Glycobiology Advance Access originally published online on July 21, 2006
Glycobiology 2006 16(10):1007-1019; doi:10.1093/glycob/cwl023
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Down-regulation of trypsinogen expression is associated with growth retardation in 
1,6-fucosyltransferase-deficient mice: attenuation of proteinase-activated receptor 2 activity
3 Department of Glycotherapeutics, 4 Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871; 5 Takara Bio Inc., Shiga 520-2193; 6 Department of Molecular Genetics, Kochi University Graduate School of Medicine, Kochi 783-8505, Japan; 7 CREST, JST, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012; and 8 the 21st century COE program, Ministry of Education, Culture, Sports, Science and Technology, 2-5-1 Marunouchi, Chiyoda-ku, Tokyo 100-8959, Japan
2 To whom correspondence should be addressed; e-mail:kondoa{at}glycot.med.osaka-u.ac.jp
Received on June 1, 2006; revised on July 3, 2006; accepted on July 10, 2006
Alpha1,6-fucosyltransferase (Fut8) plays important roles in physiological and pathological conditions. Fut8-deficient (Fut8–/–) mice exhibit growth retardation, earlier postnatal death, and emphysema-like phenotype. To investigate the underlying molecular mechanism by which growth retardation occurs, we examined the mRNA expression levels of Fut8–/– embryos (18.5 days postcoitum [dpc]) using a cDNA microarray. The DNA microarray and real-time polymerase chain reaction (PCR) analysis showed that a group of genes, including trypsinogens 4, 7, 8, 11, 16, and 20, were down-regulated in Fut8–/– embryos. Consistently, the expression of trypsinogen proteins was found to be lower in Fut8–/– mice in the duodenum, small intestine, and pancreas. Trypsin, an active form of trypsinogen, regulates cell growth through a G-protein-coupled receptor, the proteinase-activated receptor 2 (PAR-2). In a cell culture system, a Fut8 knockdown mouse pancreatic acinar cell carcinoma, TGP49-Fut8-KDs, showed decreased growth rate, similar to that seen in Fut8–/– mice, and the decreased growth rate was rescued by the application of the PAR-2-activating peptide (SLIGRL-NH2). Moreover, epidermal growth factor (EGF)-induced receptor phosphorylation was attenuated in TGP49-Fut8-KDs, which was highly associated with a reduction of trypsinogens mRNA levels. The addition of exogenous EGF recovered c-fos, c-jun, and trypsinogen mRNA expression in TGP49-Fut8-KDs. Again, the EGF-induced up-regulation of c-fos and c-jun mRNA expression was significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between Fut8 and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathway in controlling cell growth and that the EGFR-trypsin-PAR-2 pathway is suppressed in TGP49-Fut8-KDs as well as in Fut8–/– mice.
Key words:
cell growth
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FUT8 knockdown cell
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PAR-2
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trypsinogen
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1,6-fucosyltransferase
1 These authors contributed equally to the work.
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