Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Forkhead Box Protein O

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101601

Synonyms

 AF6q21;  AFX;  DAF-16;  dFoxO;  FKH1;  FKHR;  FKHRL1;  FKHRL1P2;  FoxO1;  FoxO1a;  FoxO3;  FoxO3a;  FoxO4;  FoxO6

Background

Forkhead box (Fox) proteins are a family of transcription factors that regulate the transcription of genes regulating diverse cellular processes, including cell survival, apoptosis, oxidative stress response and redox signaling, proliferation, differentiation, metabolism, and life span. Fox proteins are classified into subclasses FoxA–FoxS, and subgroup O (FoxO) proteins are a subgroup of the Fox family, which is characterized by a conserved DNA-binding domain (the “Forkhead box,” or Fox). This domain could recognize the specific DNA sequence localized in the promoter and thus regulate the transcription/expression of these genes. Forkhead gene (fkh) was cloned for the first time from the fly Drosophila melanogaster and has been identified to play important roles during the developing process of the anterior and posterior gut of the embryo. Genetic mutation in fkh gene induced defects in head fold involution during the process of embryogenesis, leading to a featured spiked head appearance in adult flies (Weigel et al. 1989). Weigle and Jäckle compared the sequence of Fkh protein and HNF-3A protein, proposed the existence of a new class of transcription factors that is conserved from Drosophila to mammals (Lai et al. 1990; Weigel and Jackle 1990), and coined the name “forkhead domain” for this characteristic DNA-binding motif (Weigel and Jackle 1990). Galili et al. mapped FoxO1 gene to chromosome 13q14 (Galili et al. 1993), while Hillion et al. mapped the FoxO3a gene to 6q21 (Hillion et al. 1997). Since the identification of the Drosophila melanogaster gene forkhead, there are more than 100 forkhead genes and 19 subgroups (FOXA to FOXS) have been discovered (Weigel et al. 1989). The next progress in the field was the unified nomenclature that grouped the Fox proteins into subclasses (FoxA–FoxS) based on sequence conservation (Kaestner et al. 2000). Prior terminology for forkhead proteins included: forkhead in rhabdomyosarcoma (FKHR) (FoxO1), FKHRL1 (forkhead in rhabdomyosarcoma like protein 1) (FoxO3a), the Drosophila gene fork head (fkh), Forkhead Related Activator (FREAC-)-1 and FREAC-2, and the acute leukemia fusion gene located in chromosome X (AFX) (FOXO4). For the present nomenclature, an Arabic number is provided with the designation of “Fox,” and then a subclass or subgroup letter is provided, and finally the member is listed within the subclasses of the Fox proteins (Maiese et al. 2009a). All letters are capitalized for human Fox proteins and for the mouse, only the initial letter is listed as uppercase. Mammalian FoxO proteins are assigned to the O class of the forkhead box class transcription factors and consist of FoxO1, FoxO3, FoxO4, and FoxO6 (Maiese et al. 2009b). Furuyama et al. found that the DNA binding sequences for all four mammalian FoxO proteins shared a common sequence motif, TTGTTTAC (Furuyama et al. 2000). Subsequently, crystal structure of the DNA-binding domain of FoxO4 (FoxO4-DBD) and FoxO3a (FoxO3a-DBD) bound to a 13-bp DNA duplex containing a FoxO consensus binding sequence was identified at a 1.9 Å (Boura et al. 2010) and 2.7 Å (Tsai et al. 2007) resolution, respectively.

The activities of FoxO proteins are controlled by multiple posttranslational modifications, including phosphorylation, methylation, acetylation, and ubiquitination. Most of the posttranslational modification sites are located within the region of the FoxO-DBD; they affect FoxO proteins-DNA binding, transcription activity, cytoplasma/nuclear localization, and/or stability/degradation as well as interaction with other co-regulators (Urbanek and Klotz 2016). Members of subgroup “O” share the common characteristic of being regulated by phosphorylations triggered by the insulin receptor (InR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway (Dillin et al. 2002). In invertebrates, only one FoxO gene was found and identified. In the worm, it termed daf-16 and in the fly and is named dFoxO. In mammals, four FoxO genes were identified, they are FoxO1, 3, 4, and 6. The sequence of FoxO2 is identical to FoxO3 and FoxO5 is the fish orthologue of FoxO3 (Carter and Brunet 2007). In the last decade, various biological functions of FoxO proteins in different systems have been unveiled, including activation of autophagy (Warr et al. 2013), tumor immunity (Luo et al. 2016), and food intake and obesity (Ren et al. 2012).

