carolina, University of Minnesota, Boston University School of Medicine, USA). Genetic background of Lewis negative blood group phenotype and its association with atherosclerotic disease in the NHLBI Family Heart Study, J Intern Med 2000; 247: 689–698. Objectives. To examine the prevalence of four mutations, T59G, T1067A, T202C and C314T, of the human α(1,3/1,4) fucosyltransferase 3 (FUT 3) gene amongst persons with Lewis negative and those with Lewis positive blood group phenotype. An additional objective was to explore the hypothesis that these mutations are associated with coronary heart disease and inflammatory reaction. Design. A population‐based cross‐sectional study. Setting. Analysis of samples and data from the National Heart Lung and Blood Institute Family Heart Study. Subjects. All Lewis (a–b–) participants (n = 136) and a sample of Lewis positive participants (n = 136) of the Family Heart Study; all were of Caucasian ethnicity. Main outcome measures. The prevalence of examined mutations by Lewis phenotype. Results. The examined mutations were common and strongly associated with the Lewis (a–b–) phenotype. Accordingly, 90–95% of Lewis (a–b–) individuals amongst Caucasians can be identified by screening for these four mutations. Exploratory analyses suggested that with the exception of T59G, all examined mutations were positively associated with prevalent coronary heart disease, although not statistically significantly, perhaps due to the small number of prevalent coronary heart disease cases. C‐reactive protein tended to be higher amongst persons with a TC or CC genotype at position 202 (3.07 ± 0.41 vs. 2.08 ± 0.32 mg L–1, P = 0.06). Conclusions. Four specific mutations of fucosyltransferase 3 gene are responsible for the vast majority of Lewis (a–b–) phenotypes in Caucasians. These mutations are common in the population at large and may be associated with increased risk of coronary heart disease. Further studies using larger samples are warranted.
The objective of the study was to examine the prevalence and distribution of four major single nucleotide polymorphisms (SNPs) (T59G, T1067G, T202C, and C314T) of the Lewis ( FUT3)gene in a biethnic United States population. This population-based cross-sectional study was based on data from the Atherosclerosis Risk in Communities (ARIC) Study, which included 761 males and females aged 45-64 years, who had no known/detected clinical atherosclerotic disease (577 Caucasians, 184 African Americans). The main outcome measures were prevalence of the Lewis genotype and allele frequencies for four SNPs of the FUT3gene. The most common genotype was the "wild type" at all four nucleotide positions ( WWWW), which was found to be present in 46.9% of ARIC participants. At least one mutant allele was detected in 51.7% of Caucasians, and 56.7% of African Americans ( P=0.59). The frequencies of mutant alleles ranged from 6.3% to 18.4% at the four FUT3gene sites examined. The distribution of the Lewis genotype and allele frequencies differed significantly by ethnicity at sites 59, 202, and 314. The prevalence of the Lewis genotype suggesting a lack of alpha(1,3/1,4) fucosyltransferase activity was 11.6% in Caucasians and 9.9% in African Americans ( P=0.67). Four specific SNPs of the Lewis genotype are common in the population at large. However, these four SNPs seem to fail to explain the majority of Lewis-negative phenotype in African Americans, given that Lewis-negative genotype prevalence was about one-third of what was expected. Use of rapid DNA sequencing and simultaneous Lewis phenotype determination could avoid the problems associated with haplotype determination and Lewis genotype grouping. Further studies testing SNPs of the Lewisgene are warranted, in particular among African Americans.
The initial steps of leukocyte adhesion depend on selectin/ligand interactions. Surface ligands on leukocytes are often modified by addition of the sialyl Lewis x (CD15s) determinant. Biosynthesis of CD15s is dependent upon α(2,3)sialyltransferases and α(1,3)fucosyltransferases. We report the isolation of an HL60 cell line variant, HL60A2, that no longer expresses CD15s. HL60A2 cells do not adhere to cytokine‐stimulated endothelial cells. Enzymatic assays reveal that this cell line has normal α(2,3)sialyltransferase activity but is deficient in the α(1,3)fucosyltransferase responsible for biosynthesis of CD15s (FUT7). The fucosyltransferase that constructs the non‐sialylated antigen, Lewis x (CD15), is expressed at high levels (FUT4). Transcript analyses show that FUT7 and FUT4 are inversely expressed in HL60 and variant cell lines. HL60A2 cells provide a tool to study the regulation of selectin ligands and corresponding human fucosyltransferase genes.
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