Daf-16

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DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor daf-2.[2] Moreover, the tractability of C. elegans as a model and interest in teasing out this conserved aging-associated genetic pathway allowed the intricacies of Insulin and Insulin-like growth factor (IGF) Signaling (IIS) to be thoroughly characterized primarily through studies using this model organism.[3] Daf -16 is responsible for the protection of C. elegans during food deprivation [4], causing it to transform into a hibernation - like state, known as a Dauer.

Gene[edit]

Daf-16 is located on chromosome 1, at position 175-268. The exon count is 15 [5]

FOXO (Forkhead box protein O)[edit]

Daf-16 encodes FOXO (Forkhead box protein O), which binds to gene promoters that contain the sequence TTGTTTAC in their regulatory region – this is the Daf-16 binding element (DBE). [6] FOXO is involved in the Insulin / IGF1 signalling pathway (IIS) which affects longevity, dauer formation, heat shock and oxidative stress responses and lipogenesis, by activating proteins such as MnSOD and Catalase. [7] Expression of FOXO in the intestine normally leads to longevity signalling. [8] It is inhibited by the protein Akt in the IIS pathway, as Daf-16 is inactivated when phosphorylated[9], which is why a reduction in insulin signalling generally leads to longevity in C. elegans and across species. For the carbon dioxide avoidance response, inhibition of Daf-16 is needed. [10] When inhibition is lost, Daf-16 translocates to the nucleus and regulates genes that delay growth and reproduction but increase stress resistance and longevity[11]

Species, tissue, subcellular distribution[edit]

C. elegans is the only known species to contain the Daf-16 gene[12] , although orthologs are conserved across species[13]. Daf-16 may localise to the nucleus or cytoplasm, depending on resources.[14] In nutrient rich conditions, Daf-2 and Akt-1/Akt-2 in the insulin pathway inhibits entry of Daf-16 to the nucleus. However starvation, heat and oxidative stress cause Daf-16 to localise to the nucleus. [15]Daf-16 is sequestered in the cytoplasm when associated with ftt-2.[16] Translocation to the nucleus and translation of longevity genes occurs after Daf-16 associates with PRMT-1 [17] Translocation to the nucleus is also promoted by JNK-1 in heat stress and SEK-1 in oxidative stress [18] [19]


Notable scientists involved in the initial and continued characterization of DAF-16-associated aging pathways:

See also[edit]

References[edit]

  1. ^ daf-16 at WormBase www.wormbase.org
  2. ^ Ogg, S; Paradis, S; Gottlieb, S; Patterson, GI; Lee, L; Tissenbaum, HA; Ruvkun, G (Oct 30, 1997). "The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans". Nature. 389 (6654): 994–9. doi:10.1038/40194. PMID 9353126. 
  3. ^ Kenyon, C. (29 November 2010). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philosophical Transactions of the Royal Society B: Biological Sciences. 366 (1561): 9–16. doi:10.1098/rstb.2010.0276. PMC 3001308Freely accessible. PMID 21115525. 
  4. ^ Henderson, ST. "daf-16 protects the nematode Caenorhabditis elegans during food deprivation". 
  5. ^ "daf-16 Forkhead box protein O [ Caenorhabditis elegans ]". 
  6. ^ "Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues". 
  7. ^ Lin, Kui. "daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans". 
  8. ^ Libina, Nataliya. "Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan". 
  9. ^ Yen, Kelvin. "DAF-16/Forkhead Box O Transcription Factor: Many Paths to a Single Fork(head) in the Road". 
  10. ^ Bretscher, Andrew Jonathan; Busch, Karl Emanuel; de Bono, Mario (10 June 2008). "A carbon dioxide avoidance behavior is integrated with responses to ambient oxygen and food in Caenorhabditis elegans". Proceedings of the National Academy of Sciences of the United States of America. pp. 8044–8049. doi:10.1073/pnas.0707607105. 
  11. ^ Henderson, S. T.; Johnson, T. E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current biology: CB. pp. 1975–1980. 
  12. ^ Hesp, Kylie. "Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease". 
  13. ^ Lee, RY. "Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway". 
  14. ^ "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". 
  15. ^ Henderson, Samuel T.; Johnson, Thomas E. (11 December 2001). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current Biology. pp. 1975–1980. doi:10.1016/S0960-9822(01)00594-2. 
  16. ^ Takahashi, Y. "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism. 
  17. ^ Takahashi, Y. "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism. 
  18. ^ Kondo, Masaki; Yanase, Sumino; Ishii, Takamasa; Hartman, Philip S.; Matsumoto, Kunihiro; Ishii, Naoaki (NaN). "The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei". Mechanisms of Ageing and Development. pp. 642–647. doi:10.1016/j.mad.2004.11.012.  Check date values in: |date= (help)
  19. ^ Oh, Seung Wook; Mukhopadhyay, Arnab; Svrzikapa, Nenad; Jiang, Feng; Davis, Roger J.; Tissenbaum, Heidi A. (22 March 2005). "JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16". Proceedings of the National Academy of Sciences of the United States of America. pp. 4494–4499. doi:10.1073/pnas.0500749102.