FoxO Protein Structure and Function

The diverse biological functions of FoxO mentioned above are derived from the specific structure of FoxO proteins. FoxO proteins have highly evolutionarily conserved forkhead domain, which shows a butterfly-like appearance in X-ray crystallography examination (Clark et al. 1993). From the amino to carboxy terminal, FoxO proteins are composed of four domains (Fig. 1): (1) a forkhead DNA-binding domain (DBD), which is the same for all four FoxO members; (2) a nuclear localization sequence (NLS), which is located just downstream of DBD; (3) a nuclear export sequence (NES); and (4) a C-terminal containing a transactivation (TA) domain (Obsil and Obsilova 2008). The DBD contains 110 amino acids, which is common for most of the Fox family members, and consists of three α-helices (H1, H2, and H3), three β-strands (S1, S2, and S3), and two wing-like loops (W1 and W2) (Obsil and Obsilova 2008; Trinh et al. 2013). DBD and specific regions within the N- and C-terminal domains are involved in DNA binding recognition and affinity of this transcription factor. FoxO1, FoxO3a, and FoxO6 proteins have similar dimensions of about 650 amino acid residues, while the sequence for FoxO4 is shorter, it contains about 500 amino acid residues (Obsil and Obsilova 2008). All four FoxO proteins recognize two consensus sequences within the promoter region of the target gene: 5′-GTAAA(T/C)AA-3′ and 5′-(C/A)(A/C)AAA(C/T)AA-3′, the former sequence is known as the Daf-16 family member-binding element (DBE) and the latter one present in the promoter region of IGFBP-1 and named as the insulin-responsive sequence (IRE) (Obsil and Obsilova 2008; Hedrick et al. 2012). Although both sequences are closely related and include the core sequence motif 5′-(A/C)AA(C/T)A-3′, recognized by all forkhead proteins, FoxO proteins bind the DBE sequence with higher affinity (Obsil and Obsilova 2011). The NLS and the NES are phosphorylated by kinases (such as Akt) and interact with other proteins and thus modulate the subcellular localization of FoxO. The biological functions of NLS and NES are antagonistic. NLS is responsible for FoxO nuclear localization in the absence of phosphorylation, a condition occurring upon growth factor withdrawal or nutrient starvation (van der Horst and Burgering 2007). Survival factor withdrawal induces FoxO dephosphorylation and nuclear translocation. Within the nucleus, FoxO is activated and its biological functions are mediated through inducing target genes such as Fas ligand and triggers apoptosis (Brunet et al. 1999). In contrast to NLS, NES motif is responsible for FoxO nuclear export. Efficient FoxO export is based on intrinsic NES sequences, FoxO phosphorylation, and the binding of FoxO to 14–3-3 protein (Brunet et al. 2002). For example, PI3K-mediated activation of Akt directly phosphorylates FoxO at serine 256 and phosphorylated FoxO interacts with 14–3-3, leading to nuclear export and inactivation (Brunet et al. 1999). The chaperone protein 14–3-3 binds to FoxO3a in the nucleus and promotes their export from nucleus to cytoplasm. In the cytoplasm, 14–3-3 also blocks the nuclear localization signal to prevent FoxO3a nuclear re-import (Brunet et al. 2002). The transactivation domain in the C-terminal is required for coactivator recruitment (Wang et al. 2008).
Forkhead Box Protein O, Fig. 1

Regulatory motif of FoxO proteins. FoxO isoforms (FoxO1, FoxO3a, FoxO4, and FoxO6) contain the following domains: forkhead domain (DBD), a nuclear localization signal (NLS), a nuclear export sequence (NES), and a transactivation domain (TA). Phosphorylation sites of specific FoxO by Akt are given for the individual isoforms

Physiological Functions of FoxO

FoxO1, FoxO3a, and FoxO4 are all ubiquitously expressed in mammals. However, the FoxO1 and FoxO4 mRNAs are expressed at a high level in adipose and skeletal muscle tissues, respectively, while FoxO3a is abundant in many tissues including brain, heart, kidney, and spleen. FoxO6 transcript is selectively expressed in the developing and adult brain, indicating a role in central nervous system (Fu and Tindall 2008). FoxO proteins are evolutionarily conserved and represent important critical downstream transcriptional regulators substrates, of the insulin receptor (InR) and insulin-like growth factor-1 receptors (IGF-1R) in C. elegans and mammals, and are regulated via the PI3K/Akt signaling pathway (Zheng and Quirion 2006; Tullet et al. 2008; Kwon et al. 2010). Besides insulin and IGF-1, FoxO proteins may also be regulated by other growth factors, such as nerve growth factor and epidermal growth factor (Jackson et al. 2000; Zheng et al. 2002a; Wen et al. 2011). Occupancy of these tyrosine kinase receptors by respective growth factor ligands activate PI3K signaling pathway (Zheng and Quirion 2006). PI3K then promotes the conversion of membrane-bound phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 could act as a second messenger and promote the phosphorylation/activation of Akt through 3-phosphoinositide-dependent protein kinase-1. Activated Akt in turn phosphorylates a number of downstream targets and thus plays various physiological and pathological functions (Wang et al. 2012b). FoxO is one of the critical downstream targets of Akt. Akt regulates transcription through FoxO transcription factors by phosphorylating these proteins (FoxO1, FoxO3a, and FoxO4) at three conserved serine/threonine residues and FoxO6 at two phosphorylation sites. These FoxO proteins phosphorylations lead to their retention in the cytoplasm, thereby blocking the transcription of specific target genes (Wang et al. 2015). As transcription factors, FoxO family proteins differentially recognize the specific sequence in the promoter region of their target genes and bind to the promoter region to regulate their transcription in nucleus, and thus participate in the regulation of cell cycle arrest, oxidative stress resistance, cell survival, glucose metabolism, and cell apoptosis (Greer and Brunet 2005; Wen et al. 2012). The relationship between FoxO and its major downstream targets is shown in Fig. 2.
Forkhead Box Protein O, Fig. 2

