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- Herausgeber: epubli
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2021
FOX genes have different regulatory functions and influence aging, carcinogenesis, neurodegeneration etc. They can directly, indirectly, via interaction with homo-, heterodimers and other factors effect its target genes and thus influence RUNX, ROBO, CREB, RELN, FOXO1, POT1, telomerase , DYRK1A, PTEN, NCAM1, VLDLR, Vitamin D and others. MiRNA modulation, alternative splicing, sumoilation, methylation and regulation by pH, vitamins, etc., in turn, regulate the FOX genes. These processes and the structure and function of these genes and gene polymorphisms in different taxa are described in this thesis, these processes and the role of gene mutations, anti-aging products as well as suitable animal models are also discussed in detail.
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Elena Tschumak
INFLUENCE OF FOX GENES ON AGING AND AGING-ASSOCIATED DISEASES
FOX GENES AFFECT AGING AND RELATED DISEASES
FOXP2 genes have a direct and indirect effect on aging
FOX genes include 19 highly conserved, structurally related families from FoxA to FoxS (Sridhar Hannenhalli and Klaus H. Kaestner, 2009). Different publications mentioned the role of FOXgenes in aging processes.
One of the main factors of aging is telomere attrition. Telomeres modulate Rb and p53, that decrease PGC-1α and PGC-1β expression (Sahin and Depinho, 2012) and activates the cyclin-dependent kinase inhibitor p21CIP1.16 H. Shelterin (consists of Tin2, Rap1, TRF1, TRF2, Pot1-TPP1 heterodimer) protects telomers and play a role in mtDNA damage. Telomeric heterochromatin is influenced by lncRNA TERRA via binding to TRF1, TRF2,ORC, HP1 and H3K9me3(Scaffidi et al., 2005; Han and Brunet, 2011).
Tanabe et al. described 2011 in „FOXP2 Promotes the Nuclear Translocation of POT1, but FOXP2 (R553H), Mutation Related to Speech-Language Disorder, Partially Prevents It“, how
FOXP2 influences on POT1 (protection of telomeres 1) as a FOXP2-associated protein. (Tanabe et al. reported protection of nuclear-colocated telomerase.) This gene POT1 as member of the telombin family encodes a nuclear protein involved in telomere maintenance. The loss of its POT1 function induces the cell arrest. The researchers identified that POT1 is alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. FOXP2 with mutated nuclear localization signals as well as R553H mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. The authors propose FOXP2 as a binding partner for the nuclear translocation of POT1.
According to Multanii and Chang, 2007 „WRN at telomeres: implications for aging and cancer“
POT1 is critically important for telomere extension by telomerase, POT1 functions to negatively regulate telomere length by competing with telomerase for access to the telomeric substrate.
Review Wohlgemuth et al, 2014 showed that FOXP2 also provided the NMDAR-mediated neuronal plasticity affecting MAPKK. It is known that Aging also influences free radicals via Fc-gammareceptor and phagocytosis via p42/p44 MAPK signalling pathways and aging relevant ROS activate inflammatory cascade reaction via JAK/STAT, NF-κB/MAPK.
Molina-Serrano et al. showed 2019 in „Histone Modifications as an Intersection Between Diet and Longevity“ that Lysine 4 on histone H3 can be found in one of three possible methylated forms: mono, di or trimethylated (H3K4me1, -2, and -3).The trimethylated form usually localizes at the promoter of actively transcribed genes (Santos-Rosa et al., 2002), and has been shown to have a strong implication with aging in several model organisms. S. cerevisiae H3K4 methyltransferase complex COMPASS mutants had significantly reduced lifespan (Smith et al., 2008; Ryu et al., 2014; Cruz et al., 2018). “H3K9me3 was only associated with antioxidant genes in females (Strakovsky et al., 2014). Paternal HF diet changed the epigenome in spermatozoa and offspring