Author: Waterman M.L.

Source: Cancer and Metastasis Reviews, Volume 23, Numbers 1-2, January 2004 , pp. 41-52(12)

Publisher: Springer

Abstract:

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 -catenin, a cytoplasmic–nuclear shuttling protein with a potent transcription activation domain. Stabilization and subsequent nuclear localization of -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 -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 -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 -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.

Keywords: colon; HMG; LEF; TCF; Wnt; -catenin

Document Type: Research article

DOI: http://dx.doi.org/10.1023/A:1025858928620

Affiliations: 1: Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, Irvine, California, USA mlwaterm@uci.edu, Email: mlwaterm@uci.edu

Publication date: 2004-01-01

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