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Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.

Cell | Mar 21, 2008

http://www.ncbi.nlm.nih.gov/pubmed/18358814

Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

Pubmed ID: 18358814 RIS Download

Mesh terms: Animals | Caenorhabditis elegans | Caenorhabditis elegans Proteins | DNA-Binding Proteins | Gene Regulatory Networks | Insulin | Insulin-Like Growth Factor I | Intestines | Longevity | Oxidative Stress | Phosphorylation | Receptor, Insulin | Signal Transduction | Transcription Factors

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Associated grants

  • Agency: NIGMS NIH HHS, Id: 2 R01 GM062891
  • Agency: NIGMS NIH HHS, Id: 5 F32 GM070088-02
  • Agency: NIGMS NIH HHS, Id: R01 GM062891
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-05
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-06
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-07
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-08
  • Agency: NIDDK NIH HHS, Id: T32 DK07260

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