Biology:Daf-16

From HandWiki
Short description: Ortholog
DAF-16
A crystalline structure of the protein FOXO, encoded by Daf-16
Gene DAF-16
Protein FOXO
Location Chromosome 1
Position 175-268
Organism Caenorhabditis elegans

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans.[1] It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses.[2][3] It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer.[4] 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.[5] The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.[6]

Genetics

DAF-16 is a gene conserved across species, with homologs being found in C. elegans, humans, mice, and Drosophila (fruit flies).[7] In C. elegans, DAF-16 is located on Chromosome 1, at position 175-268.[8] It is made up of 15 exons.[9] DAF-16 is also located downstream of DAF-2, which signals in the IIS pathway. Mutants in this pathway age slower and have a lifespan up to twice as long as normal.[10] Further studies have demonstrated that the lifespan extension is dependent on DAF-16.[11] Other consequences of mutations in the DAF-16 gene is the inability to form dauers.[12]

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).[13] FOXO is involved in the Insulin / IGF1 signalling pathway (IIS) which affects longevity, lipogenesis, dauer formation, heat shock and oxidative stress responses, by activating proteins such as MnSOD and Catalase.[14] Expression of FOXO in the intestine normally leads to longevity signalling.[15] FOXO has been shown to have a protective role against cancer, as it regulates and suppresses genes involved in tumour formation.[16] It also has a protective role against muscular dystrophy.[17] FOXO is also important in embryonic development, as it promotes apoptosis.[18]

Insulin Signalling

Insulin and IGF1 are peptide hormones dictating energy functions such as glucose and lipid metabolism.[19] The signalling pathway is evolutionary conserved and found across species.[20] Signalling occurs through kinases such as PI3K to produce phospholipid products such as AKT.[21] 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.[22] When not phosphorylated, DAF-16 is active and present in the nucleus,[23] so FOXO can be transcribed and can up-regulate production of about 100 beneficial proteins that increase longevity.[24]

Species, tissue, subcellular distribution

C. elegans is the only known species to contain the DAF-16 gene,[25] although orthologs are conserved across species.[26] DAF-16 may localise to the nucleus or cytoplasm, depending on resources.[27] In nutrient rich conditions, DAF-2 and 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.[28] DAF-16 is sequestered in the cytoplasm when associated with ftt-2.[29] Translocation to the nucleus and translation of longevity genes occurs after DAF-16 associates with prmpt-1 [30] Translocation to the nucleus is also promoted by jnk-1 in heat stress and sek-1 in oxidative stress.[31][32]

Expression

Isoform b and Isoform c are expressed in muscles, ectoderm, the intestine and neurons.[33] Isoform b is additionally expressed in the pharynx.[34] Expression can be induced by quinic acid.[35]

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.[36] 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.[37] 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.[38] 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.[39]

C. elegans has long been used in aging research.[40] Although DAF-16 increases longevity, treating C.elegans with resveratrol extends lifespan in a method independent of DAF-16 and fully dependent on SIR2.1.[41]

Interactions

DAF-16 is known to interact with:

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.[48] 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.[49] The DAF genes 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 and DAF-23 caused the dauer - constitutive phenotype, through activation of the dauer - defective genes DAF-16 and DAF-18.[50] This showed that DAF-2 and DAF-23 prevent dauer arrest by antagonising DAF-16 and DAF-18 [51]