liver. Specifically, under HF diet, H3K4me was enriched in paternal sperm around the transcriptional start site (TSS) of genes involved in development regulatory processes such as Hoxd11, Hoxd13, Bai3, Foxp2, and Foxa2. In contrast, in the offspring liver, H3K4me was enriched in genes controlling lipid biosynthesis, fatty acid synthesis and the oxidation-reduction process (Terashima et al., 2015).Aging relevant H3K27ac and H3K14ac are acetylated via p300/CBP and its co-activator CREB. cAMP responsive CREB expression is responsible to fasting. So CBP, CREB, CRTC2 and TAF-4 activate together gluconeogenesis genes (Altarejos and Montminy, 2011)” (Molina-Serrano et al., 2019, p.11)
FOXP2 indirectly regulates the FEZF2, the RELN, the FOXO1 and the DYRK1A genes via theRUNX-AUTS2-TBR1cascade In a feedback loop the FEZF2 regulates FOXP2 expression. (Molyneaux et al., 2005) TBR1 also regulates RELN expression (Chen et al., 2002). The RELN in turn regulates FOXO1 expression, which is also indirectly regulated by RUNX2 (Kuhlwilm et al., 2013). It would be of great scientific interest to investigate further whether and to what extent FOXP2 expression via FOXO interaction can influence tumorigenesis and antiaging, as FOXO genes are generally known for their importance in cell cycle and apoptosis. (Kops et al., 2002)
Gascoyne et al. suggested 2015 in „The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest“ that “FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1)” (Gascoyne et al., 2015, p.1) They studied a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint and identified that Foxp2 expression is not neuronally restricted and is linked to regulation of the cell cycle via various mechanisms: p53 target gene cyclin-dependent kinase inhibitor p21, is as a primary controller of multiple diverse cellular pathways, e.g. neuronal differentiation, growth arrest of pre-osteoblast type 143B osteosarcoma cells etc. They reported that regarding the RUNX-2-dependent pathway for FOXP the bone-specific isoform of RUNX2, which these cells lack, is not a requirement for FOXP2 function and in “developing murine mesenchymal cells the loss of growth factor signalling upon entry to the periosteum might up-regulate Foxp2. Expression of Foxp2 during both osteoblast and some neuronal development appears to be transient and this is also observed for other family members”(Gascoyne et al., 2015, p.13), considered potential connections between FOXP2 and p53 pathways. “Normal osteoblast development is compromised in bone metastases of solid tumours and in bone malignancies such as multiple myeloma, and this characterisation of FOXP2 growth arrest function in a disease context may identify novel malignant pathways. Furthermore, FOXP2 status in osteosarcoma may provide information regarding the stage of developmental block, with potential clinical significance. Direct connection of FOXP2 to the mutated p53 pathway in osteosarcoma, via a common target p21/CDKN1A, is also likely to have implications for understanding osteosarcoma biology.” (Gascoyne et al., 2015, p.14)
Also the review of Wohlgemuth et al., 2014 showed that FOXP2 also provided the NMDAR-mediated neuronal plasticity affecting MAPKK and tyrosine phosphatase. The MARK is a RAS Downstream Effector. RAS is a GTPase that indirectly interacts with oncological relevant p21 and p53 indirectly. So FOXP2 can act alone or in combination with other members of its or other gene families. Its own expression can be influenced both by the cooperation partners and by the feedback loops or by other interactions. These innumerable tissue-specific regulation possibilities allow a fine-tuning and a rapid adaptation to ever-changing environmental conditions which need to be studied more closely.
Influence of other members of Fox-family on aging processes
