Ectopic activation of lymphoid high mobility group-box transcription factor TCF-1 and overexpression in colorectal cancer cells
✍ Scribed by Karin Mayer; Thomas Hieronymus; Jan Castrop; Hans Clevers; Wolfgang G. Ballhausen
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- French
- Weight
- 188 KB
- Volume
- 72
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Physical interaction between the lymphoid high mobility group (HMG)-box architectural transcription factors TCF/ LEF and b-catenin is associated with translocation of the heteromeric complex to the nucleus and regulation of target gene expression. Since formation of molecular complexes among b-catenin, E-cadherin, p300 apc and TCF/LEF depends on balanced expression of these constituents, we investigated the biosynthesis of TCF-1 in colorectal cancer. Here we report detailed analyses of activation and overexpression of lymphoid transcription factor TCF-1 in human colorectal cancer-derived cell lines. Northern blot analyses revealed considerable steady-state expression levels of TCF-1 mRNA of normal size. Genomic rearrangement of the 58 flanking region of the TCF-1 gene was excluded as a cause of ectopic expression. By contrast, CAT-reporter constructs depending on a 515-bp T-cell-regulated TCF-1 genomic upstream region were significantly activated in epithelial tumor cells. RT-PCR analyses revealed a heterogeneic population of mRNA isoforms due to alternative splicing in the TCF-1 gene. On Western blots of colorectal cancer cells, the TCF-1-specific monoclonal antibody 7H3 detected a similar heterogeneous spectrum of TCF-1 specific polypeptide chains. Interestingly, overexpression of TCF-1-specific splice forms correlated with the metastatic behavior of the analyzed cells and with overproduction of lymphoid tyrosine protein kinase p56 lck . We conclude that ectopic expression of the HMG-box factor TCF-1 is associated with late events in tumor progression.