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β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer

Nature Genetics volume 28, pages 53–57 (2001)Cite this article

Abstract

Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers1,2,3. Activation of this pathway is caused by genetic mutations that stabilize the β-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes3,4. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5–9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by β-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds β-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. β-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, β-catenin–sensitive forms of LEF/TCFs.

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Figure 1: LEF1 and TCF7L2 (encoding TCF4 protein) expression in normal human colon tissue and human colon carcinomas.
Figure 2: Northern-blot analysis of LEF1 expression in normal thymus tissue and cancer cell lines and identification of a second promoter in intron 2 of human LEF1.
Figure 3: LEF1 produces two different protein products that differ at the amino terminus.
Figure 4: The LEF1 promoter is activated by TCF1– and TCF4–β-catenin complexes in 2017 T lymphocytes.

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Acknowledgements

We thank H. Clevers for TCF1 and TCF4 expression plasmids and the TOPtk/FOPtk reporters; M. Schlissel for the 2017 cell line; J. Ta for assisting with the sequencing of genomic clones; J. Groden and K. Heppner Goss for the GFP/APC construct and advice; T. Pawloski for assistance with the image analysis of the in situ hybridization; and E. Stanbridge, A. Syed, O. Marcu, B. Semler, S. Sandmeyer, H. Fan, H. Mangalam and members of the Waterman and Marsh laboratories for suggestions and critique. This work was supported by the Chao Family Comprehensive Cancer Center Functional Genomics Program to J.L.M., R.F.H. and M.L.W, the UCI College of Medicine to R.F.H., NIH Research Grants RO1 HD36081 and RO1 HD36049 to J.L.M., and NIH R01 CA-83982 to M.L.W.

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Authors and Affiliations

  1. Microbiology and Molecular Genetics Department, University of California, Irvine, Irvine, California, USA

    Karine Hovanes, Tony W.H. Li, Jesus E. Munguia & Marian L. Waterman

  2. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, USA

    J. Lawrence Marsh

  3. Division of Hematology/Oncology and Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California, USA

    Trung Truong, Tatjana Milovanovic & Randall F. Holcombe

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  1. Karine Hovanes
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  8. Marian L. Waterman
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Correspondence to Marian L. Waterman.

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Hovanes, K., Li, T., Munguia, J. et al. β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat Genet 28, 53–57 (2001). https://doi.org/10.1038/ng0501-53

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