title: α-1,6-Fucosyltransferase (FUT8) inhibits hemoglobin production during differentiation of murine and K562 human erythroleukemia cells.
abstract: Erythropoiesis results from a complex combination of the expression of several transcription factor genes and cytokine signaling. However, the overall view of erythroid differentiation remains unclear. First, we screened for erythroid differentiation-related genes by comparing the expression profiles of high differentiation-inducible and low differentiation-inducible murine erythroleukemia cells. We identified that overexpression of α-1,6-fucosyltransferase (Fut8) inhibits hemoglobin production. FUT8 catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an α-1,6 linkage, leading to core fucosylation in mammals. Expression of Fut8 was down-regulated during chemically induced differentiation of murine erythroleukemia cells. Additionally, expression of Fut8 was positively regulated by c-Myc and c-Myb, which are known as suppressors of erythroid differentiation. Second, we found that FUT8 is the only fucosyltransferase family member that inhibits hemoglobin production. Functional analysis of FUT8 revealed that the donor substrate-binding domain and a flexible loop play essential roles in inhibition of hemoglobin production. This result clearly demonstrates that core fucosylation inhibits hemoglobin production. Third, FUT8 also inhibited hemoglobin production of human erythroleukemia K562 cells. Finally, a short hairpin RNA study showed that FUT8 down-regulation induced hemoglobin production and increase of transferrin receptor/glycophorin A-positive cells in human erythroleukemia K562 cells. Our findings define FUT8 as a novel factor for hemoglobin production and demonstrate that core fucosylation plays an important role in erythroid differentiation.
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Takanori
authors.initials: T
authors.lastname: Toda
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mawatari
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Rika
authors.initials: R
authors.lastname: Takaesu
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Wada
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585.
authors.forename: Dai
authors.initials: D
authors.lastname: Kato
authors.affiliation: Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101; Bio Matrix Research Inc., Chiba 270-0101, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Utsugi
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585.
authors.forename: Masaya
authors.initials: M
authors.lastname: Ohtsu
authors.affiliation: Faculty of Industrial Science and Technology, Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585; Genome and Drug Research Center, Tokyo University of Science, Chiba 270-0101; Bio Matrix Research Inc., Chiba 270-0101, Japan. Electronic address: yasufumi@rs.noda.tus.ac.jp.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D002454:Cell Differentiation; D005643:Fucose / Q000235:genetics / Q000378:metabolism; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006021:Glycophorins / Q000235:genetics / Q000378:metabolism; D006454:Hemoglobins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology*; D051379:Mice; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D006021:Glycophorins; D006454:Hemoglobins; C489427:MYC protein, human; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase
keywords: Erythropoeisis; Functional Genomics; Glycosyltransferases; Hemoglobin; Transcriptomics