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A new DAF-16 isoform regulates longevity.

The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.

Pubmed ID: 20613724

Authors

  • Kwon ES
  • Narasimhan SD
  • Yen K
  • Tissenbaum HA

Journal

Nature

Publication Data

July 22, 2010

Associated Grants

  • Agency: NIA NIH HHS, Id: AG025891
  • Agency: NIA NIH HHS, Id: AG03123
  • Agency: NIA NIH HHS, Id: R01 AG025891
  • Agency: NIA NIH HHS, Id: R01 AG025891-07
  • Agency: NIA NIH HHS, Id: R01 AG031237
  • Agency: NIA NIH HHS, Id: R01 AG031237-02

Mesh Terms

  • Active Transport, Cell Nucleus
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Gene Expression Regulation
  • Insulin
  • Insulin-Like Growth Factor I
  • Longevity
  • Mutation
  • Organ Specificity
  • Phosphatidylinositol 3-Kinases
  • Promoter Regions, Genetic
  • Protein Isoforms
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Superoxide Dismutase
  • Transcription Factors
  • Transgenes