According to Ni et al. 2012, Ribarič 2012 Foxo plays an important epigenetic role in aging and Hansen et al, 2013 describe DAF/FOXO effect on longevity. Steroid hormone dehydrogenases, cytochrome P450s and others aging relevant steroid hormone signalling pathways are influenced not only by LIPL-4 and TOR regulated autophagy but also by daf-16/FOXO (Lapierre et al., 2011).In C. Elegans daf-16/FOXO affects aging and tumor growth. (Pinkston-Gosse and Kenyon, 2007) Experiments with germline-less C. Elegans showed that FOXO3A effects NAD-dependent protein deacetylases and ADP-ribosyl transferases activity of aging relevant sirtuin (Oberdoerffer et al., 2008; Wang et al., 2008) e.g. with the help of histone H3K9 deacetylation, glucose homeostasis, genomic stability and via subunit RelA NF-κB regulating SIRT6 (Kanfi et al., 2010; Kawahara et al., 2009; Zhong et al., 2010). SIRT6 also effects telomers. (Michishita et al., 2008; Mostoslavsky et al., 2006; Tennen & Chua, 2011) AMPK and SIRT1 also directly influence PGC-1α via deacetylation and phosphorylation). Aging is associated with upregulation of chaperones and proteases level via misfolded proteins also appeared by Alzheimer’s and Parkinson’s disease,(Bernales et al., 2012) and UPRmt. UPRmt as well as FOXO signalling can be activated by NAD+ and increase longevity (Mouchiroud et al., 2013) Lon protease is another important for degradation of oxidized proteins within the mitochondrial matrix aging factor (Ngo et al., 2013, 2009; Bota et al, 2002)
FOXO3 (like mTOR and AMPK) effects aging relevant mitophagy (Rodriguez-Hernandez et al., 2009). Kim et al.,2014 describe how phosphorylation, acetylation, or ubiquitination of FoxO-genes effect histones and chromatin and change this way ROS-level. Therefore FoxO4 shows negativ effect on PI3K/Akt pathways (Karger et al. 2009) as well as on MAFbx and MURF1 in muscle aging (Clavel et al. 2006). Oxidative stress leads to FoxO phosphorylation via Akt and its transport from the nucleus to the cytoplasm. FoxO3 and FoxO4 deacetylation by Sirt1 (Jian et al. 2011) and its upregulation via catalase (Fukuoka et al. 2003; Brunet et al. 1999) play an important role in aging. FoxO1 also regulates apoptosis, DNA repair and cell cycle arrest (Yamaza et al.2010; McLoughlin, 2009; Ma et al., 2016), but also plays a key role in stem cell pluripotency. (Zhang et al., 2011). FoxO6 effects gastric carcinoma (Kim et al. 2011) and together with PGC-1a influences oxidative metabolism in skeletal muscle. Chung et al.,2013 reported that FoxO6 and PGC-1a form a regulatory loop to regulate oxidative metabolism in skeletal muscle. In addition, Foxoa2 plays a potential role in sepsis (Berg et al., 2006) and in asthmatic mucus secretion (Park et al., 2009).
An interesting aging approach (connected with adjacent to Paneth cells and crypts) are stem cells and their regulation e.g. via cancer relevant Lrig1, Wnt, Olfm4, Hopx, p57, Sox9, Tert, Bmi1, β-catenin, Ascl2, Lgr5, Myc, Ephb2, CD44, PPAR and SMAD signalling (Nalapareddy et al., 2017; Akunuru, and Geiger, 2016) Deficiencies in DNA damage repair limits the function of haematopoietic stem cells with age. (Rossi et al., 2007) Low ISC and increased ROS levels relate to Foxo1, Foxo3a and Foxo4 activity. (Tothova et al., 2007; Miyamoto et al., 2007)
But FOXO like CoQ and PGC-1α also influences electron transport changes contribute to aging effects such as cardiac failure. (Rosca et al., 2008; Frenzel et al., 2010; López-Lluch et al.,2010; Houtkooper et al., 2010) Shijin et al. mentioned 2016 in „An Update on inflammaging: Mechanisms, Prevention, and Treatment“ the influence of inflammatory cytokines on lymphocytes. Type I and type II cytokines effect CD4+ T lymphocytes (Alberti et al., 2006) and CD8+ and CD4+ T lymphocytes (Franceschi et al., 2000). Especially role on imflamaging play IL-1, IL-6, TNF-α and PGE2 (Bruunsgaard et al., 2003; Cesari et al., 2004). Aging is associated with IGF-1 down- and IL-6- and TNF-α- upregulation (Lio et al., 2003) IL-1, IL-6, and IL-8 are activated via NF-κB signalling pathway (Bartek et al., 2008).
