Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity.
Wingless (Wnt) signaling regulates many aspects of development and tissue homeostasis, and aberrant Wnt signaling can lead to cancer. Upon a Wnt signal beta-catenin degradation is halted and consequently the level of beta-catenin in the cytoplasm increases. This allows entry of beta-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 beta-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 beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. Reduced binding between TCF and beta-catenin is observed after FOXO overexpression and cellular oxidative stress, which simultaneously increases binding between beta-catenin and FOXO. Furthermore, small interfering RNA-mediated knock down of FOXO reverts loss of beta-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 beta-catenin plays a central regulatory role.
Hoogeboom
Diana
D
Department of Physiological Chemistry, Center for Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Essers
Marieke A G
MA
Polderman
Paulien E
PE
Voets
Erik
E
Smits
Lydia M M
LM
Burgering
Boudewijn M Th
BM
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin