Article

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: 7.67). 02/2011; 14(4):623-34. DOI: 10.1089/ars.2010.3490
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Heidi Tissenbaum, Feb 20, 2014
0 Followers
 · 
116 Views
  • Source
    [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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2012; 32(36):12630-40. DOI:10.1523/JNEUROSCI.0277-12.2012 · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Forkhead Box O (FOXO) transcription factors are famous for their role in longevity: both Caenorhabditis elegans and Drosophila melanogaster can extend their median and maximum lifespan in a FOXO-dependent manner, and certain single nucleotide polymorphisms in human FOXO genes are associated with reaching an age above 100 years. Ablation of FOXO1, 3a, and 4 in adult mice predisposes them to tumorigenesis and stem cell depletion, and the latter could at least partly be reversed by treatment with antioxidants. Indeed, FOXO has been known to regulate the defense against reactive oxygen species through transactivation of antioxidant genes like manganese superoxide dismutase and catalase. At the same time, reactive oxygen species regulate FOXO activity in many ways through an elaborate combination of activating as well as repressing post-translational modifications, including phosphorylation, acetylation, ubiquitinylation, and methylation. Hence, FOXO is at the centre of redox signaling, but it is unclear whether and how exactly redox signaling to and from FOXO contributes to its effects on longevity. In this forum issue we give an overview of the many facets of FOXO in worms, flies, mice, and humans.
    Antioxidants & Redox Signaling 11/2010; 14(4):559-61. DOI:10.1089/ars.2010.3778 · 7.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early onset neurodegenerative disorder. JNCL is the most common of the NCLs, a group of disorders with infant or childhood onset that are caused by single gene mutations. The NCLs, although relatively rare, share many pathological and clinical similarities with the more common late-onset neurodegenerative disorders, while their simple genetic basis makes them an excellent paradigm. The early onset and rapid disease progression in the NCLs suggests that one or more key cellular processes are severely compromised. To identify the functional pathways compromised in JNCL, we have performed a gain-of-function modifier screen in Drosophila. We find that CLN3 interacts genetically with the core stress signalling pathways and components of stress granules, suggesting a function in stress responses. In support of this, we find that Drosophila lacking CLN3 function are hypersensitive to oxidative stress yet they respond normally to other physiological stresses. Overexpression of CLN3 is sufficient to confer increased resistance to oxidative stress. We find that CLN3 mutant flies perceive conditions of increased oxidative stress correctly but are unable to detoxify reactive oxygen species, suggesting that their ability to respond is compromised. Together, our data suggest that the lack of CLN3 function leads to a failure to manage the response to oxidative stress and this may be the key deficit in JNCL that leads to neuronal degeneration.
    Human Molecular Genetics 03/2011; 20(10):2037-47. DOI:10.1093/hmg/ddr088 · 6.68 Impact Factor