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Mutations in the adenomatous polyposis coli or beta-catenin gene lead to cytosolic accumulation of beta-catenin and, subsequently, to increased transcriptional activity of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by beta-catenin overexpression, we used colorectal cell lines for transfection with the beta-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by beta-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun and fra-1, and for the urokinase-type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in beta-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of beta-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of beta-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, beta-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

16/02/1999

Volume

96

Pages

1603 - 1608

Keywords

Adenocarcinoma, Cadherins, Cell Line, Cell Polarity, Colon, Colonic Neoplasms, Colorectal Neoplasms, Cytoskeletal Proteins, Gene Expression Regulation, Neoplastic, Genes, APC, Genes, jun, Humans, Intestinal Mucosa, Membrane Proteins, Models, Biological, NF-kappa B, Neoplasm Staging, Phosphoproteins, Promoter Regions, Genetic, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Receptors, Cell Surface, Receptors, Urokinase Plasminogen Activator, Recombinant Proteins, Signal Transduction, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Urokinase-Type Plasminogen Activator, Zonula Occludens-1 Protein, beta Catenin