View source for Daf-16

{{short description|Ortholog}}
{| | border=1 align="right" class="wikitable"
!
!DAF-16
|-
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|[[File:Structure-2.png|thumb|A crystalline structure of the protein FOXO, encoded by Daf-16]]
|-
|'''Gene'''
|DAF-16
|-
|'''Protein'''
|[[FOX proteins|FOXO]]
|-
|'''Location'''
|[[Chromosome 1]]
|-
|'''Position'''
|175-268
|-
|'''Organism'''
|''[[Caenorhabditis elegans]]''
|}
'''DAF-16''' is the sole [[Homology (biology)#Orthology|ortholog]] of the [[FOX proteins|FOXO]] family of transcription factors in the [[nematode]] ''[[Caenorhabditis elegans]]''.<ref>{{cite journal|last1=Lin|first1=K.|last2=Dorman|first2=J. B.|last3=Rodan|first3=A.|last4=Kenyon|first4=C.|s2cid=36088123|title=daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans|journal=Science|pages=1319–1322|date=14 November 1997|pmid=9360933|volume=278|issue=5341|doi=10.1126/science.278.5341.1319|bibcode=1997Sci...278.1319L}}</ref> It is responsible for activating genes involved in [[longevity]], [[lipogenesis]], [[heat shock]] survival and [[oxidative stress]] responses.<ref>{{cite journal|last1=Henderson|first1=S. T.|last2=Johnson|first2=T. E.|title=daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans|journal=Current Biology|pages=1975–1980|date=11 December 2001|pmid=11747825|volume=11|issue=24|doi=10.1016/s0960-9822(01)00594-2|s2cid=12674040|doi-access=free}}</ref><ref>{{cite journal|last1=Lin|first1=K.|last2=Dorman|first2=J. B.|last3=Rodan|first3=A.|last4=Kenyon|first4=C.|s2cid=36088123|title=daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans|journal=Science|pages=1319–1322|date=14 November 1997|pmid=9360933|volume=278|issue=5341|doi=10.1126/science.278.5341.1319|bibcode=1997Sci...278.1319L}}</ref> It also protects ''C.elegans'' during food deprivation, causing it to transform into a [[hibernation]] - like state, known as a [[Dauer larva|Dauer]].<ref>{{cite journal|last1=Fielenbach|first1=Nicole|last2=Antebi|first2=Adam|title=C. elegans dauer formation and the molecular basis of plasticity|issue=16|journal=Genes & Development|volume=22|pages=2149–2165|language=en|doi=10.1101/gad.1701508|pmid=18708575|pmc=2735354|date=15 August 2008}}</ref> DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the [[Insulin-like growth factor 1 receptor|insulin-like receptor]] ''[[daf-2|DAF-2]]''.<ref>{{cite journal|last=Ogg|first=S|author2=Paradis, S |author3=Gottlieb, S |author4=Patterson, GI |author5=Lee, L |author6=Tissenbaum, HA |author7= Ruvkun, G |title=The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans.|journal=Nature|date=October 30, 1997|volume=389|issue=6654|pages=994–9|pmid=9353126|doi=10.1038/40194|bibcode=1997Natur.389..994O|s2cid=4412006}}</ref> The gene has played a large role in research into longevity and the [[insulin signal transduction pathway|insulin signalling pathway]] as it is located in ''C. elegans'', a successful ageing model organism.<ref>{{cite journal|last=Kenyon|first=C.|title=The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing|journal=Philosophical Transactions of the Royal Society B: Biological Sciences|date=29 November 2010|volume=366|issue=1561|pages=9–16|doi=10.1098/rstb.2010.0276|pmid=21115525|pmc=3001308}}</ref>
== Genetics ==
