Daf-16

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DAF-16
A crystalline structure of the protein FOXO, encoded by Daf-16 Structure-2.png
A crystalline structure of the protein FOXO, encoded by Daf-16
GeneDAF-16
Protein FOXO
Location Chromosome 1
Position175-268
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]

Contents

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:

See also

Related Research Articles

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<i>Caenorhabditis elegans</i> Free-living species of nematode

Caenorhabditis elegans is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek caeno- (recent), rhabditis (rod-like) and Latin elegans (elegant). In 1900, Maupas initially named it Rhabditides elegans. Osche placed it in the subgenus Caenorhabditis in 1952, and in 1955, Dougherty raised Caenorhabditis to the status of genus.

FOXproteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.

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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. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”

Dauer describes an alternative developmental stage of nematode worms, particularly rhabditids including Caenorhabditis elegans, whereby the larva goes into a type of stasis and can survive harsh conditions. Since the entrance of the dauer stage is dependent on environmental cues, it represents a classic and well studied example of polyphenism. The dauer state is given other names in the various types of nematodes such as ‘diapause’ or ‘hypobiosis’, but since the C. elegans nematode has become the most studied nematode, the term ‘dauer stage’ or 'dauer larvae' is becoming universally recognised when referring to this state in other free-living nematodes. The dauer stage is also considered to be equivalent to the infective stage of parasitic nematode larvae.

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<span class="mw-page-title-main">FOXO3</span> Protein-coding gene in the species Homo sapiens

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

<span class="mw-page-title-main">FOXO4</span> Protein

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.

Gary Bruce Ruvkun is an American molecular biologist at Massachusetts General Hospital and professor of genetics at Harvard Medical School in Boston. Ruvkun discovered the mechanism by which lin-4, the first microRNA (miRNA) discovered by Victor Ambros, regulates the translation of target messenger RNAs via imperfect base-pairing to those targets, and discovered the second miRNA, let-7, and that it is conserved across animal phylogeny, including in humans. These miRNA discoveries revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation. Ruvkun also discovered many features of insulin-like signaling in the regulation of aging and metabolism. He was elected a Member of the American Philosophical Society in 2019.

<span class="mw-page-title-main">Forkhead box protein O1</span> Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

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The DAF-12 gene encodes the nuclear receptor of dafachronic acid in the worm Caenorhabditis elegans, with the NRNC Symbol NR1J1 as the homolog of nuclear hormone receptor HR96 in Drosophila melanogaster. DAF-12 has been implicated by Cynthia Kenyon and colleagues in the formation of Dauer larva.

The DAF-1 gene encodes for a cell surface Enzyme-linked receptor of TGF-beta signaling pathway in the worm Caenorhabditis elegans. DAF-1 is one of the type I receptor of TGF-beta pathway. DAF-1 acts as a receptor protein serine/threonine kinase, is activated by type II receptor Daf-4 phosphorylation after the ligand Daf-7 binds to the receptor heterotetramer, and then phosphorylates Daf-8 or Daf-14, the SMAD proteins in C. elegans.

The DAF-3 or Dwarfin sma is a nematode Caenorhabditis elegans gene encoding a Co-SMAD protein of TGF-beta signaling pathway. Without daf-7 signal, DAF-3 combined with transcription factor daf-5 to form a heterodimer and started dauer development. When daf-7 binds to the receptors daf-1/daf-4, the phosphorylated daf-8/daf-14 heterodimer enter to the nucleus to inhibit this transcription.

Daf-5 is an ortholog of the mammalian protein Sno/Ski，which present in the nematode worm Caenorhabditis elegans on the downstream of TGFβ signaling pathway. Without daf-7 signal, daf-5 combined with daf-3, co-SMAD for C. elegans, to form a heterodimer and started dauer development.

The Dod-13 gene in the worm Caenorhabditis elegans encoding a cytochrome p450 enzyme, which have steroid hydroxylase activity, with the CYP Symbol CYP35B1. Dod-13 is downstream gene of Daf-16 influenced the lifespan of C. elegans.

<span class="mw-page-title-main">Collin Y. Ewald</span> Swiss molecular biologist

Collin Yvès Ewald is a Swiss scientist investigating the molecular mechanisms of healthy aging. He is a molecular biologist and a professor at ETH Zurich, where he leads the Laboratory of Extracellular Matrix Regeneration. His research focuses on the remodeling of the extracellular matrix during aging and upon longevity interventions.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

References

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  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.
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  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. Bibcode:1997Sci...278.1319L. doi:10.1126/science.278.5341.1319. PMID   9360933. S2CID   36088123.
  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. PMC   4464094 . 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.
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  44. ↑ Tao, Li; Xie, Qi; Ding, Yue-He; Li, Shang-Tong; Peng, Shengyi; Zhang, Yan-Ping; Tan, Dan; Yuan, Zengqiang; Dong, Meng-Qiu (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 . PMC   3691573 . PMID   23805378.
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