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A new beta-catenin-dependent activation domain in T cell factor
Fawzia A Atcha1, Jesus E Munguia, Tony W H Li
1Microbiology and Molecular Genetics Department, School of Medicine, University of California, Irvine, CA 92697-4025, USA.
The Journal of Biological Chemistry
|February 13, 2003
Summary
Lymphoid enhancer factor-1 (LEF1) is activated in colon cancer via the Wnt pathway. Specific LEF/TCF transcription factor isoforms with an "E" tail are crucial for this aberrant LEF1 gene activation.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Aberrant transcription of the lymphoid enhancer factor-1 (LEF1) gene occurs in sporadic colon cancer.
- LEF1 is normally unexpressed in adult colon tissue.
- LEF1 is a potential target of the Wnt pathway in colon cancer, as suggested by previous studies on its promoter activation by T cell factor (TCF)-beta-catenin complexes.
Purpose of the Study:
- To investigate the link between LEF1 expression and the Wnt pathway in colon cancer.
- To identify specific regulatory elements and factors involved in LEF1 gene activation.
Main Methods:
- Transient transfection assays to study promoter activity.
- Analysis of specific isoforms of the LEF/TCF transcription factor family.
- Identification and characterization of conserved peptide motifs within the LEF/TCF "E" tail.
Main Results:
- The LEF1 promoter is selectively activated by specific LEF/TCF transcription factor isoforms containing an alternative C-terminal "E" tail (TCF-1E and TCF-4E).
- Activation by these isoforms is dependent on beta-catenin.
- A complete "E" tail domain is necessary for full promoter activity, with two conserved peptide motifs (KKCRARFG; WCXXCRRKKKC) being essential.
Conclusions:
- Identifies a novel mechanism of Wnt pathway-mediated gene regulation in colon cancer involving specific LEF/TCF isoforms with an "E" tail.
- Discovers conserved peptide motifs within the "E" tail critical for transcriptional activation.
- Suggests these motifs are broadly utilized in Wnt pathway target gene regulation, extending to other DNA-binding proteins like papillomavirus binding factor and GLUT4 enhancer factor.