FoxO and its downstream substrates. Dephosphorylation of FoxO protein by survival factors withdrawal leads to activation of FoxO, which binds to FoxO response element (FRE) and regulates the transcription of various downstream targets, including Bim, PEPCK, IL-1b, Cyclin G2, AQP4, and others, and thereby promotes apoptosis, gluconeogenesis, inflammation, proliferation, and edema. FoxO may also reduce cell size and suppress oxidative stress through acting on Atg 12 and MnSOD

FoxO is a key component of the InR and IGF-1R signaling cascades (Zheng et al. 2002b). Signaling through the insulin and IGF-1 pathways is necessary for glucose and lipid homeostasis as well as for growth and development. In hepatocytes, FoxO proteins regulate the expression of phosphoenolpyruvate carboxykinase and glycogen-6-phosphatase (Nakae et al. 2001), critical enzymes of glucose metabolism. Therefore, modulation of expression of this transcription factor may be found beneficial for diabetes mellitus therapy. In pancreatic α-cells, FoxO1 is important in regulation of pre-pro-glucagon (PPG) expression (McKinnon et al. 2006), while in pancreatic β-cells FoxO1 mediates glucagon-like peptide-1 (GLP-1) effects on pancreatic β-cell mass (Buteau et al. 2006). GLP-1,derived from the precursor peptide PPG by hydrolytic cleavage stimulates insulin secretion, thereby contributing to the limitation of the blood glucose rise after meals (Holst 2007). Taken together, these findings implicate FoxO as an important mediator of the effects of insulin on gene expression related to glucose metabolism.

Insulin also plays important roles in adipose tissue homeostasis and longevity. In invertebrates, InR/PI3K/Akt pathway regulates life span as well as increased body and organ size (Potter et al. 2003), which reflect either increased cell number or enlarged cell volume. Interestingly, mutations in DAF-16/FoxO suppress the effects of insulin on lifespan and organ size (Lin et al. 1997), suggesting that FoxO is negatively regulated by the InR/PI3K/Akt pathway and is essential for this phenotype. In Drosophila, the IGF-1R/PI3K/Akt pathway is implicated in regulation of body size and longevity. The longevity phenotype of IGF-1R has been proved to be related with resistance to enhanced oxidative stress (Holzenberger et al. 2003). It is hypothesized that this phenomenon is due to hyperactivation of FoxO proteins based on several studies indicating that FoxO transcription factors enhance the level of superoxide dismutase and protect towards oxidative stress insults in mammalian cells as well as in C. elegans (Murakami 2006). The observation that flies with foxo mutant are hypersensitive to oxidative stress confirms the highly conserved role of FoxO proteins in cytoprotection towards stress insults (Murakami 2006). FoxO proteins primarily function as transcription factors. In this case, FoxO proteins localize in the nucleus and regulate gene expression. Recent study also suggests the nontranscription activity of FoxO. Cytosolic FoxO1 is involved in the formation of autophagy induced by rapamycin (Zhu et al. 2014). As autophagy is pivotal for normal cell metabolism, aging, and cancer, this finding raises the importance of FoxO in cell metabolism regulation independent of its transcription factor function (Zhu et al. 2014).

