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Molecular and Cellular Biology, July 2006, p. 5284-5299, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00105-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Wnt Activation and Alternative Promoter Repression of LEF1 in Colon Cancer

Tony W.-H. Li,1,{dagger} Ju-Hui T. Ting,1 Noriko N. Yokoyama,1 Alla Bernstein,1 Marc van de Wetering,2 and Marian L. Waterman1*

Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California 92697,1 Hubrecht Laboratory, Center for Biomedical Genetics, 3458 CT Utrecht, The Netherlands2

Received 17 January 2006/ Returned for modification 17 March 2006/ Accepted 2 May 2006

Alternative promoters within the LEF1 locus produce polypeptides of opposing biological activities. Promoter 1 produces full-length LEF-1 protein, which recruits ß-catenin to Wnt target genes. Promoter 2 produces a truncated form that cannot interact with ß-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)-ß-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-ß-catenin complexes. Promoter 2 is nevertheless silent in colon cancer because an upstream repressor selectively targets the basal promoter leading to destabilized TCF-ß-catenin binding. We conclude that the biological outcome of aberrant LEF1 activation in colon cancer is directed by differential promoter activation and repression.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Rm. B240, Medical Sciences I, University of California, Irvine, Irvine, CA 92697-4025. Phone: (949) 824-2885. Fax: (949) 824-8598. E-mail: mlwaterm{at}uci.edu.

{dagger} Present address: Norris Cancer Center, University of Southern California, Los Angeles, CA 90089.

Molecular and Cellular Biology, July 2006, p. 5284-5299, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00105-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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