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

Abstract

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 (2, 3). 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 ␤-catenin is bound to a multi-protein ␤-catenin destruction complex that contains several proteins, including Axin, adenomatous polyposis coli (APC), 3 casein kinase I␣ (CKI␣) and ⑀ (CKI⑀) and glycogen synthase kinase 3 (GSK-3). In this complex, CKI␣ and/or CKI⑀ and GSK phosphorylate ␤-catenin (4 -6). Phosphorylation triggers ubiquitination of ␤-catenin by ␤TrCP, a component of the SCF ␤TrCP ubiquitin-protein ligase complex and degradation of ␤-catenin by the ubiquitin-proteasome pathway (7-9). In the presence of Wnt, Dishevelled blocks ␤-catenin degradation by inducing the disassembly of the ␤-catenin destruction complex, thereby allowing accumulation of ␤-catenin within the cytosol and entry into the nucleus (10). Within the nucleus, ␤-catenin can bind to lymphoid enhancer factor/T cell factor (TCF) family of transcription factors and induce transcription of Wnt target genes (11-15). Deregulation of the Wnt signaling pathway, for example due to loss of APC, results in stabilization and nuclear accumulation of ␤-catenin and results in tumor formation (16).The FOXO subfamily of transcription factors is critically involved in the regulation of apoptosis, proliferation, and the control of oxidative stress (reviewed in Ref. 17). 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 (18). 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 (19,20). Recently we showed that ␤-catenin directly binds to FOXO and that this binding leads to enhanced FOXO transcriptional activity (1). The binding of ␤-catenin to FOXO is increased under conditions of oxidative stress, and genetic analysis in C. elegans demonstrated that the interaction between FOXO and ␤-catenin is conserved and thus reveals an evolutionary conserved function for ␤-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 G 1 , both in cells trans-*...

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…There are reports which suggest that β-catenin can bind to FOXO-1 in nucleus which results in reduced transcriptional activity of β-catenin resulting in FOXO-1 mediated apoptosis. 36 However, in infection as nuclear FOXO-1 content decreases due to AKT activation, AKT-GSK-3β mediated activation of β-catenin could effectively carry on its antiapoptotic and anti-inflammatory functions. This fact was further validated when constitutively activated FOXO-1-transfected infected cells showed a significant increase in apoptosis and pro-inflammatory responses even though AKT-GSK-3β-β-catenin pathway remained unaffected.…”

Glucocorticoids and Tumor Necrosis Factor α Increase Oxidative Stress and Suppress Wnt Protein Signaling in Osteoblasts

“…Upon its translocation into the nucleus, ␤-catenin associates with the T cell factor (TCF)/ lymphoid enhancer factor family of transcription factors and regulates the expression of Wnt target genes (27). Importantly, oxidative stress induced by H 2 O 2 promotes FoxO-mediated transcription at the expense of Wnt/TCF-mediated transcription and osteoblast differentiation (24,28).…”

FOXO1 Transcription Factor Inhibits Luteinizing Hormone β Gene Expression in Pituitary Gonadotrope Cells

“…For example, ␤-catenin has been reported to act as a coactivator on the Lhb promoter through interactions with SF1 (73) and potentially PTX1 (74). Because FOXO1 can interact with ␤-catenin (75,76), FOXO1 repression of Lhb may be mediated through FOXO1 interaction with ␤-catenin.…”