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

  • Cynthia Kenyon
  • Gary Ruvkun

See also

References

  1. ↑ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science 278 (5341): 1319–1322. doi:10.1126/science.278.5341.1319. PMID 9360933. Bibcode: 1997Sci...278.1319L. 
  2. ↑ 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 11 (24): 1975–1980. doi:10.1016/s0960-9822(01)00594-2. PMID 11747825. 
  3. ↑ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science 278 (5341): 1319–1322. doi:10.1126/science.278.5341.1319. PMID 9360933. Bibcode: 1997Sci...278.1319L. 
  4. ↑ Fielenbach, Nicole; Antebi, Adam (15 August 2008). "C. elegans dauer formation and the molecular basis of plasticity" (in en). Genes & Development 22 (16): 2149–2165. doi:10.1101/gad.1701508. PMID 18708575. 
  5. ↑ Ogg, S; Paradis, S; Gottlieb, S; Patterson, GI; Lee, L; Tissenbaum, HA; Ruvkun, G (October 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. Bibcode: 1997Natur.389..994O. 
  6. ↑ 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. PMID 21115525. 
  7. ↑ Hesp, Kylie; Smant, Geert; Kammenga, Jan E. (2015). "Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease". Experimental Gerontology 72: 1–7. doi:10.1016/j.exger.2015.09.006. PMID 26363351. 
  8. ↑ "blastp results [running"] (in en). https://www.uniprot.org/blast/uniprot/B20171126AAFB7E4D2F1D05654627429E83DA5CCEDF22E9F. 
  9. ↑ "daf-16 Forkhead box protein O [Caenorhabditis elegans - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/172981. 
  10. ↑ Lin, K.; Hsin, H.; Libina, N.; Kenyon, C. (2001). "Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling". Nature Genetics 28 (2): 139–145. doi:10.1038/88850. PMID 11381260. 
  11. ↑ Lin, K.; Hsin, H.; Libina, N.; Kenyon, C. (2001). "Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling". Nature Genetics 28 (2): 139–145. doi:10.1038/88850. PMID 11381260. 
  12. ↑ Gottlieb, S.; Ruvkun, G. (1994). "Daf-2, Daf-16 and Daf-23: Genetically Interacting Genes Controlling Dauer Formation in Caenorhabditis Elegans". Genetics 137 (1): 107–120. doi:10.1093/genetics/137.1.107. PMID 8056303. 
  13. ↑ Furuyama, Tatsuo; Nakazawa, Toru; Nakano, Itsuko; Mori, Nozomu (2000). "Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues". Biochemical Journal 349 (2): 629–634. doi:10.1042/bj3490629. PMID 10880363. 
  14. ↑ Lin, Kui (1997). "daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans". Science 278 (5341): 1319–1322. doi:10.1126/science.278.5341.1319. PMID 9360933. Bibcode: 1997Sci...278.1319L. 
  15. ↑ Libina, Nataliya (2003-11-14). "Tissue-Specific Activities of C. elegans DAF-16 in the Regulation of Lifespan". Cell 115 (4): 489–502. doi:10.1016/S0092-8674(03)00889-4. PMID 14622602. 
  16. ↑ Pinkston-Gosse, Julie; Kenyon, Cynthia (2007). "DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans". Nature Genetics 39 (11): 1403–1409. doi:10.1038/ng.2007.1. PMID 17934462. 
  17. ↑ Catoire, Hélène; Pasco, Matthieu Y.; Abu-Baker, Aida; Holbert, Sébastien; Tourette, Cendrine; Brais, Bernard; Rouleau, Guy A.; Parker, J. Alex et al. (15 July 2008). "Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1". Human Molecular Genetics 17 (14): 2108–2117. doi:10.1093/hmg/ddn109. PMID 18397876. 
  18. ↑ Nakagawa, Akihisa; Sullivan, Kelly D.; Xue, Ding (2014). "Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway". Nature Structural & Molecular Biology 21 (12): 1082–1090. doi:10.1038/nsmb.2915. PMID 25383666. 
  19. ↑ Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald (2014). "Insulin Receptor Signaling in Normal and Insulin-Resistant States". Cold Spring Harbor Perspectives in Biology 6 (1): a009191. doi:10.1101/cshperspect.a009191. PMID 24384568. 
