Genomes and Genes
Gene Symbol: daf-16
Description: Forkhead box protein O;hypothetical protein
Alias: Forkhead box protein O;hypothetical protein
Species: Caenorhabditis elegans
- Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, et al. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol. 2009;7:e1000245 pubmed publisher..Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway. ..
- Kawli T, Tan M. Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nat Immunol. 2008;9:1415-24 pubmed publisher..INS-7 secreted from the nervous system functioned in a non-cell autonomous way to activate the insulin pathway and alter basal and inducible expression of immunity-related genes in intestinal cells. ..
- Chiang W, Tishkoff D, Yang B, Wilson Grady J, Yu X, Mazer T, et al. C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genet. 2012;8:e1002948 pubmed publisher..Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function. ..
- Stout G, Stigter E, Essers P, Mulder K, Kolkman A, Snijders D, et al. Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism. Mol Syst Biol. 2013;9:679 pubmed publisher..elegans lifespan confirming the importance of these processes in Insulin/IGF-1-mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF-1-mediated extension of life. ..
- Troemel E, Chu S, Reinke V, Lee S, Ausubel F, Kim D. p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet. 2006;2:e183 pubmed..The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity. ..
- Henderson S, Johnson T. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001;11:1975-80 pubmed..We suggest that changes in the subcellular localization of DAF-16 by environmental cues allows for rapid reallocation of resources in response to a changing environment at all stages of life. ..
- Pan K, Palter J, Rogers A, Olsen A, Chen D, Lithgow G, et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell. 2007;6:111-9 pubmed..Thus, mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans. ..
- Berman J, Kenyon C. Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell. 2006;124:1055-68 pubmed..Thus, this pathway specifically enables the integration of cues from the reproductive system with central DAF-16-activation pathways to influence the aging of the animal. ..
- Kwon E, Narasimhan S, Yen K, Tissenbaum H. A new DAF-16 isoform regulates longevity. Nature. 2010;466:498-502 pubmed publisher..Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism. ..
- Jeong M, Kawasaki I, Shim Y. A circulatory transcriptional regulation among daf-9, daf-12, and daf-16 mediates larval development upon cholesterol starvation in Caenorhabditis elegans. Dev Dyn. 2010;239:1931-40 pubmed publisher..These results altogether suggest that circulatory mutual regulation among daf-9, daf-12, and daf-16 at the expression level mediates cholesterol signal to control larval development upon CS. ..
- Tullet J, Hertweck M, An J, Baker J, Hwang J, Liu S, et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell. 2008;132:1025-38 pubmed publisher..Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS. ..
- Qi W, Huang X, Neumann Haefelin E, Schulze E, Baumeister R. Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans. PLoS Genet. 2012;8:e1002836 pubmed publisher..Our data suggest that a functional balance of DAF-16 activities in different tissues determines longevity and reveals a novel, cell-nonautonomous role of FOXO/DAF-16 to affect stem cells. ..
- Jensen V, Simonsen K, Lee Y, Park D, Riddle D. RNAi screen of DAF-16/FOXO target genes in C. elegans links pathogenesis and dauer formation. PLoS ONE. 2010;5:e15902 pubmed publisher..We propose that dauer larva formation is a behavioral response to pathogens mediated by increased dauer pheromone production. ..
- Robida Stubbs S, Glover Cutter K, Lamming D, Mizunuma M, Narasimhan S, Neumann Haefelin E, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012;15:713-24 pubmed publisher..We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity. ..
- Murphy C, Lee S, Kenyon C. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2007;104:19046-50 pubmed..Our findings show that feedback regulation of insulin gene expression coordinates DAF-16 activity among the tissues, and they establish the intestine, which is the animal's entire endoderm, as an important insulin-signaling center. ..
- Neumann Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M. SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans. Genes Dev. 2008;22:2721-35 pubmed publisher..elegans SHC-1 as a critical scaffold that directly cross-connects the two parallel JNK and IIS pathways and help to explain how these signaling cascades cooperate to ascertain normal stress response and life span in C. elegans. ..
- Lee R, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol. 2001;11:1950-7 pubmed..Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of daf-16 transduce insulin-like signals in C. elegans and perhaps more generally. ..
- Cohen E, Bieschke J, Perciavalle R, Kelly J, Dillin A. Opposing activities protect against age-onset proteotoxicity. Science. 2006;313:1604-10 pubmed..Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity. ..
- Ackerman D, Gems D. Insulin/IGF-1 and hypoxia signaling act in concert to regulate iron homeostasis in Caenorhabditis elegans. PLoS Genet. 2012;8:e1002498 pubmed publisher..elegans. We suggest that IIS/DAF-16 regulation of ftn-1 modulates a trade-off between growth and stress resistance, as elevated iron availability supports growth but also increases ROS production. ..
