Biology:Daf-2

From HandWiki
Short description: Protein-coding gene in the species Caenorhabditis elegans
abnormal dauer formation protein 2
Identifiers
OrganismCaenorhabditis elegans
Symboldaf-2
Entrez175410
RefSeq (mRNA)NM_065249.5
RefSeq (Prot)NP_497650.4
UniProtQ968Y9
Other data
ChromosomeIII: 2.99 - 3.03 Mb

The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging.[1] DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens.[2] Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms.[3][4] In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”[5]

Long-lived mutants

Long-lived DAF-2 C. elegans mutants are resistant to the oxidizing agent paraquat and to UV light.[6] DAF-2 mutants also have a higher DNA repair capability than wild-type C. elegans.[6] Knockdown of the nucleotide excision repair gene Xpa-1 increases sensitivity to UV and reduces the life span of the long-lived mutants. These findings support the hypothesis that DNA damage has a significant role in the aging process.[6]

IGF-1 signal pathway

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.[7] DAF-2 is the only member of the insulin receptor family in C. elegans but it corresponds, in form and function, to multiple pathways in humans. The protein predicted from DAF-2's sequence is 35% identical to the human insulin receptor, which regulates metabolism; 34% identical to the IGF-1 receptor, which regulates growth; and 33% identical to the human insulin receptor–related receptor.[8][9] In C. elegans, the insulin/IGF-1/FOXO pathway is initiated by changes in IGF-1 levels which cause IGF-1 receptors to start a phosphorylation cascade that deactivates the FOXO transcription factor, DAF-16. When not phosphorylated, DAF-16 is active and present in the nucleus. DAF-16 is responsible for up-regulating transcription of about 100 genes that code for cell protecting products such as heat shock proteins and antioxidants.[10] Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.[1] By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.[7] In most eukaryotes, insulin activates DAF-2 signaling. However, both human insulin and insulin coded for by orthologous genes in C. elegans inhibit DAF-2 receptors in C. elegans.[11]

Role in C. elegans developmental stages

Caenorhabditis elegans, which progresses through a series of larval stages into a final reproductive adult, may instead enter a less metabolically active dauer diapause stage if food scarcity or overcrowding occurs before reaching adulthood.[10] Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays senescence and prevents reproductive maturity.[11]

Diet’s interaction with the IGF-1 pathway

Research into the interaction between diet and the insulin/IGF-1 pathway has shown sugar intake to be negatively correlated with DAF-16 activity and longevity. One study found that glucose ingestion reduced the rate of dauer formation and shortened the life-spans of DAF-2 knock-downs to resemble that of normal C. elegans, suggesting that DAF-16 mediated gene expression associated with longevity is suppressed by glucose ingestion. Wild type C. elegans fed a diet that included 2% glucose showed reduced Daf-16 activity and lifespan was shortened by 20% compared to worms fed on glucose-free media. These findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms.[12]

See also

References

  1. ↑ 1.0 1.1 "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philos Trans R Soc Lond B Biol Sci 366 (1561): 9–16. January 2011. doi:10.1098/rstb.2010.0276. PMID 21115525. 
  2. ↑ "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31–7. February 2006. doi:10.1111/j.1474-9726.2006.00188.x. PMID 16441841. 
  3. ↑ "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans". Genetics 141 (4): 1399–1406. December 1995. doi:10.1093/genetics/141.4.1399. PMID 8601482. 
  4. ↑ "Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span". Cell 95 (2): 199–210. October 1998. doi:10.1016/s0092-8674(00)81751-1. PMID 9790527. 
  5. ↑ Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. [Audio podcast]. Retrieved from http://www.radiolab.org/2007/jun/14/
  6. ↑ 6.0 6.1 6.2 "Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans". Nucleic Acids Research 36 (4): 1380–9. March 2008. doi:10.1093/nar/gkm1161. PMID 18203746. 
  7. ↑ 7.0 7.1 "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans". Nature 424 (6946): 277–83. July 2003. doi:10.1038/nature01789. PMID 12845331. Bibcode: 2003Natur.424..277M. 
  8. ↑ "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans". Science 277 (5328): 942–6. August 1997. doi:10.1126/science.277.5328.942. PMID 9252323. 
  9. ↑ "The plasticity of aging: insights from long-lived mutants". Cell 120 (4): 449–60. February 2005. doi:10.1016/j.cell.2005.02.002. PMID 15734678. 
  10. ↑ 10.0 10.1 Hu, 2007 Hu, P.J. (2007). Dauer. In WormBook, The C. elegans Research Community, ed. 10.1895/wormbook.1.144.1, http://www.wormbook.org.
  11. ↑ 11.0 11.1 "Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family". Genes & Development 15 (6): 672–86. March 2001. doi:10.1101/gad.867301. PMID 11274053. 
  12. ↑ "Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression". Cell Metabolism 10 (5): 379–91. November 2009. doi:10.1016/j.cmet.2009.10.003. PMID 19883616. 



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