  20. ↑ Barbieri, Michelangela; Bonafè, Massimiliano; Franceschi, Claudio; Paolisso, Giuseppe (2003). "Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans". American Journal of Physiology. Endocrinology and Metabolism 285 (5): E1064–1071. doi:10.1152/ajpendo.00296.2003. PMID 14534077. 
  21. ↑ Gami, Minaxi S; Wolkow, Catherine A (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31–37. doi:10.1111/j.1474-9726.2006.00188.x. PMID 16441841. 
  22. ↑ O'Neill, Brian T.; Lee, Kevin Y.; Klaus, Katherine; Softic, Samir; Krumpoch, Megan T.; Fentz, Joachim; Stanford, Kristin I.; Robinson, Matthew M. et al. (1 September 2016). "Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis". The Journal of Clinical Investigation 126 (9): 3433–3446. doi:10.1172/JCI86522. PMID 27525440. 
  23. ↑ 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 11 (24): 1975–1980. doi:10.1016/s0960-9822(01)00594-2. PMID 11747825. 
  24. ↑ Greer, Eric L; Brunet, Anne (14 November 2005). "FOXO transcription factors at the interface between longevity and tumor suppression" (in En). Oncogene 24 (50): 7410–7425. doi:10.1038/sj.onc.1209086. PMID 16288288. 
  25. ↑ Hesp, Kylie (December 2015). "Caenorhabditis elegans DAF-16/FOXO transcription factor and its mammalian homologs associate with age-related disease". Experimental Gerontology 72: 1–7. doi:10.1016/j.exger.2015.09.006. PMID 26363351. 
  26. ↑ Lee, RY (2001). "Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway.". Curr Biol 11 (24): 1950–7. doi:10.1016/s0960-9822(01)00595-4. PMID 11747821. 
  27. ↑ Henderson, ST; Johnson, TE (2001-12-11). "daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans". Current Biology 11 (24): 1975–1980. doi:10.1016/S0960-9822(01)00594-2. PMID 11747825. 
  28. ↑ 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 11 (24): 1975–1980. doi:10.1016/S0960-9822(01)00594-2. PMID 11747825. 
  29. ↑ Takahashi, Y (2011). "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.". Cell Metabolism 13 (5): 505–16. doi:10.1016/j.cmet.2011.03.017. PMID 21531333. 
  30. ↑ Takahashi, Y (2011-05-04). "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16.". Cell Metab 13 (5): 505–16. doi:10.1016/j.cmet.2011.03.017. PMID 21531333. 
  31. ↑ Kondo, Masaki; Yanase, Sumino; Ishii, Takamasa; Hartman, Philip S.; Matsumoto, Kunihiro; Ishii, Naoaki (2005). "The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei". Mechanisms of Ageing and Development 126 (6–7): 642–647. doi:10.1016/j.mad.2004.11.012. PMID 15888317. 
  32. ↑ 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 102 (12): 4494–4499. doi:10.1073/pnas.0500749102. PMID 15767565. Bibcode: 2005PNAS..102.4494O. 
  33. ↑ Wolf, Marc; Nunes, Frank; Henkel, Arne; Heinick, Alexander; Paul, Rüdiger J. (2008). "The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation, and influences over temperature-dependent insulin-like signaling, stress responses, and fitness". Journal of Cellular Physiology 214 (3): 721–729. doi:10.1002/jcp.21269. PMID 17894411. 
  34. ↑ Lee, R. Y.; Hench, J.; Ruvkun, G. (11 December 2001). "Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway". Current Biology 11 (24): 1950–1957. doi:10.1016/s0960-9822(01)00595-4. PMID 11747821. 
  35. ↑ Zhang, Longze; Zhang, Junjing; Zhao, Baolu; Zhao-Wilson, Xi (2012). "Quinic acid could be a potential rejuvenating natural compound by improving survival of Caenorhabditis elegans under deleterious conditions". Rejuvenation Research 15 (6): 573–583. doi:10.1089/rej.2012.1342. PMID 22950425. 