- Raices M, Maruyama H, Dillin A, Karlseder J. Uncoupling of longevity and telomere length in C. elegans. PLoS Genet. 2005;1:e30 pubmed..Collectively, our data indicate that telomere length and life span can be uncoupled in a post-mitotic setting, suggesting separate pathways for replication-dependent and -independent aging. ..
- Larsen P, Albert P, Riddle D. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics. 1995;139:1567-83 pubmed..This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan. ..
- Valentini S, Cabreiro F, Ackerman D, Alam M, Kunze M, Kay C, et al. Manipulation of in vivo iron levels can alter resistance to oxidative stress without affecting ageing in the nematode C. elegans. Mech Ageing Dev. 2012;133:282-90 pubmed publisher..These results show that high levels of iron can increase molecular damage and reduce lifespan, but overall suggest that iron levels within the normal physiological range do not promote ageing in C. elegans. ..
- Chavez V, Mohri Shiomi A, Maadani A, Vega L, Garsin D. Oxidative stress enzymes are required for DAF-16-mediated immunity due to generation of reactive oxygen species by Caenorhabditis elegans. Genetics. 2007;176:1567-77 pubmed..Because insulin-signaling mutants overproduce oxidative stress response enzymes, the model provides an explanation for their increased resistance to pathogens. ..
- Li W, Gao B, Lee S, Bennett K, Fang D. RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination. Dev Cell. 2007;12:235-46 pubmed..Overexpression of DAF-16 in rle-1 mutants increases worm lifespan, while disruption of DAF-16 expression in rle-1 mutants reverses their longevity. Thus, RLE-1 is an E3 ubiquitin ligase of DAF-16 that regulates C. elegans aging. ..
- Anyanful A, Easley K, Benian G, Kalman D. Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli by activating genes that regulate lifespan and innate immunity. Cell Host Microbe. 2009;5:450-62 pubmed publisher..Our findings suggest that the molecular pathways that control innate immunity and lifespan may be regulated or "conditioned" by exposure to pathogens to allow survival in noxious environments. ..
- Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001;28:139-45 pubmed..Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging. ..
- Lehtinen M, Yuan Z, Boag P, Yang Y, Villen J, Becker E, et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006;125:987-1001 pubmed
- Riedel C, Dowen R, Lourenco G, Kirienko N, Heimbucher T, West J, et al. DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol. 2013;15:491-501 pubmed publisher..Thus, we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation. ..
- Alam H, Williams T, Dumas K, Guo C, Yoshina S, Mitani S, et al. EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity. Cell Metab. 2010;12:30-41 pubmed publisher..Our results implicate EAK-7 as a FoxO regulator and highlight the biological impact of a regulatory pathway that governs the activity of nuclear FoxO without altering its subcellular location. ..
- Oh S, Mukhopadhyay A, Dixit B, Raha T, Green M, Tissenbaum H. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat Genet. 2006;38:251-7 pubmed..We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream targets. The large number of target genes discovered provides insight into how DAF-16 controls diverse biological functions. ..
- McElwee J, Schuster E, Blanc E, Thomas J, Gems D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem. 2004;279:44533-43 pubmed..By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated. ..
- Wang J, Nakad R, Schulenburg H. Activation of the Caenorhabditis elegans FOXO family transcription factor DAF-16 by pathogenic Bacillus thuringiensis. Dev Comp Immunol. 2012;37:193-201 pubmed publisher..Taken together, our data highlight that a FOXO transcription factor directly responds to pathogens and thus contributes to immune defence. ..
- McElwee J, Bubb K, Thomas J. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell. 2003;2:111-21 pubmed..Finally, we examined the in vivo role of 35 of these target genes by RNA-mediated interference and identified one gene encoding a putative protease that is necessary for the daf-2 Age phenotype. ..
- Love D, Ghosh S, Mondoux M, Fukushige T, Wang P, Wilson M, et al. Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc Natl Acad Sci U S A. 2010;107:7413-8 pubmed publisher..The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration. ..
- Libina N, Berman J, Kenyon C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell. 2003;115:489-502 pubmed..We suggest that this network of tissue interactions and feedback regulation allows the tissues to equilibrate and fine-tune their expression of downstream genes, which, in turn, coordinates their rates of aging within the animal. ..
- Lee S, Kennedy S, Tolonen A, Ruvkun G. DAF-16 target genes that control C. elegans life-span and metabolism. Science. 2003;300:644-7 pubmed..elegans, and RNA interference inactivation of the candidates showed that many of these genes mediate distinct aspects of daf-16 function, including longevity, metabolism, and development. ..