Different publications mentioned that FOX genes are an important factor in the development of tumors (Nishimura et al.,1998; Wang et al., 2015; Tian et al., 2015; Lo et al., 2016,2018; Lu et al., 2017; Nik et al., 2013; Shi et al., 2016; Yu et al., 2017; Dou et al., 2017; Milewski et al., 2017; Cai et al., 2015; Xian et al., 2018; Herrero and Gitton, 2018; Toma et al., 2011; Zhang et al., 2012; Rousso et al., 2012; Howarth et al., 2008; Teufel et al., 2003; Li and Tucker, 1993; Ji et al., 2016; Myatt et al., 2007) The FOXO family and the transcription factor NF-kB influence the upstream protein kinase B e.g. in connection with the receptors of the Trk family (e.g. the Neurotrophin). Inhibition of NF-κB signalling, NLRP3 inflammasome and other pro-inflammatory pathways or hormonal treatments eventually can restore aging relevant Progerin level, elevated by telomeres disfunction. (Osorio et al., 2010; Cao et al., 2011) In the same time senescence is accompanied by increased IL-1ß level and activated tumor necrosis factor and interferons production. (Review López-Otín, 2013; Green et al., 2011; Salminen et al., 2012, 2019; Adler et al.,2007). The Hsp90 and the IκB-Kinase (IKK) inactivate the NF-κB pathway and inhibit autophagy via induction a cell signalling switch from autophagy to apoptosis in tumor cells downregulation and of Beclin 1 expression. (Jiang et al, 2011) NF-κB also reduces GnRH production (Zhang et al., 2013) and affects this way muscle weakness, reduced neurogenesis, bone fragility and skin atrophy. Further NF-κB decreases H3K27me3 level via H3K27me3 demethylase (Lauren et al., 2016; De Santa et al., 2007). BCL2, transcriptionally regulated by nuclear factor-kappa B, affects cell shrinkage (Chakraborty et al., 2015; Lambie1 and Conradt, 2016) and acts directly on apoptosis-activating BH3. Reqmi et al. discovered that BCL2-related proteins also regulate mitochondrial dynamics using dynamin-related GTPases. (Lüpertz, 2008; Hornstein et al., 2013)
Hsp90 protects 20S proteasome from oxidative damage inactivation (Höhn et al., 2017; Conconi et al., 1998) and helps to fold oncogenic proteins e.g. of p53 (Saibi et al., 2013). Aging relevant Hsp70 is activated with the help of HSF-1deacetylation by SIRT1 (Westerheide et al., 2009). Aging dependent changes in the amount of sensitive to diet and exercise NAD+ (Cantó et al., 2015) can affect the activity of sirtuins. SIRT1 activity can be decreased via NAD+ level, which also increases activity of the HIF-1α transcription factor resulting in changed in oxidative phosphorylation and mitochondrial dysfunction. (Gomes et al., 2012, 2013; Greer et al., 2007) SIRT1, p53 and HIF-1α in turn effect NAD+ level. Also, AMPK, which inhibits insulin/IGF-1/mTOR, cooperate with SIRT1 to create new mitochondria with the help of PGC-1 and p53. In the same time mitochondria influences TCA cycle. (Salminen et al., 2014) Tollefsbol described 2014 the connection between caloric restriction and longevity. Schultz and Sinclair described 2016 that intestinal stem cells can renewal via BST1 (converts NAD+ cADPR) (Yilmaz et al., 2012 These cells express Notch ligand delta Dl and ESG.
Low protein-high carbohydrate diet influences energy level via enhancing FGF21 expression and in the same time reduction of mTOR activity. This increases Brain-derived neurotrophic factor expression (Zaptan et al., 2015) and influences neural precursor cells (Marosi and Mattson, 2014; Vivar and van Praag, 2013) Neural progenitor cells are also positively influenced by nutrient-sensing protein FOXO3 ( Renault et al., 2009; Devin et al., 2016; Renault et al., 2009) Also grey matter volume of subcortical regions is positively affected this way. (Colman et al., 2009)
Low caloric intake has also positive effect on SIRT1 activity which leads to dendritic outgrowth and plasticity and low inflammatory cytokine activity. (Maalouf et al., 2009) Ohkura et al., 2010 described how FOXO interacts with the sirtuin, which is relevant to aging and cancer. Sirtuin in turn decreases apoptosis via FOXO or BAX. (Dang et al., 2009; Dang et al., 2009; Martins et al., 2015) According to „CYB5R3: a key player in aerobic metabolism and aging?“ (de Cabo et al. 2010) coenzyme Q (CoQ) helps to reduce NADH-level in mitochondria and regulate this way NAD+-dependent enzymes e.g., sirtuins. So, cytochrome b5 coding reductase CYB5R needs NADH and CoQ for its function.(Villalba et al., 1995) Also low calories intake enhanced aerobic metabolism. This needs cytosolic cooperation of N-myristoylated CYB5R3 (a component of P-450 mediated hydroxylation of drugs and steroid hormones (Passon and Hultquist, 1972), fatty acid elongation (Keyes and Cinti ,1980) and cholesterol biosynthesis (Reddy et al, 1977)) and SIRT1. SIRT1 in turn needs lysine acetylation for this cooperation. It modifies CYB5R3 activity and regulates this way the cytosolic NAD+/NADH level.
