Post-translational regulation of FOXO

Xie, Qi; Chen, Jing; Yuan, Zengqiang

doi:10.1093/abbs/gms067

Cited by 45 publications

(44 citation statements)

References 51 publications

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“…Previous studies have shown that the FOXO proteins are exquisitely regulated by a variety of post-translational modifications including phosphorylation, acetylation, ubiquitination, and arginine and lysine methylation (15). Additionally, the activity of FOXO can be modulated through direct binding to other proteins including PGC-1␣ and ␤-catenin (31,32).…”

Section: Discussionmentioning

confidence: 99%

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E2F Transcription Factor 1 Regulates Cellular and Organismal Senescence by Inhibiting Forkhead Box O Transcription Factors

Xie

Shan

et al. 2014

Journal of Biological Chemistry

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Background: E2F1 and FOXO3 are two transcription factors participating in cellular senescence. Results: E2F1 represses FOXO3 transactivity through interaction. Conclusion: E2F1-FOXO3 regulatory mechanism is conserved and participates in regulating cellular senescence. Significance: Drugs and/or therapies that inhibit the physical interaction might be candidates for reducing cellular senescence and increasing longevity.

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Section: Discussionmentioning

confidence: 99%

“…Visualization and Quantitation of Protein and RNA-Western blots were performed as described (15). Total RNA was isolated from cells using Trizol reagent (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

E2F Transcription Factor 1 Regulates Cellular and Organismal Senescence by Inhibiting Forkhead Box O Transcription Factors

Xie

Shan

et al. 2014

Journal of Biological Chemistry

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“…We measured phosphorylation of FOXO1 on Ser256, a site predominantly phosphorylated by Akt, and to a lesser extent serum/glucocorticoid inducible kinase. Other kinases are known to phosphorylate FOXO at alternate sites, including mammalian sterile 20-like kinase (MST), cyclindependent kinases, AMP-activated protein kinase (AMPK), extracellular signal-related kinase (ERK) and IκB kinase (IKK) [49]. In contrast, under fasting conditions, where insulin levels were significantly elevated in insulinresistant and type 2 diabetic individuals, there was a concomitant increase in basal FOXO phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Tonks

Miller

et al. 2013

Diabetologia

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Aims/hypothesis Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. Methods We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. Results Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. Conclusions/interpretation These results highlight nonlinearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2811-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…FOXO1 has been shown to undergo posttranslational modifications, including phosphorylation, acetylation, ubiquitination, lysine and arginine methylation, and glycosylation, which can regulate the transactivation function of FOXO1 by modulating its subcellular localization, protein stability, DNA binding, transcriptional activity, and interaction with other proteins (2,3,36). In addition, we previously reported that poly(ADP-ribose)polymerase 1 (PARP1) binds and poly(ADP-ribosyl)ates FOXO1; however, the functional significance of poly(ADP-ribosyl)ation remains unclear (37).…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, the FOXO family consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6, while invertebrates have only one FOXO gene, such as dFOXO in Drosophila flies and daf-16 in Caenorhabditis elegans. FOXO proteins are tightly regulated by multiple posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and arginine methylation (2,3). Among them, a major form of regulation is Akt-mediated phosphorylation, which is downstream from the insulin or insulin-like growth factor 1 (IGF-1) signaling pathway and results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby repressing the transcription of FOXO target genes (4).…”

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confidence: 99%

Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

Daitoku

Kaneko

Yoshimochi

et al. 2016

Molecular and Cellular Biology

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Forkhead box O (FOXO; DAF-16 in nematodes) transcription factors activate a program of genes that control stress resistance, metabolism, and life span. Given the adverse impact of the stochastic DNA damage on organismal development and aging, we examined the role of FOXO/DAF-16 in UV-induced DNA damage response. Knockdown of FOXO1 but not of FOXO3a increases sensitivity to UV irradiation when exposed during S phase, suggesting a contribution of FOXO1 to translesion DNA synthesis (TLS), a replicative bypass of UV-induced DNA lesions. Actually, FOXO1 depletion results in sustained activation of ATR-Chk1 signaling and a reduction of proliferating cell nuclear antigen (PCNA) monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes, but it binds to replication protein A 1 (RPA1), which coats single-stranded DNA and acts as a scaffold for TLS. In Caenorhabditis elegans, daf-16-null mutants show UV-induced retardation in larval development and are rescued by overexpressing a DAF-16 mutant lacking the transactivation domain but not a mutant whose amino acid substitutions render it unable to interact with RPA1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independent of its transactivation activity.

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Post-translational regulation of FOXO

Cited by 45 publications

References 51 publications

E2F Transcription Factor 1 Regulates Cellular and Organismal Senescence by Inhibiting Forkhead Box O Transcription Factors

E2F Transcription Factor 1 Regulates Cellular and Organismal Senescence by Inhibiting Forkhead Box O Transcription Factors

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

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