A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span

Lehtinen, Maria K.; Yuan, Zengqiang; Boag, Peter R.; Yang, Yongmei; Villén, Judit; Becker, Esther B. E.; DiBacco, Sara; Iglesia, Núria de la; Gygi, Steven P.; Blackwell, T. Keith; Bonni, Azad

doi:10.1016/j.cell.2006.03.046

Cited by 745 publications

(752 citation statements)

References 46 publications

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“…Upon oxidative stress, MST1 binds and phosphorylates FOXO3 (34,35). Phosphorylation of FOXO3 mediated by MST1 disrupts its connection with 14-3-3, prompting the accumulation of it in the nucleus, and therefore, upregulates the expression of pro-apoptotic genes that induce neuronal cell death (36). Certain studies have reported that MST1 can affect the expression of downstream target genes of FOXO1 by similar mechanisms (37).…”

Section: Mammalian Sterile 20-like Kinase (Mst) and Jun-n-terminal Kimentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Section: Mammalian Sterile 20-like Kinase (Mst) and Jun-n-terminal Kimentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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“…For example, insulin induces the phosphorylation of FOXO1, FOXO3 and FOXO4 through Akt/protein kinase B, leading to the exclusion of FOXO from the nucleus and the inhibition of FOXO transcription activities (Biggs et al, 1999;Brunet et al, 1999;Kops et al, 1999;Rena et al, 1999;Takaishi et al, 1999). 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).…”

Section: Introductionmentioning

confidence: 99%

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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“…For example, mammalian Ste20-like kinase-1 (MST1) is a Ser/Thr kinase that is activated by apoptosis-inducing stimuli (de Souza and Lindsay, 2004). Lehtinen et al (2006) reported that MST1 is activated by H 2 O 2 and induces cell death by phosphorylating the transcription factor FOXO in primary mammalian neurons. Furthermore, Ste20 mediates H 2 O 2 -induced cell death by phosphorylating histone H2B in Saccharomyces cerevisiae (Ahn et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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Mammalian Ste20-like kinase-1 (MST1) kinase mediates H 2 O 2 -induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H 2 O 2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H 2 O 2 -induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H 2 O 2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H 2 O 2 -induced MST1 activation. Live-cell imaging showed H 2 O 2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H 2 O 2 -induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span

Cited by 745 publications

References 46 publications

Post-translational modifications of FOXO family proteins

Post-translational modifications of FOXO family proteins

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

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

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