FoxO proteins emerge as critical regulators of both somatic and embryonic stem cell proliferation and differentiation besides their critical role in InR and IGF-1R signaling. Functional maintenance of hematopoietic stem cells is constantly challenged by different insults such as DNA damage and oxidative stress. It has been repeatedly reported that Foxo3a is essential for the maintenance of hematopoietic, neural, and leukemic stem cells (Miyamoto et al. 2007; Renault et al. 2009; Naka et al. 2010). Foxo3a is an important regulator of the self-renewal of hematopoietic stem cells and contributes to the maintenance of their pool during aging by providing resistance to oxidative stress (Li et al. 2015). Studies using Foxo3a-deficient mice reveal that hematopoietic progenitors proliferation and differentiation processes were normal, when compared with wild type mice, but Foxo3a−/− knockout mice showed significantly reduced numbers of colony-forming cells present in bone marrow and stromal cells (Miyamoto et al. 2007). Compared to wild-type mice, adult FoxO3−/− mice were also characterized by lower numbers of neural stem cells (NSCs) in supra ventricular zone. NSCs isolated from adult FoxO3−/− mice have decreased self-renewal ability and cannot be committed to different neural lineages (Renault et al. 2009). Moreover, FoxO3a is required for Notch signaling pathway activity in the self-renewal process of stem cells (Gopinath et al. 2014). FoxO3a, but not FoxO1, prevented autophagy-related genes expression and auto-phagosome formation in mesenchymal stem cells exposed to cadmium (Yang et al. 2016).Normal expression of FoxO1 is also essential for the maintenance of human embryonic stem cell pluripotency. This function is probably mediated through direct regulation of OCT4 and SOX2 genes by activation of their respective promoters (Zhang et al. 2011).

Activation of FoxOs can directly promote the transcription of genes involved in the extrinsic and/or intrinsic apoptotic pathways. FoxO3a may induce apoptosis through activation of FASLG and FASLG-dependent extrinsic apoptosis-inducing metabolic pathways. In addition, FoxO1 and FoxO3a can activate extrinsic apoptotic pathway through activation of TRAIL protein (Modur et al. 2002). FoxO3a may also activate intrinsic apoptotic pathway through upregulation of Bim protein (Zhang et al. 2010), which is an inhibitor of Bcl-2, probably by cytochrome C release from the mitochondria. Moreover, FoxO3a induces synthesis of PUMA protein which influences the cells to be more sensitive to proapoptotic signals (Zhang et al. 2010). In addition, FoxO4 can promote apoptosis through downregulation of antiapoptotic proteins such as FLIP (Cornforth et al. 2008)

Individual FoxO proteins appear to have selective expression in the different neuronal cells and nuclei of the nervous system indicating an important physiological role in a variety of neurological functions (Wang et al. 2013a; Maiese 2015; Maiese 2016). FoxO1 may have an important role in astrocyte oxidative stress-induced cell death (Lee et al. 2014), modulation of embryonic endothelial stem cell differentiation and survival (Merkely et al. 2015), neuroprotection in brain stroke (Xiong et al. 2014), memory (Zhang et al. 2016), and neuronal autophagy (Vidal et al. 2012). FoxO3 may have a critical role in maintenance of auditory synaptic transmission (Gilels et al. 2013), regulates hypoxia-induced blood brain barrier microcapillaries endothelial cell permeability (Hyun and Jung 2014), selective gene transcription via epigenetic modification during oxidative stress injury in mouse cerebellar granule neurons (Peng et al. 2015), and hippocampal neuronal cell survival during oxidative stress (Wang et al. 2013c). FoxO6 may oversee memory consolidation and emotion (Salih et al. 2012) and regulates neuronal polarity (de la Torre-Ubieta et al. 2010) since it is present in several regions of the brain, such as the hippocampus, the amygdala, and the nucleus accumbens (Hoekman et al. 2006).

Posttranslational Mechanisms of Regulation of FoxO Proteins Transcriptional Activity

While chronic modulation of FoxO proteins level and function is mediated by synthesis, acute regulation of FoxOs protein activity is based on posttranslational modifications, such as phosphorylation, acetylation, and ubiquitination. Depending on this modified state, the activity may vary. Phosphorylation is a major regulator of FoxO proteins nucleocytoplasmic shuttling but also affects their binding to DNA. FoxO is a canonical target of PI3K/Akt signal pathway. In the presence of different growth factors such as NGF or IGF-1, PI3K/Akt signal pathway is activated leading to the phosphorylation of FoxO3a on Thr-32 and Ser-253 by Akt (Stitt et al. 2004). Phosphorylated FoxO3a then interacts with 14–3-3 scaffold protein and is retained in the cell cytoplasm (Tzivion et al. 2011). On the contrary, growth factor withdrawal induces FoxO proteins dephosphorylation and promotes translocation of FoxO3a from the cytoplasm to the nucleus (Dijkers et al. 2002) where FoxO3a protein would bind to the DNA and induce transcription of target genes. The direction of nucleocytoplasmic shuttling of FoxO3a depends on its phosphorylation site: phosphorylation by Akt, ERK1/2, the serum- and glucocorticoid-regulated kinase (SGK), and cyclin-dependent kinase (CDK) 1/2 may promote the location in the cytoplasm, while other protein kinases, such as mammalian Ste20-like kinase 1 (Mst1), AMP-activated protein kinase (AMPK), and MAPKAPK5 (MAPK-activated protein kinase MK5), may promote its translocation into the nucleus (Zhao et al. 2011). For example: (1) MST1 could phosphorylate FoxO3a on Ser-207 under the condition of oxidative stress, which causes dissociation from YWHAB/14–3-3-beta and nuclear translocation (Lehtinen et al. 2006); (2) AMPK could directly phosphorylate FoxO3a and regulate its transcriptional activity without affecting subcellular localization (Greer et al. 2007); (3) phosphorylation of FoxO3a by MAPKAPK5 also promotes nuclear localization and enhances DNA-binding (Kress et al. 2011). A schematic presentation of tyrosine kinase receptor induced PI3K/Akt, MEK/ERK, JNK, and Mst1 pathways regulating FoxO activity and subcellular localization is presented in Fig. 3.
Forkhead Box Protein O, Fig. 3.

