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Daf-16

Summary

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]

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

Genetics edit

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) 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).[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 edit

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 edit

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 edit

DAF-16 is known to interact with:

History edit

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:

See also edit

References edit

  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. Bibcode:1997Sci...278.1319L. doi:10.1126/science.278.5341.1319. PMID 9360933. S2CID 36088123.
  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. S2CID 12674040.
  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. Bibcode:1997Sci...278.1319L. doi:10.1126/science.278.5341.1319. PMID 9360933. S2CID 36088123.
  4. ^ Fielenbach, Nicole; Antebi, Adam (15 August 2008). "C. elegans dauer formation and the molecular basis of plasticity". Genes & Development. 22 (16): 2149–2165. doi:10.1101/gad.1701508. PMC 2735354. 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. Bibcode:1997Natur.389..994O. doi:10.1038/40194. PMID 9353126. S2CID 4412006.
  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. PMC 3001308. 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]". www.uniprot.org.
  9. ^ "daf-16 Forkhead box protein O [Caenorhabditis elegans] - Gene - NCBI". www.ncbi.nlm.nih.gov.
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  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. PMC 1205929. 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. PMC 1221187. PMID 10880363.
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  17. ^ Catoire, Hélène; Pasco, Matthieu Y.; Abu-Baker, Aida; Holbert, Sébastien; Tourette, Cendrine; Brais, Bernard; Rouleau, Guy A.; Parker, J. Alex; Néri, Christian (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.
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