Wnt activation and alternative promoter repression of LEF1 in colon cancer

Tony W.H. Li, Ju Hui T. Ting, Noriko N. Yokoyama, Alla Bernstein, Marc Van De Wetering, Marian L. Waterman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

91 Citaten (Scopus)


Alternative promoters within the LEF1 locus produce polypeptides of opposing biological activities. Promoter 1 produces full-length LEF-1 protein, which recruits β-catenin to Wnt target genes. Promoter 2 produces a truncated form that cannot interact with β-catenin and instead suppresses Wnt regulation of target genes. Here we show that promoter 1 is aberrantly activated in colon cancers because it is a direct target of the Wnt pathway. T-cell factor (TCF)-β-catenin complexes bind to Wnt response elements in exon 1 and dynamically regulate chromatin acetylation and promoter 1 activity. Promoter 2 is delimited to the intron 2/exon 3 boundary and, like promoter 1, is also directly regulated by TCF-β-catenin complexes. Promoter 2 is nevertheless silent in colon cancer because an upstream repressor selectively targets the basal promoter leading to destabilized TCF-β-catenin binding. We conclude that the biological outcome of aberrant LEF1 activation in colon cancer is directed by differential promoter activation and repression.

Originele taal-2Engels
Pagina's (van-tot)5284-5299
Aantal pagina's16
TijdschriftMolecular and Cellular Biology
Nummer van het tijdschrift14
StatusGepubliceerd - jul. 2006
Extern gepubliceerdJa


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