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Glycobiology Advance Access first published online on July 21, 2006
This version published online on August 4, 2006
Glycobiology, doi:10.1093/glycob/cwl023
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© 2006 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited
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.

The copyright line has been corrected.


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