  36. ↑ Cypser, James R.; Johnson, Thomas E. (2003). "Hormesis in Caenorhabditis elegans dauer-defective mutants". Biogerontology 4 (4): 203–214. doi:10.1023/A:1025138800672. PMID 14501184. 
  37. ↑ Murphy, Coleen. "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans | Learn Science at Scitable" (in en). https://www.nature.com/scitable/content/Genes-that-act-downstream-of-DAF-16-13901. 
  38. ↑ Joeng, Kyu Sang; Song, Eun Joo; Lee, Kong-Joo; Lee, Junho (2004). "Long lifespan in worms with long telomeric DNA". Nature Genetics 36 (6): 607–611. doi:10.1038/ng1356. PMID 15122256. 
  39. ↑ Lin, K.; Dorman, J. B.; Rodan, A.; Kenyon, C. (14 November 1997). "daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science 278 (5341): 1319–1322. doi:10.1126/science.278.5341.1319. PMID 9360933. Bibcode: 1997Sci...278.1319L. 
  40. ↑ Tissenbaum, Heidi A. (30 January 2015). "Using C. elegans for aging research". Invertebrate Reproduction & Development 59 (sup1): 59–63. doi:10.1080/07924259.2014.940470. PMID 26136622. 
  41. ↑ Viswanathan, Mohan; Kim, Stuart K.; Berdichevsky, Ala; Guarente, Leonard (2005). "A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span". Developmental Cell 9 (5): 605–615. doi:10.1016/j.devcel.2005.09.017. PMID 16256736. 
  42. ↑ Li, Wensheng; Gao, Beixue; Lee, Sang-Myeong; Bennett, Karen; Fang, Deyu (2007). "RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination". Developmental Cell 12 (2): 235–246. doi:10.1016/j.devcel.2006.12.002. PMID 17276341. 
  43. ↑ Takahashi, Yuta; Daitoku, Hiroaki; Hirota, Keiko; Tamiya, Hiroko; Yokoyama, Atsuko; Kako, Koichiro; Nagashima, Yusuke; Nakamura, Ayumi et al. (4 May 2011). "Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16". Cell Metabolism 13 (5): 505–516. doi:10.1016/j.cmet.2011.03.017. PMID 21531333. 
  44. ↑ Tao, Li; Xie, Qi; Ding, Yue-He; Li, Shang-Tong; Peng, Shengyi; Zhang, Yan-Ping; Tan, Dan; Yuan, Zengqiang et al. (25 June 2013). "CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16". eLife 2: e00518. doi:10.7554/eLife.00518. PMID 23805378. 
  45. ↑ Tao, Li; Xie, Qi; Ding, Yue-He; Li, Shang-Tong; Peng, Shengyi; Zhang, Yan-Ping; Tan, Dan; Yuan, Zengqiang et al. (25 June 2013). "CAMKII and calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16". eLife 2: e00518. doi:10.7554/eLife.00518. PMID 23805378. 
  46. ↑ 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 102 (12): 4494–4499. doi:10.1073/pnas.0500749102. PMID 15767565. Bibcode: 2005PNAS..102.4494O. 
  47. ↑ Berdichevsky, Ala; Viswanathan, Mohan; Horvitz, H. Robert; Guarente, Leonard (16 June 2006). "C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span". Cell 125 (6): 1165–1177. doi:10.1016/j.cell.2006.04.036. PMID 16777605. 
  48. ↑ Goldstein, Bob (2016). "Sydney Brenner on the Genetics of Caenorhabditis elegans". Genetics 204 (1): 1–2. doi:10.1534/genetics.116.194084. PMID 27601612. 
  49. ↑ The c. elegans Sequencing Consortium (1998). "Genome sequence of the nematode C. elegans: a platform for investigating biology.". Science 282 (5396): 2012–8. doi:10.1126/science.282.5396.2012. PMID 9851916. Bibcode: 1998Sci...282.2012.. 
  50. ↑ Murphy, Coleen T (2005). "Insulin/insulin-like growth factor signaling in C. elegans". WormBook: 1–43. doi:10.1895/wormbook.1.164.1. PMID 24395814. PMC 4780952. https://www.ncbi.nlm.nih.gov/books/NBK179230/. 
  51. ↑ Hung, Wesley L (2014). "A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication". Development 141 (8): 1767–79. doi:10.1242/dev.103846. PMID 24671950. 



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