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 | |
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Gene | DAF-16 |
Protein | FOXO |
Location | Chromosome 1 |
Position | 175-268 |
Organism | Caenorhabditis elegans |
Genetics
editDAF-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)
editDAF-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
editC. 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
editImplication 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
editDAF-16 is known to interact with:
History
editIn 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
editReferences
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- ^ 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.
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