Unravelling the tumor-suppressive functions of FOXO proteins

Dansen, Tobias B.; Burgering, Boudewijn M.T.

doi:10.1016/j.tcb.2008.07.004

Cited by 239 publications

(211 citation statements)

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“…But the underlying mechanism was not clear. Because we found SIRT1 promotes FOXO3 degradation and FOXO3 can function as a tumor suppressor (Dansen and Burgering, 2008), we detected FOXO3 levels in PrEC, PC3 and DU145 prostate cells. We confirmed that SIRT1 expression was elevated in PC3 and DU145 cells in an order of PrEC oPC3 oDU145 (Figure 7a).…”

Section: Scf-skp2 Ubiquitinates Foxo3mentioning

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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Section: Scf-skp2 Ubiquitinates Foxo3mentioning

confidence: 99%

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

et al. 2011

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“…The 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].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…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 [2].…”

Section: Introductionmentioning

confidence: 99%

“…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 [2].Based on the homology of IKK-ε and IKK-β, we hypothesized that IKK-ε may regulate FOXO3 protein activity and thereby influence the expression of cell-cycle arrest-and apoptosis-related genes. Here, we demonstrate that IKK-ε is indeed able to interact with and phosphorylate FOXO3, resulting in its inactivation and nuclear exclusion.…”

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confidence: 99%

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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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Identifying New Targets for Personalised Cancer Therapy

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Madureira

Hill

2013

Encyclopedia of Life Sciences

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Personalised medicine requires the use of patient‐specific information to predict individual responses to disease treatment. Consequently, this approach requires the diagnostic ability to stratify patients based on their potential to benefit from a specific treatment (as opposed to an alternative) and the availability of molecularly targeted therapies. On the basis of the heterogeneity of the disease, cancer diagnosis and therapy is currently at the forefront of personalised medicine. Cancer therapy is currently undergoing a significant paradigm change, from nonspecific cytotoxic agents to considerably more specific approaches based on the unique molecular features of cancer cells. The identification and validation of disease relevant targets is crucial for the development of molecularly targeted anticancer therapies. Our advancing understanding of the molecular basis of cancer in tandem with novel approaches to interfere with signal transduction pathways have opened new horizons for anticancer target discovery. Specifically, the image‐based large‐scale analysis of cellular phenotypes that arise from genetic or chemical perturbations paved the way for the identification and validation of disease relevant molecular targets independent of preconceived notions of mechanistic relationships. Key Concepts: Cancer therapy is undergoing a change from nonspecific cytotoxic to molecularly targeted treatment. Targeted cancer therapies need new relevant targets. A good therapeutic target is essential and specific. Targeting specific molecular targets are expected to be beneficial only for a subset of patients. Companion diagnostics based on specific biomarkers is essential to guide treatment decisions. Targeted treatment has to be intimately linked to the causal changes for each neoplasm. The selection of appropriate combinations of molecular targets specific for different cancers will be essential to develop successful anticancer therapies. Image‐based high content screening allows for the identification of disease relevant molecular targets independent of preconceived notions of mechanistic relationships.

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Unravelling the tumor-suppressive functions of FOXO proteins

Cited by 239 publications

References 82 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

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

Identifying New Targets for Personalised Cancer Therapy

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