DAF-16 is a gene conserved across species, with [[homologs]] being found in ''C. elegans'', [[humans]], [[mice]], and ''[[Drosophila]]'' (fruit flies).<ref>{{cite journal|last1=Hesp|first1=Kylie|last2=Smant|first2=Geert|last3=Kammenga|first3=Jan E.|title=Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease|journal=Experimental Gerontology|year=2015 |pages=1–7|doi=10.1016/j.exger.2015.09.006|pmid=26363351|volume=72|doi-access=free}}</ref> In ''C. elegans'', DAF-16 is located on [[Chromosome 1]], at position 175-268.<ref>{{cite web|title=blastp results [running]|url=https://www.uniprot.org/blast/uniprot/B20171126AAFB7E4D2F1D05654627429E83DA5CCEDF22E9F|website=www.uniprot.org|language=en}}</ref> It is made up of 15 [[exons]].<ref>{{cite web|title=daf-16 Forkhead box protein O [Caenorhabditis elegans] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/172981|website=www.ncbi.nlm.nih.gov}}</ref> DAF-16 is also located downstream of [[Daf-2|DAF-2]], which signals in the [[insulin signal transduction pathway|IIS]] pathway. [[Mutants]] in this pathway age slower and have a lifespan up to twice as long as normal.<ref>{{cite journal|last1=Lin|first1=K.|last2=Hsin|first2=H.|last3=Libina|first3=N.|last4=Kenyon|first4=C.|title=Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling|journal=Nature Genetics|year=2001 |pages=139–145|doi=10.1038/88850|pmid=11381260|volume=28|issue=2|s2cid=24436462}}</ref> Further studies have demonstrated that the lifespan extension is dependent on DAF-16.<ref>{{cite journal|last1=Lin|first1=K.|last2=Hsin|first2=H.|last3=Libina|first3=N.|last4=Kenyon|first4=C.|title=Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling|journal=Nature Genetics|year=2001 |pages=139–145|doi=10.1038/88850|pmid=11381260|volume=28|issue=2|s2cid=24436462}}</ref> Other consequences of mutations in the DAF-16 gene is the inability to form dauers.<ref>{{cite journal|last1=Gottlieb|first1=S.|last2=Ruvkun|first2=G.|title=Daf-2, Daf-16 and Daf-23: Genetically Interacting Genes Controlling Dauer Formation in Caenorhabditis Elegans|journal=Genetics|year=1994 |pages=107–120|pmc=1205929|pmid=8056303|volume=137|issue=1|doi=10.1093/genetics/137.1.107}}</ref>
== FOXO (Forkhead box protein O) ==
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).<ref>{{cite journal|title=Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues|journal=Biochemical Journal|volume=349|issue=2|pages=629–634|doi=10.1042/bj3490629|year=2000|last1=Furuyama|first1=Tatsuo|last2=Nakazawa|first2=Toru|last3=Nakano|first3=Itsuko|last4=Mori|first4=Nozomu|pmid=10880363|pmc=1221187}}</ref> FOXO is involved in the [[Insulin signal transduction pathway|Insulin / IGF1 signalling pathway (IIS)]] which affects [[longevity]], [[lipogenesis]], [[dauer larva|dauer formation]], [[heat shock]] and [[oxidative stress]] responses, by activating proteins such as [[MnSOD]] and [[Catalase]].<ref>{{cite journal|last1=Lin|first1=Kui|s2cid=36088123|title=daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans|journal=Science|volume=278|issue=5341|pages=1319–1322|doi=10.1126/science.278.5341.1319|pmid=9360933|year=1997|bibcode=1997Sci...278.1319L}}</ref> Expression of FOXO in the intestine normally leads to longevity signalling.<ref>{{cite journal|last1=Libina|first1=Nataliya|title=Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan|doi=10.1016/S0092-8674(03)00889-4|pmid=14622602|volume=115|issue=4|journal=Cell|pages=489–502|date=2003-11-14|s2cid=9369021|doi-access=free}}</ref> FOXO has been shown to have a protective role against [[cancer]], as it regulates and suppresses genes involved in [[tumour]] formation.