Journal of Biochemistry Advance Access published online on January 29, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp022
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Requirement of Fut8 for the expression of vascular endothelial growth factor receptor-2: a new mechanism for the emphysema-like changes observed in Fut8-deficient mice
From the 1Department of Disease Glycomics, Institute for Microbial Diseases, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 Japan; 2Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsusima, Aobaku, Sendai, Miyagi 981-8558 Japan; 3Department of Glycotherapeutics, Osaka University Graduate School of Medicine, B1, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; 4Key Laboratory of Bio-organic Chemistry, College of Bioengineering, Dalian University, Dalian 116622, China; 5Department of Molecular Biochemistry and Clinical Investigation, Division of Health Science, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871 Japan; 6Systems Glycobiology Group, Disease Glycomics Team, RIKEN, Wako 351-0198, Japan
*To whom correspondence should be addressed: Department of Disease Glycomics, Institute for Microbial Diseases, Osaka University, 4th Floor, Center for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka Suita, Osaka 565-0871, Japan; E-mail: tani52{at}wd5.so-net.ne.jp; or Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aobaku, Sendai, Miyagi 981-8558, Japan Tel: 81-22-727-0216; Fax: 81-22-727-0078; E-mail: jgu{at}tohoku-pharm.ac.jp
Received November 26, 2008; Accepted January 22, 2009
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Abstract |
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1,6-Fucosylation plays key roles in many biological functions, as evidenced by the study of 1,6-fucosyltransferase (Fut8)-knockout (Fut8-/-) mice. Phenotypically, Fut8-/- mice exhibit emphysema-like changes in the lung, and severe growth retardation. Fut8-/- cells also show marked dysregulation of the TGF-β1 receptor, EGF receptor, integrin activation and intracellular signaling, all of which can be rescued by reintroduction of Fut8. The results of the present study demonstrated that vascular endothelial growth factor receptor-2 (VEGFR-2) expression was significantly suppressed in Fut8-/- mice, suggesting that Fut8 was required for VEGFR-2 expression. The expression of VEGFR-2 mRNA and protein was consistently down regulated by knockdown of the Fut8 gene with small interference RNA in A549 cells, as well as in TPG49 cells, suggesting that suppression occurs at the level of transcription. In contrast, the expression level of ceramide, an inducer of cell apoptosis, was increased in the lungs of Fut8-/- mice. The terminal transferase dUTP nick end-labeling (TUNEL) assay was used to identify apoptotic cells. The number of TUNEL-positive septal epithelia and endothelia cells was significantly increased in the alveolar septa of lungs from Fut8-/- mice when in comparison with lungs from wild type mice. It is well known that, in emphysema, ceramide expression can be greatly enhanced by blockade of the VEGFR-2. Thus, suppression of VEGFR-2 expression may provide a novel explanation for the emphysema-like changes in Fut8-/- mice.
Key Words: apoptosis, emphysema, fucosylation, Fut8, VEGFR-2 expression