FoxO regulation by receptor-induced phosphorylations. Binding of growth factors (such as IGF-1 and NGF) to their respective tyrosine kinase receptors leads to the activation of multiple signaling pathways including the PI3K/Akt and MAPK. Activation of PI3K/PDK1/Akt and Ras/Raf/MEK/ERK leads to the phosphorylation and inactivation of FoxO. Under the condition of stress insults, FoxO may also be phosphorylated by JNK and Mst1. Phosphorylated FoxO localizes in the cytoplasm, while inhibition of the PI3K/Akt and MAPK pathways causes the dephosphorylation and the activation of FoxO. FoxO then translocates to the nucleus and regulates the expression of target genes

Acetylation/deacetylation is another important posttranslational modification of FoxO3a. Oxidation of FoxO proteins cysteine residues mediates interaction with coregulatory factors and may contribute to insult-induced FoxO acetylation, activity, and nucleocytoplasmic shuttling (Putker et al. 2015). Upon cell exposure to oxidative stress insult, FoxO3a may be acetylated by NAD-dependent histone deacetylases (Daitoku et al. 2004; Perrot and Rechler 2005). Acetylated FoxO3A is a stronger activator of proapoptotic proteins, such as Bim and FASL6, but, at the same time, a weaker inducer of endogenous antioxidants such as superoxide dismutase (Brunet et al. 2004; Giannakou and Partridge 2004). The extent of FoxO3a acetylation may reflect the extent to which the cell has been damaged by environmental factors. FoxO3a acetylation represents to eukaryotic cells a serious damage and may promote apoptosis in response to oxidative or genotoxic stress insults (Watroba et al. 2012). Quite opposite effects may be achieved through deacetylation of FoxOs by sirtuins and other deacetylase enzymes. Deacetylated isoform of FoxO3a is a weaker inducer of proapoptotic proteins such as Bim and FASL6 and a stronger inducer of endogenous antioxidants and Gadd-45. Cells possessing deacetylated isoforms of FoxO3a are more likely to enter reversible metabolic quiescence and repair the damages after exposal to harmful environmental factors (Shiota et al. 2010) and are less likely to undergo apoptosis. In this context, deacetylation of FoxO3a may have a cytoprotective effect. Besides, deacetylated FoxO1 is more sensitive to Akt-dependent phosphorylation (Matsuzaki et al. 2005). For example, deacetylation of FoxO3a by sirt2 enhances the transcriptional activity of FoxO3a under conditions of oxidative stress (Wang et al. 2007). Deacetylation by sirt1 or sirt2 also stimulates interaction of FoxO3a with SKP2 and facilitates FoxO3a ubiquitination and subsequently promotes degradation by proteasome (Wang et al. 2012a). Set9 is a methyltransferase which could directly methylate FoxO3a at lysine 271. Methylation of FoxO3a by Set9 decreases FoxO3 protein stability, while moderately increases transcriptional activity. Interestingly, methylation affects the biological function of FoxO3a, but does not affect its subcellular localization (Calnan et al., 2012).

Polyubiquitination of FoxO molecules by S-phase kinase associated protein 2 (SKP2) and the murine double minute 2 (MDM2) cell cycle regulator and proto-oncogenes seems to be a signal for their proteasome degradation (Wu et al. 2013), which may result in the loss of both their quantity and transcriptional activity. However, FoxO proteins are not sensitive to SKP2- dependent ubiquitination without having been previously phosphorylated by Akt at Ser 256 (Reagan-Shaw and Ahmad 2007). On the other hand, ubiquitination of FoxOs seems to enhance their nuclear import and transcriptional activity (Vogt et al. 2005; van der Horst et al. 2006). Figure 4 summarizes the above posttranslational modifications regulating FoxO activity.
Forkhead Box Protein O, Fig. 4.

