Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas

Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1603-8. doi: 10.1073/pnas.96.4.1603.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • Membrane Proteins
  • NF-kappa B
  • PLAUR protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Proteins
  • TJP1 protein, human
  • Trans-Activators
  • Transcription Factor AP-1
  • Zonula Occludens-1 Protein
  • beta Catenin
  • fos-related antigen 1
  • Urokinase-Type Plasminogen Activator