The activity of FOXO/DAF-16 is positively and negatively regulated by different molecular players (e.g., the insulin/IGF signalling pathway and the nutrient sensor AMPK) and stresses (e.g., oxidative and heat stress). (Eijkelenboom and Burgering, 2013; Salih and Brunet, 2008; Dervis and al., 2008) Sirtuins and H2S induced AMPK and IIS (influences FOXO and mTOR (effected by GH)) have opposite actions. (Barzilai et al., 2012; Fontana et al., 2010; Kenyon, 2010, 2005; Blagosklonny, 2006; Kapahi et al., 2010; Stanfelet al., 2009; Polak and Hall, 2015; Moskalevet al., 2014) FOXO also effects detoxification enzymes MnSOD and GADD45. (Kops et al., 2002; Nemoto and Finkel, 2002)
Apolipoprotein E4 (apoE4) and FOXO are not only associated with quick cell aging (Aksenov et al., 2001; Martins, et al., 2015) but also with Alzheimer’s disease (Sando et al., 2008; DiLoreto & Murphy, 2015).
Further aging factors are rapamycin target S6K activator and 4EBP1 inhibiter mTORC1 and cytoskeletal relevant TORC2 protein kinases (Zoncu et al., 2011),
AMP/ATP ratio and metformin activated AMPK, insulin and IGF1 influenced (FOXO) , which in turn activates MnSOD.
a 200-nt-long ncRNA BCYRN1 is associated with AD b and aging (Mus et al., 2007) but also with breast (Iacoangeli et al. 2004), parotid, tongue, oesophagus, lung, cervix and ovary cancer (Chen et al, 1997).
GAS5 lncRNA suppressed GR and induced apoptosis (Mourtada-Maarabouni et al., 2009) and is downregulated in human HCC and breast cancer (Tu and al., 2014).
lncRNA-17A BACE1, repressed GABABR2 variant A, promoted variant B, and enhanced accumulation of peptides Aβ42 and Aβ40 (Massone et al., 2011), BCYRN1 (Mus et al.,2007) and GOMAFU (MIAT)BC089918 GAS5 RMSTAS are associated with neurodegeneration. (Wapinski et al.; 2011Yu et al., 2013; Ng et al., 2013; Kim et al., 2013; Meier et al., 2010) and cancer (Mourtada-Maarabouni et al., 2009)
BACE1 protein levels and activity increase with brain aging and AD (Modarresi et al., 2011; Fukumoto et al., 2002)
7 SL interacts with the TP53 mRNA and suppresses p53 translation, during HuR can displace 7SL and increase p53 translation. lncRNA 7SLsuppresses TP53 (Abdelmohsen et al., 2014) and influences autophagy, senescence and cancer (Grammatikakis et al., 2014; Chen et al., 1997).
FOXP2 and mRNA in aging
But other RNAs are also an important component of aging, e.g., extracellular RNA play an important role in this process.(Douglas et al. 2016) 24–31nts piRNAs are responsible for proper genome in germ-line cells. 142.22 nts microRNAs cooperate with the 3′ UTR of target mRNAs binding RISC. This complex leads to mRNA degradation and disturbs protein translation. This affects components of the RNA spliceosome, 100–300 nucleotides Small nuclear RNAs (snRNAs), which process mRNAs in the nucleus. (Carthew et al. 2009) Aging relevant oxidative stress effects 5′ tRNA and 3′ tRNA fragments (Fu et al., 2009), which are necessary for cellular proliferation and interact with Argonauts proteins like extracellular miRNAs. (O'Brien et al., 2018) AGO2 is known to influence tumorigenesis through miRNAs-dependent or independent ways. (ZhenLong et al., 2015) Inflammatory miR-223 regulate the help of HDL ICAM-1 46 protein expression and snoRNAs, responsible for chromatin remodelling and rRNA modification. (Vickers and Remaley, 2017; Tabet et al., 2014) 200 nts non-coding lncRNAs regulate gene expression via chromatin association, Y-RNA 80–112 nts, coded in 4 genes, initiate DNA replication (Kheir & Krude, 2017; Yeri at al.2017) and are important for apoptosis. (Chakrabortty et al. 2015; Fritz et al., 2016). Circular RNAs, created from spliced exons and introns, influence tissue-specific development via miRNA. (Chen et al., 2015 Salzman et al., 2016). In endothelial cells miRNAs influence senescence, inflammation, cell differentiation and angiogenesis with the help of HDL Cockerill et al., 1995; Tabet et al., 1995, 2009; Schroen et al, 2012; Sun X, et al.,2012; Kane et al., 2012; Sumi et al. 2007;Pu and Liu L., 2008) Mi 223 also corelates with Hepatitis C healing. (Hyrina et al., 2017)
