Interaction of FOXO with β-Catenin Inhibits β-Catenin/T Cell Factor Activity

Abstract

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. 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. Wnt proteins are closely related secreted glycoproteins that act as growth factors on cells and play critical roles in cell proliferation and cell fate determination at many stages of development (2Cadigan K.M. Nusse R. Genes Dev. 1997; 11: 3286-3305Crossref PubMed Scopus (2206) Google Scholar, 3Wodarz A. Nusse R. Annu. Rev. Cell Dev. Biol. 1998; 14: 59-88Crossref PubMed Scopus (1716) Google Scholar). Genetic and biochemical experiments in Drosophila melanogaster, Xenopus laevis, and mammalian cells have established a framework for the Wnt signaling pathway. In the absence of a Wnt signal, cytoplasmic β-catenin is bound to a multi-protein β-catenin destruction complex that contains several proteins, including Axin, adenomatous polyposis coli (APC), 3The abbreviations used are: APCadenomatous polyposis coliGSKglycogen synthase kinase 3HAhemagglutininTCFT cell factorFOXOForkhead box-OJNKc-Jun N-terminal kinase4OHT4-hydroxy-tamoxifenHIFhypoxia-inducible factorTOPTCF Optimal PromoterFOPFake Optimal Promoter. 3The abbreviations used are: APCadenomatous polyposis coliGSKglycogen synthase kinase 3HAhemagglutininTCFT cell factorFOXOForkhead box-OJNKc-Jun N-terminal kinase4OHT4-hydroxy-tamoxifenHIFhypoxia-inducible factorTOPTCF Optimal PromoterFOPFake Optimal Promoter. casein kinase Iα (CKIα) and ϵ (CKIϵ) and glycogen synthase kinase 3 (GSK-3). In this complex, CKIα and/or CKIϵ and GSK phosphorylate β-catenin (4Behrens J. Jerchow B.A. Wurtele M. Grimm J. Asbrand C. Wirtz R. Kuhl M. Wedlich D. Birchmeier W. Science. 1998; 280: 596-599Crossref PubMed Scopus (1095) Google Scholar, 5Ikeda S. Kishida S. Yamamoto H. Murai H. Koyama S. Kikuchi A. EMBO J. 1998; 17: 1371-1384Crossref PubMed Scopus (1087) Google Scholar, 6Batlle E. Henderson J.T. Beghtel H. van den Born M.M. Sancho E. Huls G. Meeldijk J. Robertson J. van de Wetering M. Pawson T. Clevers H. Cell. 2002; 111: 251-263Abstract Full Text Full Text PDF PubMed Scopus (920) Google Scholar). Phosphorylation triggers ubiquitination of β-catenin by βTrCP, a component of the SCFβTrCP ubiquitin-protein ligase complex and degradation of β-catenin by the ubiquitin-proteasome pathway (7Aberle H. Bauer A. Stappert J. Kispert A. Kemler R. EMBO J. 1997; 16: 3797-3804Crossref PubMed Scopus (2122) Google Scholar, 8Hart M. Concordet J.P. Lassot I. Albert I. del los Santos R. Durand H. Perret C. Rubinfeld B. Margottin F. Benarous R. Polakis P. Curr. Biol. 1999; 9: 207-210Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, 9Kitagawa M. 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Genes Dev. 2000; 14: 1837-1851PubMed Google Scholar). adenomatous polyposis coli glycogen synthase kinase 3 hemagglutinin T cell factor Forkhead box-O c-Jun N-terminal kinase 4-hydroxy-tamoxifen hypoxia-inducible factor TCF Optimal Promoter Fake Optimal Promoter. adenomatous polyposis coli glycogen synthase kinase 3 hemagglutinin T cell factor Forkhead box-O c-Jun N-terminal kinase 4-hydroxy-tamoxifen hypoxia-inducible factor TCF Optimal Promoter Fake Optimal Promoter. The FOXO subfamily of transcription factors is critically involved in the regulation of apoptosis, proliferation, and the control of oxidative stress (reviewed in Ref. 17Burgering B.M. Medema R.H. J. Leukocyte Biol. 2003; 73: 689-701Crossref PubMed Scopus (368) Google Scholar). FOXOs are negatively regulated by the phosphoinositide-3 kinase/protein kinase B pathway. Activation of phosphoinositide-3 kinase/protein kinase B will induce phosphorylation and nuclear exclusion of FOXO, thereby inhibiting FOXO transcriptional activity. Recently, we and others have obtained evidence that FOXOs are also controlled by oxidative stress. In contrast to insulin signaling, increased cellular oxidative stress relocalizes FOXO to the nucleus and results in FOXO activation (18Essers M.A. Weijzen S. de Vries-Smits A.M. Saarloos I. de Ruiter N.D. Bos J.L. Burgering B.M. EMBO J. 2004; 23: 4802-4812Crossref PubMed Scopus (608) Google Scholar). Activation by increased cellular oxidative stress requires phosphorylation by JNK and this is evolutionary conserved. In D. melanogaster and Caenorhabditis elegans dFOXO and DAF-16 are also phosphorylated by JNK, and JNK activity increases lifespan in D. melanogaster and C. elegans in a dFOXO/DAF1-16 dependent manner (19Wang M.C. Bohmann D. Jasper H. Dev. Cell. 2003; 5: 811-816Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 20Oh S.W. Mukhopadhyay A. Svrzikapa N. Jiang F. Davis R.J. Tissenbaum H.A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 4494-4499Crossref PubMed Scopus (406) Google Scholar). Recently we showed that β-catenin directly binds to FOXO and that this binding leads to enhanced FOXO transcriptional activity (1Essers M.A. de Vries-Smits L.M. Barker N. Polderman P.E. Burgering B.M. Korswagen H.C. Science. 2005; 308: 1181-1184Crossref PubMed Scopus (589) Google Scholar). The binding of β-catenin to FOXO is increased under conditions of oxidative stress, and genetic analysis in C. elegans demonstrated that the interaction between FOXO and β-catenin is conserved and thus reveals an evolutionary conserved function for β-catenin, independent of TCF. Consistent with regulation of FOXO by phosphoinositide-3 kinase and Ras signaling, ligand-independent activation of FOXO causes a cell cycle arrest in G1, both in cells transformed with oncogenic Ras and cells with a deletion of, or a mutation in, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (21Medema R.H. Kops G.J. Bos J.L. Burgering B.M. Nature. 2000; 404: 782-787Crossref PubMed Scopus (1207) Google Scholar). Interestingly, colon carcinoma cells transformed by activated β-catenin/TCF signaling due to an APC truncation are also arrested in G1 by activation of FOXO (22Kops G.J. Medema R.H. Glassford J. Essers M.A. Dijkers P.F. Coffer P.J. Lam E.W. Burgering B.M. Mol. Cell. Biol. 2002; 22: 2025-2036Crossref PubMed Scopus (366) Google Scholar), suggesting that FOXO expression can suppress β-catenin/TCF signaling toward proliferation. Therefore, we here investigated the consequences of the binding between β-catenin and FOXO for signaling through the β-catenin-TCF complex. We show that activation of FOXO leads to inhibition of TCF transcriptional activity. This suggested that interaction of FOXO and β-catenin competes with the binding of β-catenin with TCF. Consistent with this, increased cellular oxidative stress resulting from H2O2 treatment reduced the TCF/β-catenin interaction and this is likely mediated via FOXO as siRNA-mediated knockdown of FOXO expression alleviated H2O2-induced reduction in β-catenin-TCF complex formation. Taken together, these data provide evidence for a novel mechanism of cross-talk between Wnt and phosphoinositide-3 kinase signaling whereby β-catenin acts as a pivot between essential downstream elements of these signaling pathways, TCF and FOXO, respectively. Cell Culture, Transfection, and Infection—DL23 cells, DLD1 cells expressing a conditionally active FOXO3a.A3-ER fusion, were created as (22Kops G.J. Medema R.H. Glassford J. Essers M.A. Dijkers P.F. Coffer P.J. Lam E.W. Burgering B.M. Mol. Cell. Biol. 2002; 22: 2025-2036Crossref PubMed Scopus (366) Google Scholar). DLD1 colon carcinoma cells, cells, and colon carcinoma cells were in with and cells were with 4-hydroxy-tamoxifen for or to the cells and cells expressing the were in with and and cells were to the of were cells were with or cells were with or after of the cells cells were by the of the cells with after the The after cells were in have G.J. de Ruiter N.D. Vries-Smits A.M. Bos J.L. Burgering B.M. Nature. 1999; PubMed Scopus Google Scholar), T. T. I. N. J. 2000; PubMed Scopus Google Scholar), S. V. L. F. M. M. 1996; PubMed Scopus Google from a from M. van de Wetering The were and into of is the and were cell β-catenin obtained from obtained from obtained from The β-catenin by van and Clevers The and cells were in 10 and and were for 10 at at were for at with of or or of β-catenin and of The were with and for and of were to and to analysis under conditions and the and cells were with a of an or a of a of the S. V. L. F. M. M. 1996; PubMed Scopus Google Scholar). DLD1 cells were with or a control and DLD1 cells were with for the were were with and in and activity a and a to the The of activity on the by the on the and this TCF Optimal Promoter Optimal Promoter expression of TCF target genes in and cells by transcription of by from and cells the the from the on an with the for were a from N. Barker The FOXO the interaction between β-catenin and FOXO the function of β-catenin as a of TCF transcriptional we the of FOXO activation on this we used cells, which are DLD1 colon carcinoma cells expressing a conditionally active G.J. Polderman P.E. Saarloos I. Wirtz Coffer P.J. Bos J.L. Medema R.H. Burgering B.M. Nature. 2002; PubMed Scopus Google Scholar). activity can on in these cells by cells with the G.J. Polderman P.E. Saarloos I. Wirtz Coffer P.J. Bos J.L. Medema R.H. Burgering B.M. Nature. 2002; PubMed Scopus Google Scholar). of a mutation in the APC these cells of β-catenin and thus β-catenin/TCF transcriptional activity. Activation of in these cells, by in inhibition of transcription as by the S. V. L. F. M. M. 1996; PubMed Scopus Google Activation of the which contains of an reduced by activated FOXO, FOXO on the which contains of a of the S. V. L. F. M. M. 1996; PubMed Scopus Google Scholar). expression of and in DLD1 cells TCF transcriptional suggesting this to to or the activation of FOXOs the activity of the TCF transcription of TCF transcriptional activity FOXO activation through FOXO activation in β-catenin β-catenin were by treatment In addition, we also the observed inhibition of activity due to reduced of β-catenin phosphorylated on this of β-catenin phosphorylated at we the to β-catenin, we a in Recently, the of β-catenin a of M. Meeldijk J. van R. Destree O. Clevers H. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), and it that the of this of is of this it can that the observed inhibition of activity is likely the of increased β-catenin The observed inhibition of activity FOXO activation also from FOXO with TCF for binding to the TCF in the We in binding of FOXO to TCF binding in the binding of to bind to the within the it to with the within the gene J. Yu X. Munnerlyn A. Eresh S. Hsu S.C. Grosschedl R. Bienz M. Cell. 1997; 88: 777-787Abstract Full Text Full Text PDF PubMed Scopus (391) Google This that for binding is Furthermore, in a the binding to β-catenin/TCF transcriptional activity inhibition of TCF signaling by FOXOs is independent of FOXO binding activity and due to direct between FOXO and TCF for binding to the TCF Activation of FOXOs in DLD1 cells causes a cell cycle arrest in G1 G.J. Polderman P.E. Saarloos I. Wirtz Coffer P.J. Bos J.L. Medema R.H. Burgering B.M. Nature. 2002; PubMed Scopus Google Scholar). that the inhibition of TCF signaling by FOXOs to the of FOXOs to induce a cell cycle we the in the presence of the cell cycle or of these cell cycle in and DLD1 cells a G1 arrest and this in a reduction of transcription suggesting that a cell cycle arrest in G1 in these cells to the reduced β-catenin/TCF activity. TCF activity reduced activation of in the cells that a cell cycle arrest to the inhibition of TCF signaling by FOXO this inhibition for the of FOXO. inhibition is to the of FOXOs to induce a cell cycle arrest in these we showed that β-catenin bind both and (1Essers M.A. de Vries-Smits L.M. Barker N. Polderman P.E. Burgering B.M. Korswagen H.C. Science. 