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CMLS, Cell. Mol. Life Sci. 62 (2005) 1711781420-682X/05/020171-8DOI 10.1007/s00018-004-4349-8 Birkhuser Verlag, Basel, 2005 CMLS
Cellular and Molecular Life Sciences
Research Article
a
a-1,3-Fucosyltransferase-VII stimulates the growthof hepatocarcinoma cells via the cyclin-dependent kinase inhibitor p27Kip1
Q.Y. Wang, P. Guo, L. L. Duan, Z. H. Shen and H. L. Chen*
Key Laboratory of Glycoconjugate Research, Ministry of Health, Department of Biochemistry, Shanghai Medical College, Fudan University, Shanghai 200032 (China), Fax: +86 21 64164489, e-mail: [email protected]
Received 5 August 2004; received after revision 25 October 2004; accepted 11 November 2005
Abstract. After the transfection of a-1,3-fucosyltransferase (FucT)-VII cDNA into H7721 human hepatocarcinoma cells, the protein expression of some cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDIs) p16INK4 and p21waf1/Cip1 were unchanged. However, CDI p27Kip1 protein, both the total amount and the amount that bound to CDK2, but not its mRNA, was significantly reduced. The de-inhibited CDK2 stimulated the phosphorylation of retinoblastoma (Rb) protein and facilitated the G1/S transition and growth rate of the cells. The decrease of p27Kip1 protein,
the increase of CDK2 activity and Rb phosphorylation, as
well as the cell growth and percentage of S phase cells were correlated to the increased amount of cell surface sialyl Lewis X (SLex) antigen in cells with different a-1,3-FucT-VII expression. The reduction in p27Kip1 and the
difference in its expression among different transfected cells were blocked by the SLex antibody KM93 in a dose-dependent manner, indicating that p27Kip1 expression was influenced by a-1,3-FucT-VII and its product SLex. The
MEK/MAPK signaling pathway was more important than the PI-3K pathway in the regulation of p27Kip1 ex
pression.
Key words. a-1,3-Fucosyltransferase (FucT)-VII; sialyl Lewis X; cyclin-dependent kinase (CDK); cyclin-dependent kinase inhibitor (CDI); p27Kip1; retinoblastoma (Rb) protein.
Human fucosyltransferase (FucT) is a family of glycosyltransferases responsible for the synthesis of fucosyl-containing compounds, including the A, B and O blood groups and Lewis antigens. It catalyzes the transfer of a fucosyl residue from GDP-a-L-fucose to a sugar acceptor, usually galactose or N-acetylglucosamine, in the sugar chains of glycoproteins or glycolipids. Human FucT is divided into three subfamilies, a-1,2-FucT, a-1,3-FucT and a-1,6-FucT [1]. Among these, the a-1,3-FucT sub-family is the main glycosyltransferase participating in the synthesis of Lewis antigens, which are a series of fucosylated galactose-b-1,3-/b-1,4-N-acetylglucosamine (sia-
* Corresponding author.
lylated or not sialylated)...