73 miRNAs e.g. miR-24-3p, miR-371a-5p, miR-3175, miR-3162-5p, miR-671-5p, miR-4667-5p, 146a-5p, 342-5p and miRs 5107-5p, which influence Gpx3 and thyroids, have significantly increased level in serum of old mouse. Level of 47 miRNAs e.g. miR-195a-5p and miR-34c-5p, also decrease with age. (Machida et al., 2015) This process can be influenced by caloric restriction. Mi RNAs also effects axon growth, melanogenesis, MARK, adherent and gap junctions (Victoria et al. 2015) and neuronal activity is affected by miRs 5107-5p, 146a-5p, and 342-5p. miR-5107-5 protects thyroids via Gpx3 and miR-195a-5p affect the aging relevant PI3K-AKT signalling pathway. miRNAs can also influence HTLV-1 infection, pluripotent stem cells, bone microarchitecture, osteoarthritis and cancer. (Hafez et al, 2015; Rodriguez-Fontenla et al. 2014; Wu et al., 2014) as well es aging relevant Bmpr1a,Vegfa, Bcl-2, Map2k1 Wnt4. MiR-34-5p influences GABAergic neurons, vascular aging response and cancer relevant Notch1, Notch4, Ccne2, E2f3, Gabra3 and Cylcin E2 through a Notch-dependent mechanism and Sirt1 (Li et al. 2011) Prop1 leads to decreased level of GH, Igf-1 and TSH. (Bartkeet al. 2001; Victoria et al., 2015) Lysine-, Valine-, Arginine-, Cysteine-, Glycine tRNA were decreased and Histidine- and Aspartic- acid derived 5′ tRNA increased in age. These changes were also CR sensitive (Dhahbi et al. 2013)
Aging is also associated with increased mRNAs level of CSF2, which is necessary for monocytes activation (Croxfordet al. 2015), granulocyte and macrophage maturation (Hamilton, 2002), energy homeostasis and metabolism. mRNA of subunit of pyruvate dehydrogenase enzyme DLD, which is necessary for exocytosis is also increased. RAB3 GTPase activating Protein Subunit 2 (Bem et al., 2011), an alternative splicing nuclear protein, which is involved in metastasis suppression with the help of splicing factor SRSF1 RRP1B (Lee et al. 2014), CSF2RA, SLC35B4, LAMB2 (Schaeffer, 2012), LAMB2 and LC35B4 showed increased mRNA level. Some lncRNAs were also hyperexpessed in ageing. At the same time 12 snoRNAs and 20 piRNAs were decreased. Decreased rRNA, which interacts with TTF1, may play a role in age related Alzheimer disease. (Freedman et al.,2016) miR-31 decrease is associated with aging relevant chronic myeloid leukaemia and ovarian carcinoma (Mitamura et al., 2013; Rokah et al.,2012; Korner et al., 2013; Zhong et al., 2013) miR-485-5p expression also alternates in aging. (Faghihi et al.,2008; 2010;Lee et al. 2014)
FOXP2 and mi RNA in oncological processes
Like the other genes in the FOXP family, the Fox P2 gene can be inactivated in cancer cells through miRNAs and alter its action this way. The recent study by Herrero and Gitton (2018) showed that FOXP2 can be blocked by TWIST activated miRs 199a-214, miR-762, miR-1915, let-7b and miR-34a and miR-3666. let-7a-d, miRs, miR-26a, miR-10,1miR-200b (which leads to increased MT1-MMPu und decreased PTEN- expression) (Soubani et al., 2012) and decreases prostaglandin, NF-kappaB,PEG2, VEGF activity ( Ali et al., 2010; Bao et al., 2011), EpCAM and EZH2 level and inhibits NOTCH-1 in pancreatic cancer (Bao et al., 2012). Wen-Zhuo et al. (2016) investigated the regulation of the FOXP2 gene by the microRNA-190 in gastric cancer. Valencia-Sanchez et al. (2006) showed that miRNAs destroy FOXP2-mRNA through its interaction with 3 'UTR, prevent its translation and this way negatively regulate the FOXP2 target genes. Many other studies also indicated that miRNA dysregulation may play an important role in the initiation and progression of oncological processes. (Barbrotto et al., 2008; Kasinski and Slack, 2011) Two years earlier the group of Wen-Zhuo et al. used the dual luciferase enzyme assays and confirmed that the miR-190 interacts with the FOXP2. RT-PCR and Western blot verified that miR-190 overexpression suppresses expression of FOXP2. Decrease of miRNA-190 expression leads in turn to FOXP2-mRNA and -protein increase. Because FoxP2 plays an important role in many oncological processes, the miR-190 could serve as a potential gastric cancer marker. Zhang et al. (2009) investigated various miRNAs and identified eight of them, which levels were increased in pancreatic cancer, e.g. the miR-190. This miRNA correlated with the progression of gliomas (Almog et al., 2012; Cuiffo et al.,2014) demonstrated suppression of FOXP2 expression by miR-199a in breast cancer mesenchymal cells. In lung, breast, bladder, colerectal and liver cancers MiRNA expression was also increased. (Ichimi et al., 2009; Lowery et al., 2009; Navon et al., 2009; Ura et al., 2009; Ng et al., 2009) The results indicate that miRNAs play a different role in different tumor types at different stages. The influence of various miRNAs on pancreatic cancer (Zhang et al., 2009), lymphoma (Musilova and Mraz, 2014; Jones et al., 2014) and breast cancer (Wu et al., 2009) was also shown. It would be useful to study whether this miRNAs dysregulation also influences these and other cancers in connection with FOXP2?