<ref>{{cite journal|last1=Pinkston-Gosse|first1=Julie|last2=Kenyon|first2=Cynthia|title=DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans|journal=Nature Genetics|year=2007 |pages=1403–1409|doi=10.1038/ng.2007.1|pmid=17934462|volume=39|issue=11|s2cid=23496539}}</ref> It also has a protective role against [[muscular dystrophy]].<ref>{{cite journal|last1=Catoire|first1=Hélène|last2=Pasco|first2=Matthieu Y.|last3=Abu-Baker|first3=Aida|last4=Holbert|first4=Sébastien|last5=Tourette|first5=Cendrine|last6=Brais|first6=Bernard|last7=Rouleau|first7=Guy A.|last8=Parker|first8=J. Alex|last9=Néri|first9=Christian|title=Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1|journal=Human Molecular Genetics|pages=2108–2117|doi=10.1093/hmg/ddn109|date=15 July 2008|pmid=18397876|volume=17|issue=14|doi-access=free}}</ref> FOXO is also important in [[embryonic development]], as it promotes [[apoptosis]].<ref>{{cite journal|last1=Nakagawa|first1=Akihisa|last2=Sullivan|first2=Kelly D.|last3=Xue|first3=Ding|title=Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway|journal=Nature Structural & Molecular Biology|year=2014 |pages=1082–1090|doi=10.1038/nsmb.2915|pmid=25383666|pmc=4256149|volume=21|issue=12}}</ref>
'''Insulin Signalling'''
Insulin and IGF1 are peptide [[hormones]] dictating energy functions such as glucose and lipid [[metabolism]].<ref>{{cite journal|last1=Boucher|first1=Jérémie|last2=Kleinridders|first2=André|last3=Kahn|first3=C. Ronald|title=Insulin Receptor Signaling in Normal and Insulin-Resistant States|journal=Cold Spring Harbor Perspectives in Biology|year=2014 |doi=10.1101/cshperspect.a009191|pmid=24384568|pmc=3941218|volume=6|issue=1|page=a009191}}</ref> The signalling pathway is evolutionary conserved and found across [[species]].<ref>{{cite journal|last1=Barbieri|first1=Michelangela|last2=Bonafè|first2=Massimiliano|last3=Franceschi|first3=Claudio|last4=Paolisso|first4=Giuseppe|s2cid=6811695|title=Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans|journal=American Journal of Physiology. Endocrinology and Metabolism|year=2003 |pages=E1064–1071|doi=10.1152/ajpendo.00296.2003|pmid=14534077|volume=285|issue=5}}</ref> Signalling occurs through kinases such as [[PI3K]] to produce phospholipid products such as [[AKT]].<ref>{{cite journal|last1=Gami|first1=Minaxi S|last2=Wolkow|first2=Catherine A|title=Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan|journal=Aging Cell|year=2006 |pages=31–37|doi=10.1111/j.1474-9726.2006.00188.x|pmid=16441841|pmc=1413578|volume=5|issue=1}}</ref> This causes downstream [[phosphorylation]] of targets such as DAF-16 by a [[phosphorylation cascade]], blocking nuclear entry. Therefore, a reduction in insulin signalling generally leads to an increase in FOXO expression, as DAF-16 is no longer inhibited by AKT.<ref>{{cite journal|last1=O'Neill|first1=Brian T.|last2=Lee|first2=Kevin Y.|last3=Klaus|first3=Katherine|last4=Softic|first4=Samir|last5=Krumpoch|first5=Megan T.|last6=Fentz|first6=Joachim|last7=Stanford|first7=Kristin I.|last8=Robinson|first8=Matthew M.|last9=Cai|first9=Weikang|last10=Kleinridders|first10=Andre|last11=Pereira|first11=Renata O.|last12=Hirshman|first12=Michael F.|last13=Abel|first13=E. Dale|last14=Accili|first14=Domenico|last15=Goodyear|first15=Laurie J.