Posttranslational modifications of FoxO. Phosphorylation is the most important posttranslational modification of FoxO. FoxO can be phosphorylated by many protein kinases, such as Akt, SGK, ERK1/2, IKK, AMPK, CDK, JNK, and p38MAPK. FoxO is also regulated by several posttranslational modifications including acetylation, methylation, and ubiquitination

Clinical Significance of FoxO Transcription Factors

Over the last decade, loss of function studies has found that FoxO proteins play critical physiological roles. Genetic deletion of FoxO genes in mice provided a clear insight into their functions. Global deletion of FoxO1 causes embryonic cell death, as FoxO1 is critical for the development of blood vessels and angiogenesis (Hosaka et al. 2004). Foxo3a null mice males were not lethal, but females with Foxo3a deficiency showed age-dependent changes in the ovarian follicular development and infertility (Hosaka et al. 2004). Global deletion of FoxO4 rendered mice more susceptible to gastrointestinal colitis in response to inflammatory stimuli (Zhou et al. 2009). FoxO6 deficiency resulted in less dendritic spines in hippocampal neurons both in vitro and in vivo, suggesting a role in synapse formation required for brain cognition and memory consolidation (Salih et al. 2012). FoxO transcription factor is a key regulator of cellular proliferation, survival, differentiation, and metabolism. Inactivation of FoxO has been observed in several tumors, leads to increased cell survival, and provides a basis for cancer susceptibility (Katoh and Katoh 2004). Since FoxO proteins regulate the expression of many genes, including those involved in response to growth factors, DNA damage, and oxidative stress, mild inhibition is expected upon cell response to extracellular growth signals. In such conditions, basal activity of FoxO proteins can be cytoprotective, mainly due to prevention of apoptosis. However, strong activity (hyperactivation) of FoxOs is usually either associated with cell response to oxidative damage or coupled with intracellular signaling to metabolic quiescence (e.g., those induced by AMPK and sirtuins). Genes that encode FoxO proteins may be also regarded as tumor suppressor genes. On the other hand, dysregulation of FoxO protein level, activity, and/or nucleocytoplasmic shuttling can induce tissue pathogenesis leading to many types of diseases including cancer, chronic inflammatory diseases, diabetes, cardiovascular disease, host response, wound healing, aging, and different neurological disorders (Watroba et al. 2012; Nho and Hergert 2014; Wang et al. 2014). Better understanding of the regulation of FoxO target specificity is still needed in order to establish FoxO as a therapeutic target for drug development (Monsalve and Olmos 2011).

FoxO1 and FoxO6 in Diabetes

As mentioned above, FoxO proteins are negatively regulated by insulin and FoxO could regulate the transcription of genes involved in glucose metabolism. FoxO proteins are potential targets for novel interventions in type 2 diabetes. In the diabetic animal models, the hepatic glucose production, gluconeogenesis, and glycogenolysis are all increased due to insulin resistance. Most interestingly, the elevated glucose is presumably due to upregulated FoxO1 (Rector et al. 2013). While in animals with haplo-insufficient FoxO1, the sensitivity of insulin was partially restored, and hepatic glucose production subsequently decreased (Kim et al., 2009). Similarly, in another high fat diet (HFD)-induced diabetic animal model, increased insulin resistance is also observed in both skeletal and liver cells. However, when haplo-insufficient FoxO1 mice were administrated with the same HFD, the insulin resistance in skeletal and liver cells was decreased notably (Kim et al. 2009). These results emphasize that targeting FoxO1 activity may alleviate insulin desensitization in type 2 diabetes. This strategy could be achieved through gene therapy-based approach (such as siRNA approach or CRISPR/Cas9 system) or FoxO1 functional inhibition. Aside from targeting FoxO1 alone, currently, researchers are interested in studying the dual/combined potential of FoxO1 and Notch-1 haplo-insufficiency in mice, as it has been suggested that in HFD-fed mice, the combination of FoxO1 and Notch-1 haplo-insufficiency was more effective at controlling glucose and increasing insulin sensitivity than in FoxO1 haplo-insufficiency alone (Pajvani et al. 2011). Insulin inhibits FoxO6 activity similar to FoxO1 and FoxO3a inhibition, by promoting its phosphorylation and blocking the binding of FoxO6 to its target genes. Additional studies indicate that FoxO6 promotes gluconeogenesis in liver, and FoxO6 inhibition is probably helpful for restricting excessive production of hepatic glucose and maintaining glucose balance in diabetes (Kim et al. 2011).

FoxO1 and FoxO3a in Cancer and Inflammation

FoxOs are frequently phosphorylated and inactivated in tumor cells due to the activation of the PI3K/Akt pathway. Both FoxO1 and FoxO3a are known as a tumor suppressor, as in most cases, active FoxO1 and FoxO3a promote the transcription of apoptotic genes, which is beneficial for the treatment of cancer. For example, in breast cancer, the basal phosphorylated Akt is relatively high, which leads to the inactivation of FoxO3a. Paclitaxel, a chemotherapeutic drug, upregulates the level of FoxO3a, which results in increased levels of Bim mRNA and protein, and eventually promotes the apoptosis in breast cancer cells (Sunters et al. 2003). FoxO3a may also inhibit tumorigenesis by inducing cell cycle arrest. Inactivation of FoxO3a upregulated the level of the cyclins D1 and D3 and downregulated the expression of p21Cip1 and p27Kip1, which are inhibitory proteins of the cell cycle, and thus promotes the malignant transformation of breast cancer cells (Scodelaro Bilbao and Boland 2013).

