The core fucosylation (␣1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated ␣1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that Fut8 ؊/؊ mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8 ؊/؊ mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-␤1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, Fut8 ؊/؊ mice have a marked dysregulation of TGF-␤1 receptor activation and signaling, as assessed by TGF-␤1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-␤1 receptor defects found in Fut8 ؊/؊ cells can be rescued by reintroducing Fut8 into Fut8 ؊/؊ cells. Furthermore, exogenous TGF-␤1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8 ؊/؊ lung. We propose that the lack of core fucosylation of TGF-␤1 receptors is crucial for a developmental and progressive͞ destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.fucosylation ͉ glycobiology ͉ matrix metalloproteinase

G lycans include oligosaccharides (short carbohydrate chains) and large complex molecules, i.e. complex carbohydrates such as glycoproteins, glycolipids, and proteoglycans. Glycans are mostly found on the cell surface and extracellular matrix (ECM), and also in various organellae such as Golgi, ER, lysosome, cytosol, and nuclei. As compared to research on DNA, RNA, and proteins, studies on glycans are technically difficult and research in this field has been not emphasized for a long period; the same is true for glycomics as compared to proteomic research. In order to characterize the structures of glycans, glycobiology including glycomics is essential for understanding of the structures and functions of proteins.Among the various post-translational modification reactions involving proteins, glycosylation is the most common; nearly 50% of all proteins are thought to be glycosylated.(1) Glycosylation reactions are catalyzed by the actions of glycosyltransferases, sugar chains being added to various complex carbohydrates. In the last couple of years most glycosyltransferases (over 180 glycosyltransferase genes) have been identified, based on the genome sequence data bases and bioinformatics approach. (4-8) Cell surface carbohydrates are involved in a variety of interactions between a cell and its extracellular environment, since they are located on the outermost layer of the cell; carbohydrates are the first molecules to be encountered and recognized by other cells, antibodies, invading viruses, and bacteria. Many secreted molecules such as hormones and toxins have also been reported to bind to carbohydrate receptors on the cell surface. In addition, most receptors on the cell surface are N-glycosylated, including epithelial growth factor receptor (EGFR), integrins, and transforming growth factor β receptor (TGFβR). Modified oligosaccharides affect protein folding and stability, and have the ability to interfere with carbohydrate-carbohydrate, carbohydrate-protein, and glycoprotein-glycoprotein interactions, and as a result, regulate many physiological and pathological events, including cell growth, migration, differentiation, and tumor invasion, and host-pathogen interactions, cell trafficking, and transmembrane signaling. Therefore, it is not surprising that aberrant glycosylation patterns can serve as markers for certain disease states including cancer metastasis, development, and differentiation. (9) In this review, we mainly focus on the modification of N-glycans of receptors on the cell surface to further address the important roles of N-glycans in cancer science. Important functions of N-acetylglucosaminyltransferasesGnT-V. N-Acetylglucosaminyltransferase V (GnT-V) (10)(11)(12) has been thought to have a close relationship with cancer metastasis. (13,14) GnT-V catalyzes the formation of β1,6 GlcNAc branching structures, which play important roles in tumor metastasis (Fig. 1).(15) GnT-V deficient mice were generated to assess the functions of GnT-V products in normal development and cancer progression.(16) T...

Disruption of the circadian rhythm is a contributory factor to clinical and pathophysiological conditions, including cancer, the metabolic syndrome, and inflammation. Chronic and systemic inflammation are a potential trigger of type 2 diabetes and cardiovascular disease and are caused by the infiltration of large numbers of inflammatory macrophages into tissue. Although recent studies identified the circadian clock gene Rev-erbα, a member of the orphan nuclear receptors, as a key mediator between clockwork and inflammation, the molecular mechanism remains unknown. In this study, we demonstrate that Rev-erbα modulates the inflammatory function of macrophages through the direct regulation of Ccl2 expression. Clinical conditions associated with chronic and systemic inflammation, such as aging or obesity, dampened Rev-erbα gene expression in peritoneal macrophages from C57BL/6J mice. Rev-erbα agonists or overexpression of Rev-erbα in the murine macrophage cell line RAW264 suppressed the induction of Ccl2 following an LPS endotoxin challenge. We discovered that Rev-erbα represses Ccl2 expression directly through a Rev-erbα–binding motif in the Ccl2 promoter region. Rev-erbα also suppressed CCL2-activated signals, ERK and p38, which was recovered by the addition of exogenous CCL2. Further, Rev-erbα impaired cell adhesion and migration, which are inflammatory responses activated through the ERK- and p38-signaling pathways, respectively. Peritoneal macrophages from mice lacking Rev-erbα display increases in Ccl2 expression. These data suggest that Rev-erbα regulates the inflammatory infiltration of macrophages through the suppression of Ccl2 expression. Therefore, Rev-erbα may be a key link between aging- or obesity-associated impairment of clockwork and inflammation.

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