|last16=Nair|first16=K. Sreekumaran|last17=Kahn|first17=C. Ronald|title=Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis|journal=The Journal of Clinical Investigation|pages=3433–3446|doi=10.1172/JCI86522|date=1 September 2016|pmid=27525440|pmc=5004956|volume=126|issue=9}}</ref> When not phosphorylated, DAF-16 is active and present in the nucleus,<ref>{{cite journal|last1=Henderson|first1=S. T.|last2=Johnson|first2=T. E.|title=daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans|journal=Current Biology|pages=1975–1980|date=11 December 2001|pmid=11747825|volume=11|issue=24|doi=10.1016/s0960-9822(01)00594-2|s2cid=12674040|doi-access=free}}</ref> so FOXO can be transcribed and can up-regulate production of about 100 beneficial proteins that increase longevity.<ref>{{cite journal|last1=Greer|first1=Eric L|last2=Brunet|first2=Anne|title=FOXO transcription factors at the interface between longevity and tumor suppression|issue=50|journal=Oncogene|volume=24|pages=7410–7425|language=En|doi=10.1038/sj.onc.1209086|pmid=16288288|date=14 November 2005|doi-access=free}}</ref>
== Species, tissue, subcellular distribution ==
''C. elegans'' is the only known species to contain the DAF-16 gene,<ref>{{cite journal|last1=Hesp|first1=Kylie|title=Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease|doi=10.1016/j.exger.2015.09.006|pmid=26363351|volume=72|journal=Experimental Gerontology|pages=1–7|date=December 2015|doi-access=free}}</ref> although [[orthologs]] are conserved across species.<ref>{{cite journal|last1=Lee|first1=RY|title=Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway.|pmid=11747821|volume=11|issue=24|journal=Curr Biol|pages=1950–7|doi=10.1016/s0960-9822(01)00595-4|year=2001|s2cid=18193060|doi-access=free}}</ref> DAF-16 may localise to the [[Cell nucleus|nucleus]] or [[cytoplasm]], depending on resources.<ref>{{cite journal|title=daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans| doi=10.1016/S0960-9822(01)00594-2 | volume=11|issue=24|journal=Current Biology|pages=1975–1980|pmid=11747825 | last1 = Henderson | first1 = ST | last2 = Johnson | first2 = TE|date=2001-12-11 | s2cid=12674040 | doi-access=free }}</ref> In nutrient rich conditions, [[Daf-2|DAF-2]] and [[Akt|AKT-1/AKT-2]] in the insulin pathway inhibits entry of DAF-16 to the nucleus as it is [[phosphorylated]]. However starvation, heat and oxidative stress inhibit phosphorylation by AKT and allow the localisation of DAF-16 to the nucleus.<ref>{{cite journal|last1=Henderson|first1=Samuel T.|last2=Johnson|first2=Thomas E.|title=daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans|journal=Current Biology|pages=1975–1980|doi=10.1016/S0960-9822(01)00594-2|date=11 December 2001|volume=11|issue=24|pmid=11747825|s2cid=12674040|doi-access=free}}</ref> DAF-16 is sequestered in the cytoplasm when associated with ''ftt-2''.<ref>{{cite journal|last1=Takahashi|first1=Y|title=Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.|journal=Cell Metabolism|pmid=21531333|doi=10.1016/j.cmet.2011.03.017|volume=13|issue=5|pages=505–16|year=2011|doi-access=free}}</ref> [[Chromosomal translocation|Translocation]] to the nucleus and translation of longevity genes occurs after DAF-16 associates with ''prmpt-1'' <ref>{{cite journal|last1=Takahashi|first1=Y|title=Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.|doi=10.1016/j.cmet.2011.03.017|pmid=21531333|volume=13|issue=5|journal=Cell Metab|pages=505–16|date=2011-05-04|doi-access=free}}</ref> Translocation to the nucleus is also promoted by ''jnk-1'' in heat stress and ''sek-1'' in oxidative stress.