Authors: Tullet JM; Hertweck M; An JH; Baker J; Hwang JY; Liu S; Oliveira RP; Baumeister R; Blackwell TK
Abstract: 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.Keywords: Animals; Caenorhabditis elegans/*physiology; Caenorhabditis elegans Proteins/*metabolism; DNA-Binding Proteins/*metabolism; Gene Regulatory Networks; Insulin/metabolism; Insulin-Like Growth Factor I/metabolism; Intestines; Longevity; Oxidative Stress; Phosphorylation; Receptor, Insulin/metabolism; *Signal Transduction; Transcription Factors/*metabolism
Date: March 25, 2008
Select reference article to upload
Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132: 1025-38.