Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity

Dansen, Tobias B.; Smits, Lydia M.M.; Triest, Miranda H. van; Keizer, Peter L.J. de; Leenen, Dik van; Koerkamp, Marian J. A. Groot; Szypowska, Anna A.; Meppelink, Amanda; Brenkman, Arjan B.; Yodoi, Junji; Holstege, Frank C.P.; Burgering, Boudewijn M.T.

doi:10.1038/nchembio.194

Cited by 179 publications

(151 citation statements)

References 44 publications

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“…The dynamic resolution of the heterodimer complex is in turn regulated by Trx. This thioldependent regulation of FOXO was supported by both substitution of critical cysteine residues and treatment with NAC, which abrogated the p300-lysine interaction (20).…”

mentioning

confidence: 90%

Involvement of Redox State in the Aging ofDrosophila melanogaster

Orr

Radyuk

Sohal

2013

Antioxidants & Redox Signaling

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Significance: The main objective of this review was to provide an exposition of investigations, conducted in Drosophila melanogaster, on the role of reactive oxygen species and redox state in the aging process. While early transgenic studies did not clearly support the validity of the oxidative stress hypothesis of aging, predicated on the accumulation of structural damage, they spawned a broader search for redox-related effects that might impact the aging process. Recent Advances: Initial evidence implicating the thiol redox state as a possible causative factor in aging has been obtained in Drosophila. Overexpression of genes, such as GCL, G6PD, Prx2, and Prx5, which are involved in the maintenance of thiol redox homeostasis, has strong positive effects on longevity. Further, the depletion of peroxiredoxin activity in the mitochondria through the double knockdown of Prx5 and Prx3 not only results in a redox crisis but also elicits a rapid aging phenotype. Critical Issues: Herein, we summarize the present status of knowledge about the main components of the machinery controlling thiol redox homeostasis and describe how age-related redox fluctuations might impact aging more acutely through disruption of the redox-sensitive signaling mechanisms rather than via the simple accumulation of structural damage. Future Directions: Based on these initial insights into the plausible impact of redox fluctuations on redox signaling, future studies should focus on the pathways that have been explicitly implicated in aging, such as insulin signaling, TOR, and JNK/FOXO, with particular attention to elements that are redox sensitive. Antioxid. Redox Signal. 19, 788-803. Historical BackgroundLinkage between energy utilization and life span S tudies in the fruit fly, Drosophila melanogaster, have historically made important contributions toward the development of basic concepts in many areas of biology, including the aging process, especially in defining the role of oxygen metabolism in the determination of life span. In 1917, Loeb and Northrop showed that the life span of D. melanogaster is inversely associated with the ambient temperature (61), which, in turn, was later demonstrated to be linked to the rate of oxygen consumption within the physiological range, whose upper limit for long-term survival and optimal fecundity is *27°C (67). A major advance in the field of aging that can be largely credited to the Drosophila model was Pearl's (77) interpretation of the effects of temperature on longevity, namely, shorter life spans at elevated temperatures are ascribable to a relatively higher physical activity or the rate of living (ROL). As originally proposed, the length of life of an individual organism is governed by two distinct factors: (i) a genetically determined metabolic potential, that is, the total amount of energy consumed during life, which varies in different genotypes, and (ii) the rate at which this metabolic potential is expended by the individual or the rate of its metabolism. It is a widely recognized phe...

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confidence: 90%

Involvement of Redox State in the Aging ofDrosophila melanogaster

Orr

Radyuk

Sohal

2013

Antioxidants & Redox Signaling

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“…One of the major ways in which metabolism can affect signaling pathways is through alterations of ROS levels. In turn, ROS can directly react with various proteins, such as kinases, phosphatases or transcription factors, to alter processes that regulate cell cycle progression, apoptosis, quiescence or differentiation (Dansen et al, 2009;Guo et al, 2010b;Velu et al, 2007). Furthermore, ROS can also directly modify metabolic enzymes or proteins that participate in nutrient-sensing pathways to direct the metabolic flux (Anastasiou et al, 2011;Brunelle et al, 2005;Sarbassov and Sabatini, 2005).…”

Section: Ros In Stem Cell Metabolismmentioning

confidence: 99%

“…Oxidation of Cys in PTEN catalytic sites causes inactivation (Lee et al, 2002) Modulation of the PI3K/AKT pathway PTEN inactivation by NOX-generated ROS increases PI3K-AKT activation in NSCs (Le Belle et al, 2011) Sirtuins (SIRTs) Cys oxidation inhibits SIRT1 activity (Zee et al, 2010) SIRTs are NAD + -dependent deacetylases that modulates the activity of FOXO TFs (Brunet et al, 2004;Kobayashi et al, 2005;Daitoku et al, 2004;Motta et al, 2004;van der Horst et al, 2004) SIRT3 controls ROS levels during HSC ageing (Brown et al, 2013) FOXOs possess 5-10 reactive Cys; the FOXO4 signaling switch from cell cycle arrest to apoptosis is redox mediated (direct); redox modulation of PTEN and AKT impact FOXOs negatively or positively, respectively (indirect) (Dansen et al, 2009) Can regulate the transcription of antioxidant enzymes, such as SOD2, catalase and GPX1…”

Section: Box 1 Tools For Ros Detection and Their Limitationsmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

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“…Co-precipitation analysis revealed that the acetyltransferase CBP/p300 binds the first 52 amino acids of the N-terminal region of FOXO3a (14). Interestingly, p300 also directly acetylates FOXO transcription factors at several conserved lysine residues, Lys-242, Lys-245, and Lys-262 of FOXO3a (15)(16)(17). However, p300-dependent acetylation has been shown to have a dual function in FOXO-mediated transcription; either it can attenuate FOXO transcriptional activity or it can promote the recruitment and assembly of the transcriptional machinery, increasing their DNA-binding ability and transcriptional activity (18,19).…”

Section: Introductionmentioning

confidence: 99%

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Consolaro

Ghaem‐Maghami

Bortolozzi

et al. 2015

Molecular Cancer Research

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Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/ JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells.

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Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity

Cited by 179 publications

References 44 publications

Involvement of Redox State in the Aging ofDrosophila melanogaster

Involvement of Redox State in the Aging ofDrosophila melanogaster

Stem cells and the impact of ROS signaling

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

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