FoxO1 and FoxO3a are the best-studied members of FoxO subfamily. In recent years, the clinical significance of FoxO4 and FoxO6 becomes more evident. FoxO4 has been reported to activate transcription of the matrix metalloproteinase 9 (MMP9) gene in response to inflammatory signaling. Inhibition of FoxO4 expression reduces the migration of vascular smooth muscle cells, and this effect is associated with reduced MMP9 expression (Li et al. 2007a). These studies indicate that FoxO4 may serve as a potential therapeutic target for the treatment of proliferative arterial diseases, such as atherosclerosis and restenosis, both of them characterized by inflammation-induced vascular smooth muscle cell proliferation and migration.

FoxO3a And FoxO6 in Neurological Disorders

FoxO6 is mostly expressed in neurons and promotes the development and function of the adult central nervous system. Obesity is considered as a risk factor for learning deficits and dementia in later life (Gustafson et al. 2003). Hyperinsulinemia is one of the most common clinical characteristics in overweight or obese patients, which leads to further desensitization of insulin receptors to insulin action. Balanced insulin signaling plays pivotal roles in the brain; thus, sustained elevated level of insulin might be harmful for cognition and has been viewed as risk factor for dementia. Furthermore, insulin and IGF-1 signaling is reduced in the brains of patients suffering from Alzheimer’s disease (AD). High-fat diet specifically reduces the expression of FoxO3a and FoxO6, suggesting that IR/IGF-1-FoxO-mediated transcription is involved in the pathogenesis of obesity-associated cognitive impairment (Moll and Schubert 2012). Current studies support the concept that FoxO6 promotes memory consolidation by regulating neuronal connectivity and synaptic function in the hippocampus (Salih et al. 2012). In relation to neurodegeneration and neurodegenerative disorders, activation of FoxO proteins under most conditions leads to cell death (Maiese et al. 2008; Wang et al. 2013b; Zeng et al. 2016). Iron-induced oxidative stress responsible for apoptotic death of hippocampal neurons can lead to a neuroprotective response that activates Akt and blocks FoxO3a protein translocation to the nucleus (Uranga et al. 2013). Protection of primary hippocampal neurons by glutamatergic metabotropic receptors during exposure to radical oxygen species (ROS) requires the phosphorylation and inactivation of FoxO3a (Chong et al. 2006). Treatment with phenolic antioxidants to protect cortical and hippocampal neuronal cell lines during excitotoxicity (Bahia et al. 2012) and in experimental models of Alzheimer’s disease (AD) such as amyloid β-peptide (Aβ)-induced neurotoxicity (Zeldich et al. 2014) result with FoxO3a inactivation and blockade of its shuttling to the cell nucleus (Bahia et al. 2012). During brain ischemia, FoxO3a expression increases in the hippocampus (Yoo et al. 2012), and FoxO3a interaction with cell cycle proteins may play a pivotal role in neuronal apoptotic cell death (Peng et al. 2015). Furthermore, cortical neurons and PC12 cells exposure to toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or glutamate induces expression of p27kip1 and FoxO3a, leading to apoptosis (Zheng and Quirion 2009; Xu et al. 2014). Also, in microglial cells and neurons, knockdown of FoxO3a and prevention of nuclear shuttling lead to the increased survival during oxidative stress (Shang et al. 2010; Wang et al. 2013c). During hyperglycemia, cortical neurons (Wilk et al. 2011) and cerebral microcapillaries endothelial cells (Hou et al. 2010) are protected through inhibitory phosphorylation of FoxO3a and the nuclear export of this protein. However, under some experimental conditions, FoxO proteins may be also tied to enhanced neuronal survival. Excessive exposures to selenium in the environment have been definitively linked to motor neuron disease in both animals and humans. Using the soil nematode C. elegans as a model, it has been found that adverse behavioral deficits during selenium exposure have been associated with increased FoxO protein expression (Estevez et al. 2014). FoxO3a also may be necessary for cochlear auditory activity and the maintenance of synaptic function (Gilels et al. 2013). In Drosophila models of Aβ toxicity, loss of FoxO results in decreased survival and locomotor activity (Hong et al. 2012). Dopaminergic neurons are particularly vulnerable to changes in FoxO3a activity in the basal ganglia’s substantia nigra. Constitutive activation of FoxO3a promotes neuronal loss. However, FoxO3a activity also protected dopaminergic neurons from the accumulation of human α-synuclein, indicating FoxO3a as an important determinant of dopaminergic neurons survival (Pino et al. 2014). In line with these findings, the recent data indicating increased nuclear retention of FoxO3a in neurons and glia in response to oxidative stress indicate that FoxO3a may also promote the expression of antioxidant genes. FoxO3a triggers apoptosis in the absence of survival factors, and it also plays a key role in regulating the expression of neuroprotective antioxidant genes providing neuroprotection to the ageing brain (Fluteau et al. 2015). These findings reveal the complexity of FoxO3a roles in controlling neuronal fate.

