Article

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

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.

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Available from: T Keith Blackwell, Dec 10, 2014
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    • "Our previous studies demonstrated that SKN-1 is under direct regulation by a WD40 repeat protein named WDR-23; WDR-23 directly binds to SKN-1 to restrain its nuclear accumulation under basal conditions presumably by recruiting the transcription factor to a ubiquitin ligase (Choe et al. 2009). SKN-1 also functions downstream of target of rapamycin (TOR) and insulin/IGF-1-like signaling (IIS) (Tullet et al. 2008; Wang et al. 2010; Robida-Stubbs et al. 2012) pathways that influence longevity and is required for lifespan extension by dietary restriction (Tang and Choe 2015; Bishop and Guarente 2007). Regulation of SKN-1 and the mechanisms by which it influences longevity and stress resistance are highly active areas of research (Blackwell et al. 2015; Ewald et al. 2015; Steinbaugh et al. 2015; Tang and Choe 2015; Dresen et al. 2015; Chew et al. 2015). "
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    • "Also, studies have shown that loss-of-function mutations in daf-2 increases worms' lifespan (Kenyon et al., 1993;Kimura et al., 1997). This is partly because the disruption of DAF-2 releases the transcription factor DAF-16 to the nucleus allowing for increased expression of many genes related to resilience (Kimura et al., 1997;Hsu et al., 2003;Samuelson et al., 2007;Tullet et al., 2008;Kenyon, 2010b). In addition to DAF-16, other transcription factors have their function modified by DAF-2, such as SKN-1, HSF-1 and PQN-1 (Kimura et al., 1997;Hsu et al., 2003;Samuelson et al., 2007;Kenyon, 2010b;Bansal et al., 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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