Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center
Cell (Impact Factor: 32.24). 04/2008; 132(6):1025-38. DOI: 10.1016/j.cell.2008.01.030
Source: PubMed


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.

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Available from: T Keith Blackwell, Dec 10, 2014
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    • "Two conserved signaling pathways known to increase lifespan have been characterized in C. elegans (Cohen et al., 2006; Kenyon, 2005; Leavy, 2011; Murshid et al., 2013; Tissenbaum, 2012); one involves disruption of the insulin/IGF-1 receptor, DAF-2 (abnormal Dauer formation-2) signaling pathway, while the other involves activation of the NAD + dependent histone deacetylase SIR-2.1. C. elegans loss-of-function mutations in daf-2 have an extended lifespan, which is dependent on the activation of the transcription factor DAF-16 (homologous to human FOXO genes) (Apfeld and Kenyon, 1998; Gems et al., 1998; Tullet et al., 2008). Dietary restriction is one of the most consistent methods for producing lifespan extension in model organisms, activates DAF-16 through a decrease in PI3K/AKT signaling (Weinkove et al., 2006). "
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    • "In this figure the positive values indicated the increased expressions compared to the controls while the negative values indicated the decreased expressions compared to the controls, the control values were 0. affects the anti-oxidation capacity of the cells. It is considered GCS-1 encodes for the heavy chain of GCS (An and Blackwell, 2003; An et al., 2005; Hayes and McMahon, 2001; Inoue et al., 2005; Meister and Anderson, 1983; Tullet et al., 2008). The glutathione-S-transferases (GSTs) are recognized as playing important protective roles for detoxifying reactive species by conjugating GSH to electrophilic centers. "
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    • "It is possible that CncC alone is binding to the Nrf2 binding site. But it has also been reported that CncC homolog Nrf2 unlike SKN-1 is not able to bind as a monomer and does require a heterodimer partner (Tullet et al., 2008). Nrf2 can also heterodimerize with other bZIP-transcription factors (Jun, Fos and ATF4) and can bind to the ARE sequence but the importance of these heterodimer partners in controlling the downstream genes is unknown (Venugopal and Jaiswal, 1998; He et al., 2001). "
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