Summary

Aging plays an important role in the occurrence and development of various diseases such as cancer, and cardiovascular and neurodegenerative disorders. It has been widely accepted that human lifespan is influenced by both environmental and genetic factors. Genetic contribution to the determination of healthy aging and lifespan provides basis for the research on which “protective genes and transcription factors” are carried by long-lived individuals. Studies have consistently revealed FoxO is a promising candidate to regulate the expression of molecules related to aging and longevity (Martins et al. 2016). PI3K-Akt-FoxO signaling pathway has also been known to be closely related to the growth of many tumors. Constitutive PI3K-Akt pathway activation causes phosphorylation and downregulation of FoxO activity and drives the growth of cancer cells (Bullock 2016). FoxO proteins are expressed in multiple organs and regulate important cellular processes including cell growth, survival, apoptosis, inflammation, oxidative stress, and metabolism through regulation of different downstream cellular targets. The biological and pathological functions of FoxO have been investigated in invertebrate and mammalian animal models of disease. In some cases, inhibition of FoxO may be beneficial, in other cases, FoxO activation is required. FoxO paradoxical response to stress is twofold: short-term activation or mild stress results in the stimulation of protective mechanisms and promotes cellular survival. However, intensive stress and a sustained FoxO activation may trigger cellular apoptosis. For example, FoxO1 and FoxO3a could regulate and increase the expression of atrogin-1, which can block cardiac hypertrophy (Li et al. 2007b); thus, FoxO1 and FoxO3a may be good targets for controlling the development of cardiac hypertrophy. Foxo3a attenuated the proliferation of vascular smooth muscle cells, and this effect may be helpful for the treatment of atherosclerosis and hypertension. Therefore, FoxO may be exploited for cardioprotection. However, metabolic stress-induced activation of FoxO1 contributes to insulin resistance and diabetic cardiomyopathy under the condition of diabetes. Therefore, knocking down the expression of FoxO specifically in cardiomyocytes will sustain cardiac function under metabolic stress (Battiprolu et al. 2012). FoxO3a is widely distributed in the central nervous system, and its activity is regulated by growth factors and neurotrophins, such as IGF-1, NGF, and brain-derived neurotrophic factor (BDNF), resulting in transcriptional inactivation of FoxO3a (Zheng and Quirion 2004; Mao et al. 2007), a process involved in neuroprotection (Soriano et al. 2006). However, inactivation of FoxO is also expected to enhance oxidative stress associated with aging and the risk of developing neurodegenerative disorders such as Alzheimer’s. Oxidative stress is an important determinant not only in insulin resistance but also in the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s. FoxO transcription factors are involved in both insulin receptor signaling and the cellular response to oxidative stress, thereby providing a potential integrative link between insulin resistance and neurodegenerative disorders. In light of the important involvement of FoxO transcription factors in different cellular functions, the ability of cytoprotection via PI3K/Akt/FoxO balanced signaling (Su et al. 2016) should be carefully addressed. Given that FoxO has profound biological functions in cellular stress resistance, it is ideal to target FoxO for therapies that aim towards the origin rather than the symptoms of different diseases. Promising prospects in favor of this future perspective require a deeper understanding of FoxO complex functions and regulation in physiological and pathological processes. Clinical strategies based on the monotherapy or combination therapies based on FoxOs activity may include the following approaches: (1) signaling pathways (such as tyrosine kinase receptor signaling) that converge on and negatively regulate the activity of FoxO; (2) cellular trafficking machinery responsible for the nucleocytoplasmic shuttling of FoxOs; iii) proteasome independent and dependent degradation of FoxO; and (4) the DNA-binding motif and activity of the FoxO proteins themselves; (5) Aberrant posttranscriptional regulations of FoxO in various disease states; and (6) The interaction between FoxO and its coregulators. These therapeutic strategies warrant future investigation directed to elucidate the delicate balance FoxO holds over cellular function and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens.

Notes

Acknowledgments

This research was financially supported by the Guangdong Provincial Project of Science and Technology (2011B050200005), the National Natural Science Foundation of China (31371088), SRG2015-00004-FHS and MYRG2016-00052-FHS from University of Macau, and the Science and Technology Development Fund (FDCT) of Macao (FDCT 021/2015/A1).

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Faculty of Health SciencesUniversity of MacauTaipa, MacauChina
  2. 2.School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
  3. 3.School of Pharmacy Institute for Drug Research, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael