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-*...

Cellular damage invoked by reactive oxygen species plays a key role in the pathobiology of cancer and aging. Forkhead box class O (FoxO) transcription factors are involved in various cellular processes including cell cycle regulation, apoptosis and resistance to reactive oxygen species, and studies in animal models have shown that these transcription factors are of vital importance in tumor suppression, stem cell maintenance and lifespan extension. Here we report that the activity of FoxO in human cells is directly regulated by the cellular redox state through a unique mechanism in signal transduction. We show that reactive oxygen species induce the formation of cysteine-thiol disulfide-dependent complexes of FoxO and the p300/CBP acetyltransferase, and that modulation of FoxO biological activity by p300/CBP-mediated acetylation is fully dependent on the formation of this redox-dependent complex. These findings directly link cellular redox status to the activity of the longevity protein FoxO.

By comparative analysis of RNA polymerase II and FOXO3 ChIP-sequencing, combined with 4C-sequencing and ChIPs on histone modifications, general mechanisms of FOXO3-mediated target gene regulation are identified.

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive. FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. .