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Glycobiology Advance Access published online on July 21, 2006
Glycobiology, doi:10.1093/glycob/cwl023
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received June 1, 2006
Revised July 3, 2006
Accepted July 10, 2006

Article

Down regulation of trypsinogen expression is associated with growth retardation in {alpha}1,6-fucosyltransferase-deficient mice: attenuation of proteinase-activated receptor 2 activity

Wenzhe Li 1 a, Takatoshi Nakagawa 2 a, Nobuto Koyama 3 a, Xiangchun Wang 4, Jinhua Jin 4, Yoko Mizuno-Horikawa 4, Jianguo Gu 5, Eiji Miyoshi 5, Ikunoshin Kato 6, Koichi Honke 7, Naoyuki Taniguchi 8, and Akihiro Kondo 9 *

1 Department of Glycotherapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; the 21st century COE program
2 Department of Glycotherapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; CREST
3 Takara Bio Inc., Shiga 520-2193, Japan; CREST
4 Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
5 Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; CREST
6 Takara Bio Inc., Shiga 520-2193, Japan
7 Department of Molecular Genetics, Kochi University Graduate School of Medicine, Kochi 783-8505, Japan
8 Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; the 21st century COE program
9 Department of Glycotherapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; CREST; the 21st century COE program

* To whom correspondence should be addressed.
Akihiro Kondo, E-mail: kondoa{at}glycot.med.osaka-u.ac.jp


  Abstract

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) using a cDNA microarray. The DNA microarray and real-time 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 growth rate decreased, 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 were significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between Fut8 and the regulation of 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.

Keywords: {alpha}1,6-fucosyltransferase/cell growth/FUT8 knockdown cell/PAR-2 /trypsinogen.

a W. Li, T. Nakagawa and N. Koyama contributed equally to this work.


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