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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.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





1603 - 1608


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