<ref>{{cite journal|last1=Kondo|first1=Masaki|last2=Yanase|first2=Sumino|last3=Ishii|first3=Takamasa|last4=Hartman|first4=Philip S.|last5=Matsumoto|first5=Kunihiro|last6=Ishii|first6=Naoaki|title=The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei|journal=Mechanisms of Ageing and Development|year=2005 |pages=642–647|doi=10.1016/j.mad.2004.11.012|pmid=15888317|volume=126|issue=6–7|s2cid=41258250}}</ref><ref>{{cite journal|last1=Oh|first1=Seung Wook|last2=Mukhopadhyay|first2=Arnab|last3=Svrzikapa|first3=Nenad|last4=Jiang|first4=Feng|last5=Davis|first5=Roger J.|last6=Tissenbaum|first6=Heidi A.|title=JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16|journal=Proceedings of the National Academy of Sciences of the United States of America|pages=4494–4499|doi=10.1073/pnas.0500749102|date=22 March 2005|pmid=15767565|pmc=555525|volume=102|issue=12|bibcode=2005PNAS..102.4494O|doi-access=free}}</ref>
'''Expression'''
Isoform b and Isoform c are expressed in [[muscle]]s, [[ectoderm]], the [[intestine]] and [[neurones|neurons]].<ref>{{cite journal|last1=Wolf|first1=Marc|last2=Nunes|first2=Frank|last3=Henkel|first3=Arne|last4=Heinick|first4=Alexander|last5=Paul|first5=Rüdiger J.|title=The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation, and influences over temperature-dependent insulin-like signaling, stress responses, and fitness|journal=Journal of Cellular Physiology|year=2008 |pages=721–729|doi=10.1002/jcp.21269|pmid=17894411|volume=214|issue=3|s2cid=24383053}}</ref> Isoform b is additionally expressed in the [[pharynx]].<ref>{{cite journal|last1=Lee|first1=R. Y.|last2=Hench|first2=J.|last3=Ruvkun|first3=G.|title=Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway|journal=Current Biology|pages=1950–1957|date=11 December 2001|pmid=11747821|volume=11|issue=24|doi=10.1016/s0960-9822(01)00595-4|s2cid=18193060|doi-access=free}}</ref> Expression can be induced by [[quinic acid]].<ref>{{cite journal|last1=Zhang|first1=Longze|last2=Zhang|first2=Junjing|last3=Zhao|first3=Baolu|last4=Zhao-Wilson|first4=Xi|title=Quinic acid could be a potential rejuvenating natural compound by improving survival of Caenorhabditis elegans under deleterious conditions|journal=Rejuvenation Research|year=2012 |pages=573–583|doi=10.1089/rej.2012.1342|pmid=22950425|pmc=3549210|volume=15|issue=6}}</ref>
== Clinical significance ==
'''Implication in Aging'''
DAF-16 is necessary for dauer formation and the protection of ''C. elegans'' during periods of starvation, as DAF-16, DAF-18 and DAF-12 loss - of - function mutants lose the ability to form dauers.<ref>{{cite journal|last1=Cypser|first1=James R.|last2=Johnson|first2=Thomas E.|title=Hormesis in Caenorhabditis elegans dauer-defective mutants|journal=Biogerontology|pages=203–214|date=2003|pmid=14501184|volume=4|issue=4|doi=10.1023/A:1025138800672|s2cid=12903972}}</ref> A 2003 study by Murphy et al. showed the significance of DAF-16 for longevity, as it up-regulates genes involved in lifespan extension such as stress response genes and down regulates specific life-shortening genes.<ref>{{cite web|last1=Murphy|first1=Coleen|title=Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans {{!}} Learn Science at Scitable|url=https://www.nature.com/scitable/content/Genes-that-act-downstream-of-DAF-16-13901|website=www.nature.com|language=en}}</ref> It has been proven that [[telomeres]] have an implication in the [[aging]] process, and in ''C. elegans'' the lifespan - extending effect of long telomeres is dependent on DAF-16.