Search

Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post-translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences., (© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Significance: Transcription factors of the Forkhead box O class (FOXOs) are associated with lifespan and play a role in age-related diseases. FOXOs, therefore, serve as a paradigm for developing an understanding as to how age-related diseases, such as cancer and diabetes interconnect with lifespan. Understanding the regulatory inputs on FOXO may reveal how changes in these regulatory signaling pathways affect disease and lifespan., Recent Advances: Numerous regulators of FOXO have now been described and a clear and evolutionary conserved role has emerged for phosphoinositide-3 kinase/protein kinase B (also known as c-Akt or AKT) signaling and c-jun N-terminal kinase signaling. Analysis of FOXO function in the context of these signaling pathways has shown the importance of FOXO-mediated transcriptional regulation on cell cycle progression and other cell fates, such as cell metabolism, stress resistance, and apoptosis in mediating disease and lifespan., Critical Issues: Persistent DNA damage is also tightly linked to disease and aging; yet, data on a possible link between DNA damage and FOXO have been limited. Here, we discuss possible connections between FOXO and the DNA damage response in the context of the broader role of connecting lifespan and disease., Future Directions: Understanding the role of lifespan in diseases onset may provide unique and generic possibilities to intervene in disease processes to ensure a healthy lifespan.

Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in fail safe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging., (2011 Elsevier B.V. All rights reserved.)

The FoxO transcription factors (FoxO1a, 3a and 4) comprise a small subfamily of the Forkhead transcription factor family. An increasing number of studies has provided genetic evidence showing that Forkhead transcription factors control crucial steps in embryogenesis and are essential for the development of all germ layers and organs (for a recent review, see Ref. ). A recent study by Castrillon et al. has now added a function for FoxO3a in the control of follicular development.

In this study, we searched for proteins regulating the tumor suppressor and life-span regulator FOXO4. Through an unbiased tandem-affinity purification strategy combined with mass spectrometry, we identified the heterodimer Ku70/Ku80 (Ku), a DNA double-strand break repair component. Using biochemical interaction studies, we found Ku70 to be necessary and sufficient for the interaction. FOXO4 mediates its tumor-suppressive function in part through transcrip-tional regulation of the cell cycle arrest p27kip1 gene. Immunoblotting, luciferase reporter assays, and flow cytometry showed that Ku70 inhibited FOXO4-mediated p27kip1 transcription and cell cycle arrest induction by >40%. In contrast, Ku70 RNAi but not control RNAi significantly increased p27kip1 transcription. In addition, in contrast to wild-type mouse embryonic stem (ES) cells, Ku70-/- ES cells showed significantly increased FOXO activity, which was rescued by Ku70 reexpression. Immunofluorescence studies demonstrated that Ku70 sequestered FOXO4 in the nucleus. Interestingly, the Ku70-FOXO4 interaction stoichiometry followed a nonlinear dose-response curve by hydrogen peroxide-generated oxidative stress. Low levels of oxidative stress increased interaction stoichiometry up to 75%, peaking at 50 u.M, after which dissociation occurred. Because the Ku70 ortholog in the roundworm Caenorhabditis elegans was shown to regulate life span involving C. elegans FOXO, our findings suggest a conserved critical Ku70 role for FOXO function toward coordination of a survival program, regulated by the magnitude of oxidative damage. [ABSTRACT FROM AUTHOR]