Regulation of other FOXP genes by various factors on the example of carcinogenic processes In oncological tissue FoxP genes as well as other FOX genes can be modulated by microRNA . (Zheng et al., 2015), (Shao et al., 2013), (Kong et al., 2013), (Zhang et al., 2015), (Kundu et al., 2016), (Mei et al., 2015), (Yu et al., 2017). This modulation determines whether FOXP2 acts as an oncogene or as a tumor suppressor gene. In these processes the FoxP genes can also be deactivated by micro RNAs. (Choi et, 2016) According to Chang et al. (2007), He et al. (2010) and Raver-Shapira et al. (2007) the transcription factor p53 induces the transcription of the microRNA miR-34s, which in turn suppresses anti-apoptotic genes, which are required for cell development and growth. According to Choi et al. (2016), Isken et al. (2008), Mraz et al. (2009), Zenz et al. (2009), miR-34a plays an important role in both chronic lymphatic and acute myeloid leukaemia and the Foxp1 is regulated by miR-34a. The miR-34a also builds a direct link between the tumor suppressor p53 and the oncoprotein Bcl-2. Rao et al. (2010) pointed out that in B lymphocytes too miR-34 modulates Foxp1 via the tumor suppressor gene p53. The tumor suppressor p53 could also be a direct FOXP2 target gene. (Herrero and Gitton, 2018)There are also further indications of androgen influences on the FoxP1 expression and associated carcinogenic processes. (Banham et al, 2007; Bates et al., 2008; Fox et al., 2004; Giatromanolaki et al., 2006; Takayama et al., 2008) Further FOXP1 appears to affect follicular lymphoma as well as in aging dependent ovarian and colorectal carcinoma. (Brown et al., 2004; Choi et al., 2016; De Smedt et al., 2015) In B cell lymphomas or hepatocellular carcinomas FOXP-1 serves as an oncogene. (Zhang et al., 2012; Jiang et al., 2012; Xia et al., 2014) In lungs, prostate and endometrial tumors FOXP1 is a potential predictor of disease progression. (Feng et al., 2012; Toma et al., 2011; Giatromanolaki et al., 2006; Takayama et al., 2008; Takayama et al., 2014)
FOXP2 and neuroplasticity
FOXP2 plays an extremely important role in neuroplasticity (Haesler et al., 2006; Ebisu et al., 2017; Konopka et al., 2009; Boeckx et al., 2014; Dodson et al., 2015; Garcia-Calero et al., 2016) and review of Wohlgemuth et al. (2014) showed that FOXP2 also provided the NMDAR-mediated neuronal plasticity affecting MAPKK and tyrosine phosphatase. The MARK is a RAS downstream effector. RAS is a a GTPase that indirectly interacts with oncological relevant ant p21 and p53 indirectly. RAS, in turn, is activated by growth factor signalling and interacts with FOXO-inhibiting PIK3. Further interaction with neuro and oncoactive Trk is also discussed. (Santos, 2011), (Mengeselt et al., 2008) It influences cell proliferation and this plays a role in the development of cancer. A direct FOXO4-p53 interaction and its importance in cell aging has been demonstrated too. (Baar et al., 2017) It would be interesting to look more closely at the role of FOXP in these processes. Possibly Fisetin, related to Qis (Zhu et al., 2017), but also FOXO4-related peptide that inhibits the PI3K/AKT/p53/p21/Serpine SCAP (Zhu et al., 2015b), recently noted to be senolytic (Baar et al., 2017) could have positive effect on cancer and aging.
