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Down-Regulation of Monocyte Chemotactic Protein-3 by Activated ß-Catenin

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639 [M. F., Y. F., Y. Nak.]; Department of Surgery II, Kumamoto University School of Medicine, Kumamoto 860-8556 [M. F., M. O.]; and Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Osaka 565-0871 [Y. Nag.] Japan

Accumulation of intracellular ß-catenin, as a result of inactivation of the adenomatous polyposis coli (APC) gene or by mutation of the ß-catenin gene (CTNNB1) itself, is involved in a wide range of human cancers. By means of fluorescent differential display using a murine fibroblast cell line (L-MT), which expresses an activated form of ß-catenin that accumulates in the cells, we found that expression of murine monocyte chemotactic protein-3 (mMCP-3) was suppressed by activated ß-catenin. Inversely, expression of MCP-3 in human colon cancer cells was induced by depletion of ß-catenin after adenovirus-mediated transfer of wild-type APC genes into the cells. A reporter-gene assay indicated that the accumulation of ß-catenin in the nucleus suppressed activity of the MCP-3 promoter through a putative T-cell factor/lymphocyte enhancer factor (Tcf/LEF)-binding site, ATCAAAG; but when the promoter sequence contained a two-base substitution in the binding site, it failed to suppress reporter-gene (luciferase) activity. An electrophoretic mobility-shift assay using the putative Tcf/LEF-binding sequence revealed interaction of the candidate sequence with the ß-catenin complex. Furthermore, induction of MCP-3 cDNA into HT-29 colon cancer cells increased expression of two markers of differentiation: alkaline phosphatase and carcinoembryonic antigen. Our results implied that activation of ß-catenin through the Tcf/LEF signaling pathway may participate in colonic carcinogenesis by inhibiting MCP-3-induced differentiation of colorectal epithelial cells.

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