Post-translational modifications of FOXO family proteins

Wang, Ziyao; Yu, Tinghe; Huang, Ping

doi:10.3892/mmr.2016.5867

Cited by 68 publications

(38 citation statements)

References 129 publications

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“…Acetylation impacts on DNA binding and transcriptional activity. Oxidative-stress-mediated FoxO deacetylation (via the NAD-dependent deacetylase sirtuin-1, Sirt-1) or monoubiquitination increases FoxO DNA binding capability and transcriptional activity [24]. Conversely, the poly-ubiquitination of FoxO results in proteasome-mediated protein degradation [24].…”

Section: Forkhead Transcription Factors: Overview and Role In Cancermentioning

confidence: 99%

Role of FoxO Proteins in Cellular Response to Antitumor Agents

Beretta

Corno

Zaffaroni

et al. 2019

Cancers

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FoxO proteins (FoxOs) are transcription factors with a common DNA binding domain that confers selectivity for DNA interaction. In human cells, four proteins (FoxO1, FoxO3, FoxO4 and FoxO6), with redundant activity, exhibit mainly a positive effect on genes involved in cell cycle, apoptosis regulation and drug resistance. Thus, FoxOs can affect cell response to antitumor agent treatment. Their transcriptional activity depends on post-translational modifications, including phosphorylation, acetylation, and mono/poly-ubiquitination. Additionally, alterations in microRNA network impact on FoxO transcripts and in turn on FoxO levels. Reduced expression of FoxO1 has been associated with resistance to conventional agents (e.g., cisplatin) and with reduced efficacy of drug combinations in ovarian carcinoma cells. FoxO3 has been shown as a mediator of cisplatin toxicity in colorectal cancer. A requirement for FoxO3-induced apoptosis has been reported in cells exposed to targeted agents (e.g., gefitinib). Recently, the possibility to interfere with FoxO1 localization has been proposed as a valuable approach to improve cell sensitivity to cisplatin, because nuclear retention of FoxO1 may favor the induction of pro-apoptotic genes. This review focuses on the role of FoxOs in drug treatment response in tumor cells and discusses the impact of the expression of these transcription factors on drug resistance/sensitivity.

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Section: Forkhead Transcription Factors: Overview and Role In Cancermentioning

confidence: 99%

Role of FoxO Proteins in Cellular Response to Antitumor Agents

Beretta

Corno

Zaffaroni

et al. 2019

Cancers

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“…The activity of FOXO3a is controlled by various post-translational modifications (PTMs), which determine its subcellular localization. Current knowledge suggests that FOXO3a PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, are the common thread of FOXO3a involvement in cellular homeostasis regulation [29,30]. In particular, FOXO3a PTMs drive FOXO3a activity towards the nuclear and/or the mitochondrial compartment in response to stress stimuli.…”

Section: Introductionmentioning

confidence: 99%

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

Fasano

Disciglio

Bertora

et al. 2019

Cells

134

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Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a variety of stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. FOXO3a activity is regulated by post-translational modifications that drive its shuttling between different cellular compartments, thereby determining its inactivation (cytoplasm) or activation (nucleus and mitochondria). Depending on the stress stimulus and subcellular context, activated FOXO3a can induce specific sets of nuclear genes, including cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species (ROS) scavengers, autophagy effectors, gluconeogenic enzymes, and others. On the other hand, upon glucose restriction, 5′-AMP-activated protein kinase (AMPK) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -dependent FOXO3a mitochondrial translocation allows the transcription of oxidative phosphorylation (OXPHOS) genes, restoring cellular ATP levels, while in cancer cells, mitochondrial FOXO3a mediates survival upon genotoxic stress induced by chemotherapy. Interestingly, these target genes and their related pathways are diverse and sometimes antagonistic, suggesting that FOXO3a is an adaptable player in the dynamic homeostasis of normal and stressed cells. In this review, we describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions.

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“…FOXO activation is complex, involving not only transcriptional activation, but also various post-transcriptional and post-translational mechanisms, including miRNA-mediated repression; 15 acetylation, phosphorylation, ubiquitination, methylation, and glycosylation; 16 protein-protein interactions; and cytoplasmic-nuclear shuttling. 17 Alterations in FOXO1 affect its nuclear import (activation) or export (inactivation) and DNA-binding activity.…”

Section: Introductionmentioning

confidence: 99%

The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

et al. 2017

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Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.

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Post-translational modifications of FOXO family proteins

Cited by 68 publications

References 129 publications

Role of FoxO Proteins in Cellular Response to Antitumor Agents

Role of FoxO Proteins in Cellular Response to Antitumor Agents

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

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