2005; 308: 1181-1184Crossref PubMed Scopus (589) Google Scholar). to overexpression of TCF transcriptional that the of FOXOs to TCF signaling with to bind from these experiments we that the observed inhibition of activity FOXO activation likely results from β-catenin binding to FOXO and consequently of β-catenin from TCF. FOXO of to we have that FOXO binds to of β-catenin, the to which TCF binds (1Essers M.A. de Vries-Smits L.M. Barker N. Polderman P.E. Burgering B.M. Korswagen H.C. Science. 2005; 308: 1181-1184Crossref PubMed Scopus (589) Google Scholar, J. von Kries J.P. Kuhl M. Bruhn L. Wedlich D. Grosschedl R. Birchmeier W. Nature. 1996; 382: 638-642Crossref PubMed Scopus (2560) Google Scholar), suggesting that between FOXO and TCF for β-catenin directly interaction between FOXO and β-catenin with the interaction between TCF and β-catenin, we binding between TCF and β-catenin in Activation of in cells by reduced the interaction between β-catenin and treatment of the control DLD1 cells this Furthermore, analysis showed that β-catenin/TCF interaction observed after of treatment This is with the of inhibition of activity as in we interaction of and β-catenin in stabilization of β-catenin through binding of and β-catenin is of in reduced interaction Taken these data that FOXO and for interaction with β-catenin and that the inhibition of TCF signaling by FOXO the of FOXO to with TCF for the interaction with the evidence that FOXO can with TCF for β-catenin binding, the also TCF can the between FOXO and β-catenin we oxidative binding between and β-catenin in the absence or presence of of TCF of TCF in loss of binding between and β-catenin, in a via cells FOXO activation after of cells with oxidative stress also results in activation of FOXO (18Essers M.A. Weijzen S. de Vries-Smits A.M. Saarloos I. de Ruiter N.D. Bos J.L. Burgering B.M. EMBO J. 2004; 23: 4802-4812Crossref PubMed Scopus (608) Google Scholar). Furthermore, treatment of cells with of oxidative stress the interaction between FOXO and β-catenin is and transcriptional activity of FOXO is enhanced (1Essers M.A. de Vries-Smits L.M. Barker N. Polderman P.E. Burgering B.M. Korswagen H.C. Science. 2005; 308: 1181-1184Crossref PubMed Scopus (589) Google Scholar). it is that cellular oxidative stress will on TCF transcriptional activity. of H2O2 in a in TCF transcriptional activity and a in interaction with β-catenin the observed in binding to β-catenin after H2O2 treatment of cells is due to increased interaction of β-catenin with FOXO H2O2 treatment of cells, we of small interfering RNA-mediated knockdown of in H2O2-induced reduction of complex formation by small interfering RNA-mediated knockdown of cells both and EMBO J. 2003; 22: PubMed Scopus Google this to that is the FOXO with results are with a that FOXO and TCF for β-catenin interaction and that cellular oxidative stress regulates this by β-catenin from TCF to FOXO. of Genes by Activation of we expression of β-catenin/TCF target genes can by activation of this we and DLD1 cells with or colon carcinoma cells with a control or a active FOXO for several target genes were on the from these activation in cells the expression of the FOXO target gene G.J. 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Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The inhibition can by the of FOXO and TCF to with gene expression regulation the of signaling pathways, and thus regulation the of TCF and FOXO signaling or the interaction between TCF and FOXO. Therefore, to as as of signaling we also TCF target Activation of by treatment in cells also the expression of the TCF target genes C. P. T. C. A. J. V. P. Kemler R. A. Cell. 2002; 111: Full Text Full Text PDF PubMed Scopus Google and E. Henderson J.T. Beghtel H. van den Born M.M. Sancho E. Huls G. Meeldijk J. Robertson J. van de Wetering M. Pawson T. Clevers H. Cell. 2002; 111: 251-263Abstract Full Text Full Text PDF PubMed Scopus (920) Google This demonstrated that activation of the expression of TCF target that the of TCF target genes is to the cells and/or the we also the of expression of active in colon carcinoma DLD1 and cells are colon carcinoma cells with of β-catenin, the of both cell is