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Gene Review

daf-2  -  Protein DAF-2

Caenorhabditis elegans

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Disease relevance of daf-2

  • We have discovered that daf-2 and age-1 mutations result in increased Cd and Cu ion resistance in a 24 h toxicity assay [1].
  • Calorie restriction enhances the activity of Delta6 and Delta5 desaturases, melatonin production, decreases daf-2 signaling, free radical generation, and augments anti-oxidant defenses that may explain the beneficial effect of diet control in the management of obesity, insulin resistance, and type II diabetes mellitus [2].
  • In a recent study published in Science Express on 13 June 2002, researchers screened for Caenorhabditis elegans mutants that survive in a low-oxygen environment and identified a number of daf-2 mutants that are resistant to hypoxia [3].

High impact information on daf-2

  • In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval development and extend lifespan in adults [4].
  • Genetic analysis in Caenorhabditis elegans has shown that the Forkhead transcription factor daf-16 is regulated by a pathway consisting of insulin-receptor-like daf-2 and PI(3)K-like age-1 [5].
  • The findings suggest that Q and the daf-2 pathway intersect at the mitochondria and imply that a concerted production coupled with enhanced scavenging of reactive oxygen species contributes to the substantial life-span extension [6].
  • A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member [7].
  • The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators [8].

Biological context of daf-2


Anatomical context of daf-2

  • Increased temperature-food association of the daf-2 mutant was dependent on neuronal Ca2+-sensor ncs-1, which modulates isothermal tracking in the AIY interneuron [13].
  • Furthermore, constitutive expression of daf-9 in the hypodermis suppresses dauer arrest of daf-7 mutant animals and inhibits dauer remodelling of some tissues in daf-2 mutant animals [14].
  • We conclude that increased expression of proteins that protect eukaryotic cells against environmental stress and/or repair stress-induced molecular damage confers hypertonic stress resistance in C. elegans daf-2/age-1 mutants [15].

Associations of daf-2 with chemical compounds


Regulatory relationships of daf-2

  • Survival curves demonstrated that both daf-2 (insulin receptor pathway) showing enhanced heat tolerance and daf-16 loss-of-function (a transcription factor mediating DAF-2 signaling) mutants benefit from AC, suggesting that the insulin receptor pathway does not mediate AC [20].
  • We found that RNAi knock down of ftt-2 specifically enhanced the daf-2-mediated dauer formation phenotype [21].
  • The pep-2 mutant enhances the developmental and longevity phenotypes of daf-2, resulting, among other effects, in a pronounced increase in adult life span [22].
  • Other effectors of soc-1/Gab1 are likely to inhibit PLCgamma-mediated signaling and stimulate the poorly defined signaling pathway that represses class 2 daf-2 phenotypes [23].
  • The increased life span caused by the daf-2 mutation can be enhanced by a daf-12 mutation and suppressed by a daf-16 mutation [24].

Other interactions of daf-2

  • These genes include an insulin-like receptor (daf-2) and a phosphatidylinositol 3-OH kinase (age-1) regulating a forkhead transcription factor (daf-16) [6, 7], as well as genes mediating metabolic throughput [8], sensory perception [9], and reproduction [10] [25].
  • RNA levels of dao-5 and dao-6 showed elevated expression in daf-2 adults, as well as being strongly expressed in dauer larvae [26].
  • Three other genes, daf-2, daf-3 and daf-5, displayed partial or complex epistasis interactions that were difficult to interpret as part of a simple linear pathway [27].
  • The transcription of old-1 is upregulated in long-lived age-1 and daf-2 mutants and is upregulated in response to heat, UV light, and starvation [25].
  • Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner [28].

