Down-regulation of monocyte chemotactic protein-3 by activated beta-catenin.

Abstract

Accumulation of intracellular beta-catenin, as a result of inactivation of the adenomatous polyposis coli (APC) gene or by mutation of the beta-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 beta-catenin that accumulates in the cells, we found that expression of murine monocyte chemotactic protein-3 (mMCP-3) was suppressed by activated beta-catenin. Inversely, expression of MCP-3 in human colon cancer cells was induced by depletion of beta-catenin after adenovirus-mediated transfer of wild-type APC genes into the cells. A reporter-gene assay indicated that the accumulation of beta-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 beta-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 beta-catenin through the Tcf/LEF signaling pathway may participate in colonic carcinogenesis by inhibiting MCP-3-induced differentiation of colorectal epithelial cells.

• Authors: M Fujita, Y Furukawa, Y Nagasawa, M Ogawa, Y Nakamura
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 23 Pg. 6683-7 (Dec 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 11118053 (Publication Type: Journal Article)

Chemical References

• CCL7 protein, human
• CTNNB1 protein, human
• CTNNB1 protein, mouse
• Ccl7 protein, mouse
• Chemokine CCL7
• Cytokines
• Cytoskeletal Proteins
• DNA-Binding Proteins
• Lymphoid Enhancer-Binding Factor 1
• Monocyte Chemoattractant Proteins
• Trans-Activators
• Transcription Factors
• beta Catenin

Topics

• Animals
• Base Sequence
• Binding Sites
• COS Cells
• Cell Differentiation (genetics)
• Chemokine CCL7
• Chlorocebus aethiops
• Colon (cytology)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Cytokines
• Cytoskeletal Proteins (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Down-Regulation
• HT29 Cells
• Humans
• L Cells
• Lymphoid Enhancer-Binding Factor 1
• Mice
• Monocyte Chemoattractant Proteins (biosynthesis, genetics)
• Promoter Regions, Genetic
• Trans-Activators
• Transcription Factors (genetics, metabolism)
• beta Catenin