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A Wnt kinase network alters nuclear localization of TCF-1 in colon cancer

Oncogene volume 28, pages 4133–4146 (2009)Cite this article

Abstract

Constitutive activation of the Wnt/β-catenin pathway has been implicated as the primary cause of colon cancer. However, the major transducers of Wnt signaling in the intestine, T-cell factor 1 (TCF-1) and TCF-4, have opposing functions. Knockout of TCF-4 suppresses growth and maintenance of crypt stem cells, whereas knockout of TCF-1 leads to adenomas. These phenotypes suggest that TCF-4 is Wnt-promoting, whereas TCF-1 acts like a tumor suppressor. Our study of TCF expression in human colon crypts reveals a mechanistic basis for this paradox. In normal colon cells, a dominant-negative isoform of TCF-1 (dnTCF-1) is expressed that is equally distributed between nuclear and cytoplasmic compartments. In colon cancer cells, TCF-1 is predominantly cytoplasmic. Localization is because of active nuclear export and is directed by an autocrine-acting Wnt ligand that requires Ca2+/calmodulin-dependent kinase II (CaMKII) activity for secretion and a downstream step in the export pathway. TCF-4 remains nuclear; its unopposed activity is accompanied by downregulation of dnTCF-1 and increased expression of full-length isoforms. Thus, the dnTCF-1 and TCF-4 balance is corrupted in cancer by two mechanisms, a Wnt/CaMKII kinase signal for nuclear export and decreased dnTCF-1 expression. We propose that dnTCF-1 provides homeostatic regulation of Wnt signaling and growth in normal colon, and the alterations in nuclear export and promoter usage contribute to aberrant Wnt activity in colon cancer.

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Acknowledgements

We specially thank Didi Mwengela, Amanda Chamberlain, Candice Solomon and David Hernandez for help in cloning and sequencing TCF-1 cDNA. We also thank Eric J Stanbridge for critical reading of the manuscript, Michelle Digman for help with confocal imaging, Tohru Ishitani, Bang Hoang and Randall T Moon for reagents and advice. This work was supported by NIH grants RO1 HD36081 and RO1 HD36049 to JLM, NIH T32 CA113265, CA096878 and CA108697 to MLW, R21 DK071591 to RAE and NIH grant CA-82450 to RFH. This work was made possible, in part, through access to the confocal facility of the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine.

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Authors and Affiliations

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

    R Najdi, L Arce, J-HT Ting, F Atcha & M L Waterman

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

    A Syed, H Theisen & J L Marsh

  3. Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA

    A V Nguyen, M Martinez & R F Holcombe

  4. Department of Pathology, University of California, Irvine, CA, USA

    R A Edwards & J L Marsh

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  1. R Najdi
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Correspondence to J L Marsh or M L Waterman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Najdi, R., Syed, A., Arce, L. et al. A Wnt kinase network alters nuclear localization of TCF-1 in colon cancer. Oncogene 28, 4133–4146 (2009). https://doi.org/10.1038/onc.2009.271

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