- Zhang P, Judy M, Lee S, Kenyon C. Direct and indirect gene regulation by a life-extending FOXO protein in C. elegans: roles for GATA factors and lipid gene regulators. Cell Metab. 2013;17:85-100 pubmed publisher..These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to DAF-16/FOXO activity. ..
- Hsu A, Murphy C, Kenyon C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science. 2003;300:1142-5 pubmed..The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease. ..
- Murphy C, McCarroll S, Bargmann C, Fraser A, Kamath R, Ahringer J, et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003;424:277-83 pubmed
- Vowels J, Thomas J. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics. 1992;130:105-23 pubmed..These results suggest that daf-11 is directly involved in chemosensory transduction essential for dauer formation, while the other Daf-c genes play roles downstream of the chemosensory step. ..
- Henis Korenblit S, Zhang P, Hansen M, McCormick M, Lee S, Cary M, et al. Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 2010;107:9730-5 pubmed publisher..Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity. ..
- Singh V, Aballay A. Regulation of DAF-16-mediated Innate Immunity in Caenorhabditis elegans. J Biol Chem. 2009;284:35580-7 pubmed publisher..These studies reveal a stress-inducible mechanism involved in the regulation of DAF-16 and indicate that uncontrolled DAF-16 activity and water homeostasis are a cause of the deleterious effects of excessive immune responses. ..
- Hung W, Hwang C, Gao S, Liao E, Chitturi J, Wang Y, et al. Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. EMBO J. 2013;32:1745-60 pubmed publisher..We propose that FSN-1 may negatively regulate insulin/IGF signalling, in part, through EGL-3-dependent insulin-like ligand processing. ..
- Curran S, Wu X, Riedel C, Ruvkun G. A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature. 2009;459:1079-84 pubmed publisher..These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival. ..
- Essers M, de Vries Smits L, Barker N, Polderman P, Burgering B, Korswagen H. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308:1181-4 pubmed..These results demonstrate a role for beta-catenin in regulating FOXO function that is particularly important under conditions of oxidative stress. ..
- Singh V, Aballay A. Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc Natl Acad Sci U S A. 2006;103:13092-7 pubmed..Considering that several coinducers of HSF-1 are currently in clinical trials, this work opens the possibility that activation of HSF-1 could be used to boost immunity to treat infectious diseases and immunodeficiencies. ..
- TeKippe M, Aballay A. C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms. PLoS ONE. 2010;5:e11777 pubmed publisher..Our studies indicate that germline-deficient mutants glp-1 and glp-4 respond to pathogen infection using common and different mechanisms that involve the activation of DAF-16. ..
- Dowell P, Otto T, Adi S, Lane M. Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem. 2003;278:45485-91 pubmed..A more general convergence of nuclear hormone receptor and forkhead factor pathways may be important for multiple biological processes and this convergence may be evolutionarily conserved. ..
- Heidler T, Hartwig K, Daniel H, Wenzel U. Caenorhabditis elegans lifespan extension caused by treatment with an orally active ROS-generator is dependent on DAF-16 and SIR-2.1. Biogerontology. 2010;11:183-95 pubmed publisher..1-dependent alterations in gene expression after a ROS challenge lead to a lifespan extension in C. elegans as long as the stressor concentration does not exceed the saturable protective capacity. ..
- Li J, Ebata A, Dong Y, Rizki G, Iwata T, Lee S. Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. 2008;6:e233 pubmed publisher..As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals. ..
- Vilchez D, Morantte I, Liu Z, Douglas P, Merkwirth C, Rodrigues A, et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature. 2012;489:263-8 pubmed publisher..Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders. ..
- Catoire H, Pasco M, Abu Baker A, Holbert S, Tourette C, Brais B, et al. Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1. Hum Mol Genet. 2008;17:2108-17 pubmed publisher..Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases...
- Pinkston Gosse J, Kenyon C. DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans. Nat Genet. 2007;39:1403-9 pubmed
- Lee S, Murphy C, Kenyon C. Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab. 2009;10:379-91 pubmed publisher..Together, these findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms. ..
- Alper S, McBride S, Lackford B, Freedman J, Schwartz D. Specificity and complexity of the Caenorhabditis elegans innate immune response. Mol Cell Biol. 2007;27:5544-53 pubmed..We also propose the existence of an "antimicrobial fingerprint," which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways. ..
- Wolff S, Ma H, Burch D, Maciel G, Hunter T, Dillin A. SMK-1, an essential regulator of DAF-16-mediated longevity. Cell. 2006;124:1039-53 pubmed..SMK-1 therefore plays a role in longevity by modulating DAF-16 transcriptional specificity without affecting other processes regulated by IIS. ..
- Berdichevsky A, Viswanathan M, Horvitz H, Guarente L. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell. 2006;125:1165-77 pubmed..We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span. ..