<ref>{{cite journal|last1=Joeng|first1=Kyu Sang|last2=Song|first2=Eun Joo|last3=Lee|first3=Kong-Joo|last4=Lee|first4=Junho|title=Long lifespan in worms with long telomeric DNA|journal=Nature Genetics|year=2004 |pages=607–611|doi=10.1038/ng1356|pmid=15122256|volume=36|issue=6|doi-access=free}}</ref> DAF-2 mutations more than double the lifespan of ''C. elegans'', and this effect is dependent on the activity of DAF-16 as it encodes a member of the [[hepatocyte]] nuclear family 3 (HNF3)/ Forkhead family of [[transcription factors]].<ref>{{cite journal|last1=Lin|first1=K.|last2=Dorman|first2=J. B.|last3=Rodan|first3=A.|last4=Kenyon|first4=C.|s2cid=36088123|title=daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans|journal=Science|pages=1319–1322|date=14 November 1997|pmid=9360933|volume=278|issue=5341|doi=10.1126/science.278.5341.1319|bibcode=1997Sci...278.1319L}}</ref>
''C. elegans'' has long been used in aging research.<ref>{{cite journal|last1=Tissenbaum|first1=Heidi A.|title=Using C. elegans for aging research|journal=Invertebrate Reproduction & Development|pages=59–63|doi=10.1080/07924259.2014.940470|date=30 January 2015|pmid=26136622|pmc=4464094|volume=59|issue=sup1}}</ref> Although DAF-16 increases longevity, treating ''C.elegans'' with [[resveratrol]] extends lifespan in a method independent of DAF-16 and fully dependent on [[SIR proteins|SIR2.1]].<ref>{{cite journal|last1=Viswanathan|first1=Mohan|last2=Kim|first2=Stuart K.|last3=Berdichevsky|first3=Ala|last4=Guarente|first4=Leonard|title=A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span|journal=Developmental Cell|year=2005 |pages=605–615|doi=10.1016/j.devcel.2005.09.017|pmid=16256736|volume=9|issue=5|doi-access=free}}</ref>
== Interactions ==
DAF-16 is known to interact with:
* RLE-1 <ref>{{cite journal|last1=Li|first1=Wensheng|last2=Gao|first2=Beixue|last3=Lee|first3=Sang-Myeong|last4=Bennett|first4=Karen|last5=Fang|first5=Deyu|title=RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination|journal=Developmental Cell|year=2007 |pages=235–246|doi=10.1016/j.devcel.2006.12.002|pmid=17276341|volume=12|issue=2|doi-access=free}}</ref>
* [[PRMT1|PRMT-1]]<ref>{{cite journal|last1=Takahashi|first1=Yuta|last2=Daitoku|first2=Hiroaki|last3=Hirota|first3=Keiko|last4=Tamiya|first4=Hiroko|last5=Yokoyama|first5=Atsuko|last6=Kako|first6=Koichiro|last7=Nagashima|first7=Yusuke|last8=Nakamura|first8=Ayumi|last9=Shimada|first9=Takashi|last10=Watanabe|first10=Satoshi|last11=Yamagata|first11=Kazuyuki|last12=Yasuda|first12=Kayo|last13=Ishii|first13=Naoaki|last14=Fukamizu|first14=Akiyoshi|title=Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16|journal=Cell Metabolism|pages=505–516|doi=10.1016/j.cmet.2011.03.017|date=4 May 2011|pmid=21531333|volume=13|issue=5|doi-access=free}}</ref>
* UNC-43 <ref>{{cite journal|last1=Tao|first1=Li|last2=Xie|first2=Qi|last3=Ding|first3=Yue-He|last4=Li|first4=Shang-Tong|last5=Peng|first5=Shengyi|last6=Zhang|first6=Yan-Ping|last7=Tan|first7=Dan|last8=Yuan|first8=Zengqiang|last9=Dong|first9=Meng-Qiu|title=CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16|journal=eLife|pages=e00518|doi=10.7554/eLife.00518|date=25 June 2013|pmid=23805378|pmc=3691573|volume=2 |doi-access=free }}</ref>