Guibinga et al. showed in "Neuropathogenesis of LNS. Striatal Neurodevelopment is Dysregulated in Purine Metabolism Deficiency and Impacts DARPP-32, BDNF / TrkB Expression and Signaling: New Insights on the Molecular and Cellular Basis of Lesch-Nyhan Syndrome" (2014) that downregulating Bcl11b in HPRT-deficient cells elicited a change in DARPP-32 level in the neural stem cells. This phosphoprotein is regulated by dopamine and cAMP. Its altered level in turn led to striatal B-cell leukaemia 11b (Bcl11b). The activator of the DARPP-32 striatal BDNF / TrkB signalling pathway was highly increased in HPRT-deficient cells as well as in the striatum of the HPRT knockout mice. This protected the cells from reactive oxygen species (ROS)-mediated cell death.
There are also FOXP2 interactions with members of the histone family (H2AFX; H3f3B), two heat shock proteins (Hsp25; Hsp90a) and Calcycline-binding proteins ARHGEF9, CtBP1 and effectors Gli1, Gli2 and Gli3, EGR1, IEGs, D1R and DARPP32. In addition, FOXP2 affects NMDAR-mediated neuronal plasticity, MAPKK and tyrosine phosphatase. (Mc Auley et al., 2017)
γH2AX foci in aged HSCs is increased (Rossi et al., 2007; Beerman et al., 2014; Moehrle et al., 2015; Flach et al., 2014)
FOXP2 and neurodegeneration
Several studies showed the significance of FoxP2 for the brain and skull development (Benítez-Burraco et al., 2015) but above all for the language. (Watkins et al., 2002; Vargha-Khadem et al., 1998; Middleton ad Strick, 2000; Watkins et al., 2002; Liegeois et al., 2003; Lai et al., 2003). The FOXP2 gene (formerly also known as SPCH1, TNRC10 or CAGH44) was mainly associated with important language functions. First, the FOXP2 became known through the work of Anthony Monaco and Svante Pääbo Group at the Institute for Evolutionary Anthropology of the Max Planck Society in Leipzig. They studied the linguistic deficient KE family and found an autosomal dominant missense point mutation in exon 14 of the 7th chromosome (in the 7q31 band guanine was replaced by adenine). This mutation replaced arginine (R) by histidine (H) at the position 553 R553H of the FOXP2 protein and caused an inhibition of the DNA-binding domain and the inoperability of the protein. Other FOXP2 mutations were also observed by dyspraxia patients. (MacDermot et al., 2005; O'Brien et al., 2003; Jiménez-Romero et al., 2016; Becker et al., 2015; Zeesman et al., 2006). In 2016 described Tborres-Ruiz et al. a girl with inherited complete chromosomal rearrangement. This rearrangement was accompanied by a fracture proximal and distal to the FOXP2 gene and resulted in cognitive disabilities. The fracture in a new neuroblastoma cell line SK-N-MC led to the decline of FOXP2 and increase of MDFIC-P protein levels. The MDFIC-P gene is localized near FOXP2. The FOXP-2 significance for the childhood apraxia of speech (CAS) and other speech disorders were also described. (Morgan et al., 2017; Kurt et al, 2012) The FOXP2 mutations are often accompanied by structural brain changes, so the new multimodal MRI study of an eight-year-old boy (A-II) with a de novo FOXP2 deletion by Liégeois et al. „Early neuroimaging markers of FOXP2 intragenic deletion“ (2016). The researchers described in their work significant bilateral structural abnormalities in the basal ganglia and in hippocampus. In the hippocampus, in the thalamus, in the globus pallidum and in the caudate nucleus a volume reduction was also observed in comparison to the control group of 26 healthy volunteers. The patients showed no detectable functional MRI activity by the repetition of nonsense phrases. FOXP2 also plays a role in the visual system (Iwai et al., 2013; Horng et al., 2009), in psychiatric disorders, and in aging dependent frontotemporal degenerative dementia accompanied by speech disorders (Sanjuán et al., 2006; Park et al., 2014; Wang et al, 2016; Bacon and Rappold, 2012; Fisher and Scharff, 2009; Premi et al., 2012; Kumar, et al., 2011). FOXP2 is important for brain development and communication in many animal taxa (e.g. songbirds, marine mammals, bats and possibly elephants) which learn to communicate through imitation and whose auditory processing needs to interact with motor control. (Scharff and Haesler, 2005)
