Mechanisms of Signal Transduction
Interaction of FOXO with β-Catenin Inhibits β-Catenin/T Cell Factor Activity*

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Wingless (Wnt) signaling regulates many aspects of development and tissue homeostasis, and aberrant Wnt signaling can lead to cancer. Upon a Wnt signal β-catenin degradation is halted and consequently the level of β-catenin in the cytoplasm increases. This allows entry of β-catenin into the nucleus where it can regulate gene transcription by direct binding to members of the lymphoid enhancer factor/T cell factor (TCF) family of transcription factors. Recently, we identified Forkhead box-O (FOXO) transcription factors as novel interaction partners of β-catenin (Essers, M. A., de Vries-Smits, L. M., Barker, N., Polderman, P. E., Burgering, B. M., and Korswagen, H. C. (2005) Science 308, 1181-1184). Here we show that the β-catenin binding to FOXO serves a dual effect. β-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with β-catenin, thereby inhibiting TCF transcriptional activity. Reduced binding between TCF and β-catenin is observed after FOXO overexpression and cellular oxidative stress, which simultaneously increases binding between β-catenin and FOXO. Furthermore, small interfering RNA-mediated knock down of FOXO reverts loss of β-catenin binding to TCF after cellular oxidative stress. Taken together, these results provide evidence for a cross-talk mechanism between FOXO and TCF signaling in which β-catenin plays a central regulatory role.

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1

Supported by a grant from the Dutch Cancer Foundation.

2

Supported by the Center of Biomedical Genetics and the Cancer Genomics Center.