Lymphoid enhancer factor/T cell factor expression in colorectal cancer.
Genetic inactivation of key components of the Wnt signal transduction system is a frequent event in colorectal cancer. These genetic mutations lead to stabilization of beta-catenin, a cytoplasmic-nuclear shuttling protein with a potent transcription activation domain. Stabilization and subsequent nuclear localization of beta-catenin produces aberrant, Wnt-independent signals to target genes, an activity tightly linked to the genesis of colon cancers. In the nucleus, the transcription factor family of LEF/TCF proteins transmits Wnt signals by binding to beta-catenin and recruiting it to target genes for activation. Such activities are carried out by full-length LEF/TCFs that are thought to be mostly interchangeable and redundant. However, truncated forms of LEF-1 and TCF-1 that do not bind to beta-catenin function as dominant negatives and an alternatively spliced TCF isoform with a unique activation function has recently been discovered. The dominant negative forms block Wnt signals because they occupy Wnt target genes and limit beta-catenin access; the alternatively spliced TCF isoform activates certain Wnt target promoters whereas other TCF isoforms and LEF-1 do not. A study of LEF/TCF expression and activity in normal intestine and colon carcinomas suggests that the relative amounts of LEF/TCF isoforms may change as tumors progress and this may influence the strength and specificity of Wnt signals in the nucleus. While the underlying mechanism for a change in the LEF/TCF isoform expression is not yet known, recent evidence implicates the Wnt signaling pathway itself as a potential modulator.
Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, USA. mlwaterm@uci.edu
Marian L
ML
Waterman
D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005091:Exons; D005799:Genes, Dominant; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008954:Models, Biological; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D020033:Protein Isoforms; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D014157:Transcription Factors