View source for Daf-2

{{short description|Protein-coding gene in the species Caenorhabditis elegans}}
{{Infobox nonhuman protein
| Name = abnormal dauer formation protein 2
| image =
| width =
| caption =
| Organism = Caenorhabditis elegans
| TaxID = 6239
| Symbol = daf-2
| AltSymbols =
| EntrezGene = 175410
| HomoloGene =
| PDB =
| RefSeqmRNA = NM_065249.5
| RefSeqProtein = NP_497650.4
| UniProt = Q968Y9
| Chromosome = III
| EntrezChromosome = NC_003281.10
| GenLoc_start = 2994514
| GenLoc_end = 3028800
}}
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.<ref name="pmid21115525">{{cite journal | vauthors = Kenyon C | title = The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing | journal = Philos Trans R Soc Lond B Biol Sci | volume = 366 | issue = 1561 | pages = 9–16 | date = January 2011 | pmid = 21115525 | pmc = 3001308 | doi = 10.1098/rstb.2010.0276 }}</ref> DAF-2 is also known to regulate reproductive development, resistance to [[oxidative stress]], thermotolerance, resistance to [[Hypoxia (medical)|hypoxia]], and resistance to bacterial [[pathogen]]s.<ref>{{cite journal | vauthors = Gami MS, Wolkow CA | title = Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan | journal = Aging Cell | volume = 5 | issue = 1 | pages = 31–7 | date = February 2006 | pmid = 16441841 | pmc = 1413578 | doi = 10.1111/j.1474-9726.2006.00188.x }}</ref> [[Mutations]] in DAF-2 and also [[Age-1]] have been shown by [[Cynthia Kenyon]] to double the lifespan of the worms.<ref name="pmid8601482">{{cite journal | vauthors = Dorman JB, Albinder B, Shroyer T, Kenyon C | title = The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans | journal = Genetics | volume = 141 | issue = 4 | pages = 1399–1406 | date = December 1995 | pmid = 8601482 | pmc = 1206875 | doi = 10.1093/genetics/141.4.1399 }}</ref><ref>{{cite journal | vauthors = Apfeld J, Kenyon C | title = Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span | journal = Cell | volume = 95 | issue = 2 | pages = 199–210 | date = October 1998 | pmid = 9790527 | doi = 10.1016/s0092-8674(00)81751-1 | doi-access = free }}</ref>  In a 2007 episode of WNYC’s [[Radiolab]], Kenyon called DAF-2 "the grim reaper gene.”<ref>Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. [Audio podcast]. Retrieved from http://www.radiolab.org/2007/jun/14/</ref>
==Long-lived mutants==
Long-lived ''DAF-2'' ''C. elegans'' [[mutant]]s are resistant to the [[oxidizing agent]] paraquat and to [[ultraviolet|UV light]].<ref name="Hyun_2008">{{cite journal | vauthors = Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B | title = Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans | journal = Nucleic Acids Research | volume = 36 | issue = 4 | pages = 1380–9 | date = March 2008 | pmid = 18203746 | pmc = 2275101 | doi = 10.1093/nar/gkm1161 }}</ref> ''DAF-2'' mutants also have a higher [[DNA repair]] capability than wild-type ''C. elegans''.<ref name = "Hyun_2008"/>  Knockdown of the [[nucleotide excision repair]] gene ''Xpa-1'' increases sensitivity to UV and reduces the [[longevity|life span]] of the long-lived mutants. These findings support the hypothesis that [[DNA damage theory of aging|DNA damage has a significant role in the aging process]].<ref name = "Hyun_2008"/>
== IGF-1 signal pathway ==
Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to [[mammals]].<ref name="Murphy">{{cite journal | vauthors = Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C | display-authors = 6 | title = Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans | journal = Nature | volume = 424 | issue = 6946 | pages = 277–83 | date = July 2003 | pmid = 12845331 | doi = 10.1038/nature01789 | bibcode = 2003Natur.424..277M | s2cid = 4424249 }}</ref> 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 [[INSR|human insulin receptor–related]] receptor.<ref>{{cite journal | vauthors = Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G | title = daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans | journal = Science | volume = 277 | issue = 5328 | pages = 942–6 | date = August 1997 | pmid = 9252323 | doi = 10.1126/science.277.5328.942 }}</ref><ref>{{cite journal | vauthors = Kenyon C | title = The plasticity of aging: insights from long-lived mutants | journal = Cell | volume = 120 | issue = 4 | pages = 449–60 | date = February 2005 | pmid = 15734678 | doi = 10.1016/j.cell.2005.02.002 | doi-access = free }}</ref> In ''C. elegans'', the insulin/IGF-1/[[FOX proteins|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|DAF-16]] is active and present in the [[Cell nucleus|nucleus]]. DAF-16 is responsible for up-regulating [[Transcription (genetics)|transcription]] of about 100 genes that code for cell protecting products such as [[heat shock protein]]s and [[antioxidants]].<ref name="Hu">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.</ref> Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 [[Gene knockdown|knock-downs]].<ref name="pmid21115525"/>  By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.<ref name="Murphy" /> 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''.<ref name="Pierce">{{cite journal | vauthors = Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, Ferguson KC, Heller J, Platt DM, Pasquinelli AA, Liu LX, Doberstein SK, Ruvkun G | display-authors = 6 | title = 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 | journal = Genes & Development | volume = 15 | issue = 6 | pages = 672–86 | date = March 2001 | pmid = 11274053 | pmc = 312654 | doi = 10.1101/gad.867301 }}</ref>
== Role in ''C. elegans'' developmental stages ==
''Caenorhabditis elegans'', which progresses through a series of [[larva]]l stages into a final reproductive adult, may instead enter a less metabolically active [[dauer larva|dauer diapause]] stage if food scarcity or overcrowding occurs before reaching adulthood.<ref name="Hu"/> Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays [[senescence]] and prevents reproductive maturity.<ref name="Pierce"/>
== 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.<ref name="Lee">{{cite journal | vauthors = Lee SJ, Murphy CT, Kenyon C | title = Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression | journal = Cell Metabolism | volume = 10 | issue = 5 | pages = 379–91 | date = November 2009 | pmid = 19883616 | pmc = 2887095 | doi = 10.1016/j.cmet.2009.10.003 }}</ref>
== See also ==
* [[Unfolded protein response]]
* [[Genetics of aging]]
== References ==
{{reflist}}
{{Dauer larva}}
[[Category:Caenorhabditis elegans genes]]
[[Category:Aging-related genes]]