A new β-catenin-dependent activation domain in T cell factor

Transcription of the lymphoid enhancer factor-1 (LEF1) gene is aberrantly activated in sporadic colon cancer, whereas this gene is not expressed in the normal adult colon. We have shown previously that promoter I of the LEF1 gene is activated by T cell factor (TCF)-beta-catenin complexes in transient transfection assays, suggesting that LEF1 is a target of the Wnt pathway in colon cancer. To further explore the link between LEF1 expression and the Wnt pathway, we studied two response elements in the promoter. Surprisingly we found that the LEF1 promoter is selectively activated by specific isoforms of the LEF/TCF transcription factor family that contain an alternative C-terminal E tail. These isoforms, TCF-1E and TCF-4E, activate the promoter in a beta-catenin-dependent manner. We show that a complete E-tail domain is necessary for fall activity and delimits residues within two highly conserved peptide motifs within the tail that are required (KKCRARFG; WCXX-CRRKKKC). These peptide motifs are not only conserved among the TCF family members but are also found in two newly identified DNA-binding proteins named papillomavirus binding factor and GLUT4 enhancer factor. This study thus identifies a new and unique set of motifs used by the Wnt pathway for target gene regulation.