DAF-16/Forkhead Box O Transcription Factor: Many Paths to a Single Fork(head) in the Road

Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 02/2011; 14(4):623-34. DOI: 10.1089/ars.2010.3490
Source: PubMed


The Caenorhabditis elegans Forkhead box O transcription factor (FOXO) homolog DAF-16 functions as a central mediator of multiple biological processes such as longevity, development, fat storage, stress resistance, and reproduction. In C. elegans, similar to other systems, DAF-16 functions as the downstream target of a conserved, well-characterized insulin/insulin-like growth factor (IGF)-1 signaling pathway. This cascade is comprised of an insulin/IGF-1 receptor, which signals through a conserved PI 3-kinase/AKT pathway that ultimately downregulates DAF-16/FOXO activity. Importantly, studies have shown that multiple pathways intersect with the insulin/IGF-1 signaling pathway and impinge on DAF-16 for their regulation. Therefore, in C. elegans, the single FOXO family member, DAF-16, integrates signals from several pathways and then regulates its many downstream target genes.

  • Source
    • "The C. elegans IIS pathway consists of an insulin/IGF-1 receptor (DAF-2) [5], a PI 3-kinase (AGE-1/AAP-1) [6,7] serine/threonine kinases (PDK-1, AKT-1, and AKT-2) [8,9], and a Forkhead Box O (FOXO) transcription factor (DAF-16) [10,11]. IIS ultimately results in the AKT-dependent phosphorylation of DAF-16, thereby preventing DAF-16 from entering the nucleus to regulate its target genes [3,4,12]. Therefore, the C. elegans FOXO ortholog, DAF-16 is the primary downstream target of the IIS pathway [10,11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans, we have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or daf-16d/f, and examined temporal expression of the isoforms to further define how these isoforms contribute to lifespan regulation. Here, we show that DAF-16a is sensitive both to changes in gene dosage and to alterations in the level of insulin/IGF-1 signaling. Interestingly, we find that as worms age, the intestinal expression of daf-16d/f but not daf-16a is dramatically upregulated at the level of transcription. Preventing this transcriptional upregulation shortens lifespan, indicating that transcriptional regulation of daf-16d/f promotes longevity. In an RNAi screen of transcriptional regulators, we identify elt-2 (GATA transcription factor) and swsn-1 (core subunit of SWI/SNF complex) as key modulators of daf-16d/f gene expression. ELT-2 and another GATA factor, ELT-4, promote longevity via both DAF-16a and DAF-16d/f while the components of SWI/SNF complex promote longevity specifically via DAF-16d/f. Our findings indicate that transcriptional control of C. elegans FOXO/daf-16 is an essential regulatory event. Considering the conservation of FOXO across species, our findings identify a new layer of FOXO regulation as a potential determinant of mammalian longevity and age-related diseases such as cancer and diabetes.
    Full-text · Article · Apr 2014
  • Source
    • "Multiple studies have indicated that FOXO factors may lie at the center of a complex network of upstream pathways such as the PI3K-AKT (insulin/IGF-1 signaling cascade), MST-1, JNK, SIR-2, and AMPK pathways, cofactors such as 14-3-3 proteins and ß-catenin and a fairly large number of either established or putative transcriptional targets. This notion has been extensively reviewed in several articles to which to refer for more details (Greer and Brunet, 2005; Calnan and Brunet, 2008; Landis and Murphy, 2010; Yen et al., 2011; Neri, 2012; Eijkelenboom and Burgering, 2013). These studies have emphasized a model in which, through a series of context-dependent post-translational modifications and nucleo-cytoplasmic interactions, FOXO proteins are signal integrators that may be repressed by insulin/IGF-1 signaling and that may function developmentally or post-developmentally to modulate cell cycle arrest, apoptosis, autophagy, angiogenesis, differentiation, stress resistance, stem cell maintenance, glucogenesis, and food intake. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The FOXO family of transcription factors is central to the regulation of organismal longevity and cellular survival. Several studies have indicated that FOXO factors lie at the center of a complex network of upstream pathways, cofactors and downstream targets (FOXO-interaction networks), which may have developmental and post-developmental roles in the regulation of chronic-stress response in normal and diseased cells. Noticeably, FOXO factors are important for the regulation of proteotoxicity and neuron survival in several models of neurodegenerative disease, suggesting that FOXO-interaction networks may have therapeutic potential. However, the status of FOXO-interaction networks in neurodegenerative disease remains largely unknown. Systems modeling is anticipated to provide a comprehensive assessment of this question. In particular, interrogating the context-dependent variability of FOXO-interaction networks could predict the clinical potential of cellular-stress response genes and aging regulators for tackling brain and peripheral pathology in neurodegenerative disease. Using published transcriptomic data obtained from murine models of Huntington's disease (HD) and post-mortem brains, blood samples and induced-pluripotent-stem cells from HD carriers as a case example, this review briefly highlights how the biological status and clinical potential of FOXO-interaction networks for HD may be decoded by developing network and entropy based feature selection across heterogeneous datasets.
    Full-text · Article · Jun 2013 · Frontiers in Aging Neuroscience
  • Source
    • "FOXO proteins are essential for stress resistance (Brunet et al., 2004), and daf-16 is required for neuroprotection by increased dosage of sirtuin sir-2.1/SIRT1 in expanded-polyQ nematodes (Parker et al., 2005). Several cofactors regulate FOXO activity, and FOXOs have many targets (Greer and Brunet, 2008; Landis and Murphy, 2010; Yen et al., 2011), suggesting that a network of genes centered onto FOXO might regulate mutant polyglutamine neuron survival and have a role in HD variability. Interestingly, in this regard FOXO activity may be conserved from C. elegans to humans, as human FOXO3A was associated with the ability to be long lived in several populations of centenarians (Willcox et al., 2008; Anselmi et al., 2009; Li et al., 2009; Soerensen et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/β-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the β-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of β-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between β-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of β-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity.
    Full-text · Article · Sep 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Show more