Analytical, diagnostic and therapeutic context of daf-2


  1. Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. Barsyte, D., Lovejoy, D.A., Lithgow, G.J. FASEB J. (2001) [Pubmed]
  2. A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Das, U.N. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  3. Oxygen? No thanks, I'm on a diet. Longo, V.D. Science of aging knowledge environment [electronic resource] : SAGE KE (2002) [Pubmed]
  4. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Tissenbaum, H.A., Guarente, L. Nature (2001) [Pubmed]
  5. Direct control of the Forkhead transcription factor AFX by protein kinase B. Kops, G.J., de Ruiter, N.D., De Vries-Smits, A.M., Powell, D.R., Bos, J.L., Burgering, B.M. Nature (1999) [Pubmed]
  6. Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. Larsen, P.L., Clarke, C.F. Science (2002) [Pubmed]
  7. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Kimura, K.D., Tissenbaum, H.A., Liu, Y., Ruvkun, G. Science (1997) [Pubmed]
  8. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Lin, K., Dorman, J.B., Rodan, A., Kenyon, C. Science (1997) [Pubmed]
  9. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. Honda, Y., Honda, S. FASEB J. (1999) [Pubmed]
  10. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. McElwee, J.J., Schuster, E., Blanc, E., Thomas, J.H., Gems, D. J. Biol. Chem. (2004) [Pubmed]
  11. Uncoupling of longevity and telomere length in C. elegans. Raices, M., Maruyama, H., Hugo, A., Karlseder, J. PLoS Genet. (2005) [Pubmed]
  12. A systematic RNAi screen for longevity genes in C. elegans. Hamilton, B., Dong, Y., Shindo, M., Liu, W., Odell, I., Ruvkun, G., Lee, S.S. Genes Dev. (2005) [Pubmed]
  13. Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans. Murakami, H., Bessinger, K., Hellmann, J., Murakami, S. J. Neurosci. (2005) [Pubmed]
  14. Intercellular signaling of reproductive development by the C. elegans DAF-9 cytochrome P450. Mak, H.Y., Ruvkun, G. Development (2004) [Pubmed]
  15. Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress. Lamitina, S.T., Strange, K. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  16. Both insulin and calcium channel signaling are required for developmental regulation of serotonin synthesis in the chemosensory ADF neurons of Caenorhabditis elegans. Estevez, A.O., Cowie, R.H., Gardner, K.L., Estevez, M. Dev. Biol. (2006) [Pubmed]
  17. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Wolkow, C.A., Kimura, K.D., Lee, M.S., Ruvkun, G. Science (2000) [Pubmed]
  18. Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans. McElwee, J.J., Schuster, E., Blanc, E., Thornton, J., Gems, D. Mech. Ageing Dev. (2006) [Pubmed]
  19. Erratum to "Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans" [Mech. Ageing Dev. 127 (5) (2006) 458-472]. McElwee, J.J., Schuster, E., Blanc, E., Thornton, J., Gems, D. Mech. Ageing Dev. (2006) [Pubmed]
  20. HIF-1 is required for heat acclimation in the nematode Caenorhabditis elegans. Treinin, M., Shliar, J., Jiang, H., Powell-Coffman, J.A., Bromberg, Z., Horowitz, M. Physiol. Genomics (2003) [Pubmed]
  21. The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis elegans. Li, J., Tewari, M., Vidal, M., Sylvia Lee, S. Dev. Biol. (2007) [Pubmed]
  22. Deletion of the intestinal peptide transporter affects insulin and TOR signaling in Caenorhabditis elegans. Meissner, B., Boll, M., Daniel, H., Baumeister, R. J. Biol. Chem. (2004) [Pubmed]
  23. The adaptor protein soc-1/Gab1 modifies growth factor receptor output in Caenorhabditis elegans. Hopper, N.A. Genetics (2006) [Pubmed]
  24. Protein carbonyl accumulation in aging dauer formation-defective (daf) mutants of Caenorhabditis elegans. Yasuda, K., Adachi, H., Fujiwara, Y., Ishii, N. J. Gerontol. A Biol. Sci. Med. Sci. (1999) [Pubmed]
  25. The OLD-1 positive regulator of longevity and stress resistance is under DAF-16 regulation in Caenorhabditis elegans. Murakami, S., Johnson, T.E. Curr. Biol. (2001) [Pubmed]
  26. DAF-16-dependent and independent expression targets of DAF-2 insulin receptor-like pathway in Caenorhabditis elegans include FKBPs. Yu, H., Larsen, P.L. J. Mol. Biol. (2001) [Pubmed]
  27. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Vowels, J.J., Thomas, J.H. Genetics (1992) [Pubmed]
  28. Genes that regulate both development and longevity in Caenorhabditis elegans. Larsen, P.L., Albert, P.S., Riddle, D.L. Genetics (1995) [Pubmed]
  29. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Tatar, M., Kopelman, A., Epstein, D., Tu, M.P., Yin, C.M., Garofalo, R.S. Science (2001) [Pubmed]
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