JNK regulates lifespan in
            <i>Caenorhabditis elegans</i>
            by modulating nuclear translocation of forkhead transcription factor/DAF-16

Oh, Seung Wook; Mukhopadhyay, Arnab; Svrzikapa, Nenad; Jiang, Feng; Davis, Roger J.; Tissenbaum, Heidi A.

doi:10.1073/pnas.0500749102

Cited by 484 publications

(431 citation statements)

References 31 publications

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“…On the other hand, in response to stress, MST1 (Lehtinen et al, 2006) and JNK1 (Essers et al, 2004) phosphorylate FOXO factors at different sites, resulting in nuclear translocation and transactivation. Similar results were also observed in C. elegans, in that DAF-16 is phosphorylated by JNK in response to heat shock, and promotes the translocation of DAF-16 into the nucleus (Oh et al, 2005). Acetylation on the lysine residue neutralizes the positive charge and reduces FOXO DNA-binding affinity (Matsuzaki et al, 2005).…”

Section: Introductionsupporting

confidence: 74%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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Section: Introductionsupporting

confidence: 74%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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“…jnk-1 overexpression enhances the lifeextending effect of a daf-2 hypomorphic mutation, suggesting that JNK-1 regulates lifespan in parallel to the insulin-/IGF-1 pathway, with both pathways converging on DAF-16. JNK-1 regulates lifespan by directly interacting with DAF-16 and modulating its nuclear translocation (Oh et al, 2005). In Drosophila, JNK activation confers resistance to oxidative stress and extends the lifespan of adult flies by inducing the expression of protective genes (Wang et al, 2003).…”

Section: Jnk and Tgf-ˇ Pathwaysmentioning

confidence: 99%

Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.

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“…The phosphorylation was observed only with the N-terminal (amino acids 83-307) fragment of DAF-16. Furthermore, it has been demonstrated that JNK-1 directly interacts with, phosphorylates, enhances nuclear localization of DAF-16, and induces its target gene expression [24]. Indeed, low levels of oxidative stress generated by treatment with H 2 O 2 activates the small GTPase Ral and induce a JNK-dependent phosphorylation of Threonine 447 and Threonine451, nuclear translocation, and transcriptional activation of FOXO4 [26].…”

Section: Regulation Of Foxos By Other Signaling Pathwaysmentioning

confidence: 99%

The FoxO transcription factors and metabolic regulation

2007

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Forkhead transcription factors FoxOs are conserved beyond species and regulated by insulin signaling pathway. FoxOs have diverse functions on differentiation, proliferation and cell survival. In calorie restriction (CR) or starvation, FoxOs are in nucleus, active transcriptionally, and increase hepatic glucose production, decrease insulin secretion, increase food intake and cause degradation of skeletal muscle for supplying substrates for glucose production. However, even in insulin resistance due to excessive calorie intake, FoxOs are active and causes type 2 diabetes and hyperlipidemia. The understanding of molecular mechanism how FoxOs affect glucose or lipid metabolism will shed light on the novel therapy of type 2 diabetes and the metabolic syndrome.

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JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16

Cited by 484 publications

References 31 publications

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Autophagy and ageing: Insights from invertebrate model organisms

The FoxO transcription factors and metabolic regulation

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