* TAX-6 <ref>{{cite journal|last1=Tao|first1=Li|last2=Xie|first2=Qi|last3=Ding|first3=Yue-He|last4=Li|first4=Shang-Tong|last5=Peng|first5=Shengyi|last6=Zhang|first6=Yan-Ping|last7=Tan|first7=Dan|last8=Yuan|first8=Zengqiang|last9=Dong|first9=Meng-Qiu|title=CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16|journal=eLife|pages=e00518|doi=10.7554/eLife.00518|date=25 June 2013|pmid=23805378|pmc=3691573|volume=2 |doi-access=free }}</ref>
* [[c-Jun N-terminal kinases|JNK-1]]<ref>{{cite journal|last1=Oh|first1=Seung Wook|last2=Mukhopadhyay|first2=Arnab|last3=Svrzikapa|first3=Nenad|last4=Jiang|first4=Feng|last5=Davis|first5=Roger J.|last6=Tissenbaum|first6=Heidi A.|title=JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16|journal=Proceedings of the National Academy of Sciences of the United States of America|pages=4494–4499|doi=10.1073/pnas.0500749102|date=22 March 2005|pmid=15767565|pmc=555525|volume=102|issue=12|bibcode=2005PNAS..102.4494O|doi-access=free}}</ref>
* FTT-2 <ref>{{cite journal|last1=Berdichevsky|first1=Ala|last2=Viswanathan|first2=Mohan|last3=Horvitz|first3=H. Robert|last4=Guarente|first4=Leonard|title=C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span|journal=Cell|pages=1165–1177|doi=10.1016/j.cell.2006.04.036|date=16 June 2006|pmid=16777605|volume=125|issue=6|s2cid=1236438|doi-access=free}}</ref>
== History ==
In 1963 [[Sydney Brenner]] realised the success of biology was due to model organisms, and ''C. elegans'' has been widely used in research laboratories since.<ref>{{cite journal|last1=Goldstein|first1=Bob|title=Sydney Brenner on the Genetics of Caenorhabditis elegans|journal=Genetics|year=2016 |pages=1–2|doi=10.1534/genetics.116.194084|pmid=27601612|pmc=5012377|volume=204|issue=1}}</ref> In 1998 the genome of ''C. elegans'' was completely sequenced and found to be a 97 megabase genomic sequence consisting of 19,000 genes, with 40% protein products having significant matches in other organisms.<ref>{{cite journal|title=Genome sequence of the nematode C. elegans: a platform for investigating biology.|journal=Science | pmid=9851916 | volume=282|issue=5396|pages=2012–8|doi=10.1126/science.282.5396.2012|year=1998 |last1=The c.&nbsp;elegans Sequencing Consortium |bibcode=1998Sci...282.2012. |s2cid=16873716 }}</ref>
The DAF genes [[Daf-2|DAF-2]] and DAF-16 were discovered in the Thomas and Ruvkun labs, after isolating dauer-constitutive ''(DAF-c)'' mutants and dauer - defective mutants ''(DAF-d)''. Mutations in [[Daf-2|DAF-2]] and DAF-23 caused the dauer - constitutive phenotype, through activation of the dauer - defective genes DAF-16 and DAF-18.<ref>{{cite journal|last1=Murphy|first1=Coleen T|title=Insulin/insulin-like growth factor signaling in C. elegans|journal=WormBook|url=https://www.ncbi.nlm.nih.gov/books/NBK179230/|year=2005|pages=1–43|doi=10.1895/wormbook.1.164.1|pmid=24395814|pmc=4780952}}</ref> This showed that [[Daf-2|DAF-2]] and DAF-23 prevent dauer arrest by antagonising DAF-16 and DAF-18 <ref>{{cite journal|last1=Hung|first1=Wesley L|title=A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication|pmc=3978837|pmid=24671950|doi=10.1242/dev.103846|volume=141|issue=8|journal=Development|pages=1767–79|year=2014}}</ref>
Notable scientists involved in the initial and continued characterization of DAF-16-associated aging pathways:
* [[Cynthia Kenyon]]
* [[Gary Ruvkun]]
== See also ==
* [[FOX proteins]]
== References ==
{{reflist}}
{{Dauer larva}}
[[Category:Caenorhabditis elegans genes]]
[[Category:Aging-related proteins]]