Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification

Tsai, Kuang‐Lei; Sun, Yuh‐Chang; Huang, Chun‐Chia; Yang, Jer Yen; Hung, Mien‐Chie; Hsiao, Chwan‐Deng

doi:10.1093/nar/gkm703

Cited by 179 publications

(189 citation statements)

References 53 publications

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“…In agreement, previous research has shown that FOXO1/3a acetylation at Lys-242 and Lys-245 is mediated through the antagonistic action of cAMP response elementbinding protein (CREB) and the NAD-dependent histone/lysine deacetylase sirtuins (17,39). However, the authors of these studies also predict that acetylation at Lys-242 and Lys-245 attenuates the DNA-binding activity and thereby impairs transcriptional activity of FOXO proteins (17,38,39). On the contrary, our results indicate that FOXO3a acetylation, particularly at Lys-242/5, is associated with nuclear localization, induction of downstream antiproliferative targets, cell proliferative arrest, and sensitivity to dexamethasone.…”

Section: Discussionsupporting

confidence: 87%

“…In attempting to explore the mechanism involved, we found that the expression of CREB-binding protein (CBP) is increased, whereas SIRT1 and SIRT2 levels are suppressed by dexamethasone treatment. In agreement, previous research has shown that FOXO1/3a acetylation at Lys-242 and Lys-245 is mediated through the antagonistic action of cAMP response elementbinding protein (CREB) and the NAD-dependent histone/lysine deacetylase sirtuins (17,39). However, the authors of these studies also predict that acetylation at Lys-242 and Lys-245 attenuates the DNA-binding activity and thereby impairs transcriptional activity of FOXO proteins (17,38,39).…”

Section: Discussionsupporting

confidence: 79%

“…The immunoprecipitates were then probed for the expression of FOXO3a, (Ser-7) FOXO3a phosphorylation, and (Lys-242/5) FOXO3a acetylation. The result showed that JNK inhibition caused a prominent increase in FOXO3a levels as well as an increase in (Ser-7) FOXO3a phosphorylation and (Lys-242/ 5) FOXO3a acetylation, which have been shown to be associated with FOXO3a nuclear relocation, stabilization, and activation (11,20,38,39). These results are consistent with the notion that dexamethasone activates FOXO3a through inducing JNK and p38 MAPKs coordinately in B-ALL.…”

Section: Mw (Kda)supporting

confidence: 87%

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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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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 79%

Section: Mw (Kda)supporting

confidence: 87%

See 1 more Smart Citation

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Consolaro

Ghaem‐Maghami

Bortolozzi

et al. 2015

Molecular Cancer Research

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“…6E. Of note, the mutant (581-651 aa) contains the entire transactivation domain of foxo3b, corresponding to the region 650-673 aa of human FOXO3a (45,46). Thus, these data suggest that the N-terminal of foxo3b (1-120 aa) is not required for the suppressive function of foxo3b on irf3/irf7 activity, and the C-terminal containing the transactivation domain of foxo3b (628-651 aa) is not sufficient to suppress irf3/irf7 activity.…”

Section: Foxo3b Suppresses Ifn Activation Via Irf3 and Irf7mentioning

confidence: 99%

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Xing

Cai

Zhang

et al. 2016

The Journal of Immunology

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Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

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“…Furthermore, a core FoxO3a-binding motif 5 0 -AAACA-3 0 (Tsai et al, 2007) was found in the promoter region at position À1139 to À1134 bp (FBE2) and three tandem repeats of this core motif were also observed in the region between À398 and À380 bp (FBE1), (Supplementary Figure 1). We also found several Smad-binding sites (5 0 -AGAC-3 0 ) within the CCNG2 promoter, two of which are in close proximity with FBEs.…”

Section: Ccng2 Gene Is a Transcriptional Target Of Foxo3amentioning

confidence: 99%

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Peng

2011

Oncogene

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Nodal, a member of the transforming growth factor-b superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptorlike kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between À398 and À380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells.

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Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification

Cited by 179 publications

References 53 publications

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

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