cells β-catenin with APC and DLD1 cells have β-catenin APC and we observed of by the expression level of a target gene to as with cells, Barker, by can the transcriptional activation of target genes in cell that with to the mechanism by which β-catenin is and the of on gene regulation is likely to at the level of Taken together, these data provide evidence that the interaction and FOXO gene The data here a in which β-catenin a between the signaling pathway and the oxidative pathway. We show that FOXO transcription by binding to β-catenin and competes with TCF. stress can the interaction between FOXO and β-catenin and Furthermore, we show that FOXO is for the inhibition of TCF/β-catenin between FOXO and TCF is as we also observed a in interaction TCF Furthermore, TCF and FOXO bind to the of β-catenin (1Essers M.A. de Vries-Smits L.M. Barker N. Polderman P.E. Burgering B.M. Korswagen H.C. Science. 2005; 308: 1181-1184Crossref PubMed Scopus (589) Google and we the presence of FOXO in TCF E. and B. Burgering, data we that FOXO and TCF for the of active FOXO can TCF and TCF can FOXO signaling, and act through β-catenin as is that the of β-catenin in gene transcription is to TCF. binding and FOXO, binding of β-catenin to and A. C. Cell Biol. 9: PubMed Scopus Google Scholar, B. A. Nature. 2005; PubMed Scopus Google Scholar). A. C. Cell Biol. 9: PubMed Scopus Google show that β-catenin can with in a to FOXO. the β-catenin/TCF interaction is the interaction is This leads to expression of target genes whereby β-catenin to is β-catenin binds to TCF and proliferation of the cells can and also via TCF. This in a manner a the expression of The interaction is phosphorylation and thus both the JNK and B. A. Nature. 2005; PubMed Scopus Google Scholar). In to regulation of TCF transcriptional activity through the destruction complex, Wnt signaling also regulates Wnt signaling that JNK and from the of the regulation of TCF activity oxidative stress as we observed signaling also TCF activity. Wnt signaling a control of TCF activity stress signaling In contrast to JNK through direct phosphorylation of FOXO increases FOXO activity (18Essers M.A. Weijzen S. de Vries-Smits A.M. Saarloos I. de Ruiter N.D. Bos J.L. Burgering B.M. EMBO J. 2004; 23: 4802-4812Crossref PubMed Scopus (608) Google Scholar), suggesting JNK a from TCF to FOXO activation under conditions of oxidative stress. in cells FOXO expression TCF transcriptional that JNK is at E. and B. Burgering, data by T. M. H. Cell Biol. PubMed Scopus Google that oxidative stress results in activation inhibition of TCF transcriptional activity. with stress the interaction between and Dishevelled to the stabilization of β-catenin and activation of TCF. results are in contrast to the for this within the of the observed effect. a activation of TCF signaling by at we and others inhibition after of stress. a is suggested by the that cells Cell. 18: PubMed Scopus Google showed that to results β-catenin/TCF signaling is reduced after stress that overexpression of Dishevelled the of Dishevelled expression an in the of TCF signaling toward oxidative stress. this to a of signal In that overexpression β-catenin to that binding of β-catenin to FOXO and TCF can simultaneously and thus or can these results the that β-catenin/TCF signaling is controlled by cellular oxidative stress. to FOXO, both and are regulated by oxidative stress can that under oxidative stress conditions it is for cells to from TCF to FOXO and transcriptional the this an for β-catenin in stress with this we observed in C. elegans that the C. elegans β-catenin regulates oxidative stress independent of binding to the TCF in C. elegans (1Essers M.A. de Vries-Smits L.M. 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EMBO J. 2000; PubMed Google Scholar). the interaction between insulin and Wnt signaling requires in this in of M., M., C. A., and S. C. J. Biol. We Barker for We A. for the We for critical of the and members of the Burgering for