IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a

Hu, Mickey C.T.; Lee, Dung‐Fang; Xia, Weiya; Golfman, Leonard S.; Ou‐Yang, Fu; Yang, Jer Yen; Zou, Yiyu; Bao, Shilai; Hanada, Norihisa; Saso, Hitomi; Kobayashi, Ryûji; Hung, Mien‐Chie

doi:10.1016/j.cell.2007.06.006

Cited by 138 publications

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“…We found that the elevation of SIRT1 and Skp2 in prostate cancer cells are responsible for the downregulation of FOXO3. As FOXO3 inhibits cell proliferation and promotes apoptosis, it has the property as a tumor suppressor (Paik et al, 2007) and its level is downregulated in some tumors (Hu et al, 2004). Our finding offers a mechanistic link between the upregulation of SIRT1 and Skp2 and the downregulation of FOXO3 in tumor cells.…”

Section: Discussionmentioning

confidence: 59%

“…Thus, the net outcome of SIRT1 or SIRT2 on FOXO target gene expression might be a balance between the positive effect through the increase of DNA binding, and the negative effect through FOXO poly-ubiquitination and degradation caused by sirtuin deacetylation of FOXO proteins. Conceivably, this balance between transactivation and degradation of FOXO could be tilted by other post-translational modifications of FOXO3, such as phosphorylation Hu et al, 2004), in response to cellular signaling events initiated by hormonal, nutritional or stress signals. The work of Brunet et al (2004) has indicated that sirtuin deacetylation of FOXO proteins may activate the transactivation of a subset of FOXO target genes but inhibit the expression of other FOXO target genes, shifting cells from apoptosis toward growth arrest and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

“…There is also evidence that Akt/protein kinase B phosphorylation promotes FOXO1 and FOXO3 poly-ubiquitination and proteasomal degradation Plas and Thompson, 2003). Additionally, IkB kinase and extracellular signal-regulated kinase also phosphorylate FOXO3 at different sites, inducing FOXO3 degradation through poly-ubiquitination and proteasomal degradation (Hu et al, 2004;Yang et al, 2008). Because both acetylation and ubiquitination modifications are on the e-amino group of the lysine residue, deacetylation may render the lysine residues open for ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…To date, a number of other mechanisms have been reported to regulate FoxO3a. For example, IkappaB kinase (IKKb) or serum-glucocorticoidrelated kinases phosphorylate FoxO3a, which triggers nuclear export and cytoplasmic sequestration, thereby inhibiting access to DNA binding sites [27,28]. Intriguingly, in the case of acute myeloid leukemia, IKKb overcomes PI3K/Akt and ERK/MAPK to control FoxO3a activity, and blockade of the IKK/nuclear factor kappa B (NFjB) signaling pathway has already been proposed as a possible therapeutic strategy [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

FoxO3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity

et al. 2011

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Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signalregulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/ mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma.

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“…1). IKK-β leads to nuclear exclusion and protein degradation of FOXO3 [16]. To determine if IKK-ε promotes the same phenomenon, FLAG-tagged expression constructs encoding IKK-β and IKK-ε, as well as their dominant negative forms, were expressed in the 293-TLR4 cells.…”

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confidence: 99%

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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Cell survival transcription factor FOXO3 has been recently implicated in moderating proinflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-β was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-β expression.We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression, providing new insight into the role of FOXO3 in immune response control.Keywords: Activation-induced cell death r Cell volume regulation r T-cell response r Taurine transporter Supporting Information available online IntroductionThe FOXO transcription factors (FOXO1, FOXO3, FOXO4, and FOXO6) are involved in a wide range of cellular processes including cell-cycle arrest, apoptosis, oxidative stress detoxification, and cellular homeostasis [1][2][3]. Given their importance in such critical cellular functions, their activity is tightly regulated by posttranslational modifications, mainly via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway [4]. In response to growth factors or cytokines, FOXO proteins are phosphorylated by AKT Correspondence: Dr. Lionel Luron e-mail: luron@ciml.univ-mrs.fr at three conserved serine/threonine residues (Thr 32 , Ser 253 , and Ser 315 of FOXO3) resulting in the protein inactivation via nuclear exclusion and subsequent degradation [5,6].More recently, FOXO factors have been shown to play a role in immunity and inflammation [7][8][9][10][11]. In addition to their critical role in homeostasis of immune-relevant cells including B and T cells [7][8][9], FOXOs are associated with inflammatory diseases [12,13]. Moreover, FOXO3 was identified as a key factor in regulation of the innate immune response [10]. In FOXO3-deficient mice, production of major proinflammatory cytokines IL-6 and TNF-α by dendritic cells (DCs) is increased in response to viral infection, resulting in a greater expansion of T-cell population [10]. Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim...

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IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a

Cited by 138 publications

References 0 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

FoxO3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

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