Glycobiology Advance Access published online on February 22, 2007
Glycobiology, doi:10.1093/glycob/cwm020
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Cell Growth Arrest by Sialic Acid Clusters in Ganglioside GM3 Mimetic Polymers
2 Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
3 Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), 4-1-8, Honcho Kawaguchi, Saitama, 332-0012, Japan
4 Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan
5 Laboratory of Bio-Macromolecular Chemistry, Division of Biological Science, Graduate School of Science, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-jo, Nishi 11-choume, Kita-ku, Sapporo 001-0021, Japan
6 Research Center of Glycoscience, National Institute of Advanced Industrial Science and Technology, Sapporo 062-8517. Japan
7 Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Science, Hokkaido University, Kita 21-jo, Nishi 11- choume, Kita-ku, Sapporo 001-0021, Japan
1 To whom correspondence should be addressed to; Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan, Tel: +81-22-727-0116; Fax: +81-22-727-0076; E-mail: jin{at}tohoku-pharm.ac.jp
Received on August 2, 2006; revised on February 8, 2007; accepted on February 19, 2007
Ganglioside GM3, one of the sialic acid containing glycosphingolipids, is known to form clusters in lipid microdomains, which serve as platforms for effective signal transduction. In attempt to clarify the GM3 cluster effect, we enzymatically synthesized GM3 mimetic polymer (GM3-p), with an acrylamide backbone from LacCer mimetic polymer (LacCer-p). Interestingly, GM3-p, but not LacCer-p, reversibly inhibited proliferation of NIH3T3 cells, which are normally resistant to exogenously added GM3. Moreover, we found that the introduction of carbonic acid into the acrylamide chain aided well-oriented cluster formation and enhanced the inhibitory effect of GM3-p. Since sialyllactosyl polymer and GM4 mimetic polymer, but not GM2 mimetic polymer, also inhibited cell proliferation, sialic acid-galactose units must be essential for the biological activity of GM3-p. These results suggest that the formation of sialic acid-galactose clusters is necessary for the suppressive effect of GM3-p. GM3-p treatment did not affect the serum-dependent activation of ERK1/2 or c-fos expression, but caused a reduction in the gene and/or protein expression of cyclin D1, cyclin E, cdk4, and cdk2, which are involved in the cell cycle. Therefore, GM3-p inhibits cell proliferation by reducing cyclin D1-cdk4 and cyclin E-cdk2 complexes without affecting growth factor signaling from serum to c-fos.
* These two authors contributed equally to this work