The family of FOXO transcription factors includes FOXO1, FOXO3, FOXO4 and FOXO6. FOXO transcription factors integrate pathways that regulate cell survival, growth, differentiation and metabolism in response to environmental changes, such as growth factor deprivation, starvation and oxidative stress (reviewed by Accili and Arden 2004, Calnan and Brunet 2008, Eijkelenboom and Burgering 2013).
View original pathway at Reactome.
van den Heuvel AP, Schulze A, Burgering BM.; ''Direct control of caveolin-1 expression by FOXO transcription factors.''; PubMedEurope PMCScholia
Waddell DS, Baehr LM, van den Brandt J, Johnsen SA, Reichardt HM, Furlow JD, Bodine SC.; ''The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene.''; PubMedEurope PMCScholia
Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A.; ''Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.''; PubMedEurope PMCScholia
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME.; ''Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.''; PubMedEurope PMCScholia
Sisci D, Maris P, Cesario MG, Anselmo W, Coroniti R, Trombino GE, Romeo F, Ferraro A, Lanzino M, Aquila S, Maggiolini M, Mauro L, Morelli C, Andò S.; ''The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness.''; PubMedEurope PMCScholia
Gai J, Ji M, Shi C, Li W, Chen S, Wang Y, Li H.; ''FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol.''; PubMedEurope PMCScholia
Chen J, Yusuf I, Andersen HM, Fruman DA.; ''FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B lymphocytes.''; PubMedEurope PMCScholia
Hughes R, Kristiansen M, Lassot I, Desagher S, Mantovani R, Ham J.; ''NF-Y is essential for expression of the proapoptotic bim gene in sympathetic neurons.''; PubMedEurope PMCScholia
Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA.; ''The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor.''; PubMedEurope PMCScholia
Nho RS, Peterson M, Hergert P, Henke CA.; ''FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas.''; PubMedEurope PMCScholia
Eijkelenboom A, Burgering BM.; ''FOXOs: signalling integrators for homeostasis maintenance.''; PubMedEurope PMCScholia
Wang H, Li Y, Wang S, Zhang Q, Zheng J, Yang Y, Qi H, Qu H, Zhang Z, Liu F, Fang X.; ''Knockdown of transcription factor forkhead box O3 (FOXO3) suppresses erythroid differentiation in human cells and zebrafish.''; PubMedEurope PMCScholia
Deng X, Zhang W, O-Sullivan I, Williams JB, Dong Q, Park EA, Raghow R, Unterman TG, Elam MB.; ''FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c.''; PubMedEurope PMCScholia
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.; ''Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.''; PubMedEurope PMCScholia
Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM.; ''Direct control of the Forkhead transcription factor AFX by protein kinase B.''; PubMedEurope PMCScholia
Allen DL, Unterman TG.; ''Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors.''; PubMedEurope PMCScholia
Hall RK, Yamasaki T, Kucera T, Waltner-Law M, O'Brien R, Granner DK.; ''Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins.''; PubMedEurope PMCScholia
Kim MS, Pak YK, Jang PG, Namkoong C, Choi YS, Won JC, Kim KS, Kim SW, Kim HS, Park JY, Kim YB, Lee KU.; ''Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis.''; PubMedEurope PMCScholia
Lützner N, De-Castro Arce J, Rösl F.; ''Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NF-Y and FOXO transcription factors.''; PubMedEurope PMCScholia
Wang J, Wang F, Zhang P, Liu H, He J, Zhang C, Fan M, Chen X.; ''PGC-1α over-expression suppresses the skeletal muscle atrophy and myofiber-type composition during hindlimb unloading.''; PubMedEurope PMCScholia
Lees SJ, Childs TE, Booth FW.; ''Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells.''; PubMedEurope PMCScholia
Boura E, Silhan J, Herman P, Vecer J, Sulc M, Teisinger J, Obsilova V, Obsil T.; ''Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding.''; PubMedEurope PMCScholia
Hughes KJ, Meares GP, Hansen PA, Corbett JA.; ''FoxO1 and SIRT1 regulate beta-cell responses to nitric oxide.''; PubMedEurope PMCScholia
Medema RH, Kops GJ, Bos JL, Burgering BM.; ''AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.''; PubMedEurope PMCScholia
Tseng AH, Shieh SS, Wang DL.; ''SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage.''; PubMedEurope PMCScholia
Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N.; ''FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress.''; PubMedEurope PMCScholia
Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMedEurope PMCScholia
Onuma H, Vander Kooi BT, Boustead JN, Oeser JK, O'Brien RM.; ''Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin.''; PubMedEurope PMCScholia
Fernández de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, Martino A, Nelson BH, Francis JM, Jones MC, Brosens JJ, Coffer PJ, Lam EW.; ''FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism.''; PubMedEurope PMCScholia
Rena G, Guo S, Cichy SC, Unterman TG, Cohen P.; ''Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.''; PubMedEurope PMCScholia
Urbich C, Knau A, Fichtlscherer S, Walter DH, Brühl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S.; ''FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells.''; PubMedEurope PMCScholia
Obsilova V, Vecer J, Herman P, Pabianova A, Sulc M, Teisinger J, Boura E, Obsil T.; ''14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4.''; PubMedEurope PMCScholia
Bakker WJ, Blázquez-Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Löwenberg B, von Lindern M, van Dijk TB.; ''FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1.''; PubMedEurope PMCScholia
Paap RH, Oosterbroek S, Wagemans CMRJ, von Oerthel L, Schellevis RD, Vastenhouw-van der Linden AJA, Groot Koerkamp MJA, Hoekman MFM, Smidt MP.; ''FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development.''; PubMedEurope PMCScholia
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL.; ''Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.''; PubMedEurope PMCScholia
Senf SM, Sandesara PB, Reed SA, Judge AR.; ''p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.''; PubMedEurope PMCScholia
Wu B, Guo B, Kang J, Deng X, Fan Y, Zhang X, Ai K.; ''Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-β-induced tumor formation.''; PubMedEurope PMCScholia
Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH.; ''FoxO6 integrates insulin signaling with gluconeogenesis in the liver.''; PubMedEurope PMCScholia
Srinivasan S, Anitha M, Mwangi S, Heuckeroth RO.; ''Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival.''; PubMedEurope PMCScholia
Kim DH, Park MH, Chung KW, Kim MJ, Jung YR, Bae HR, Jang EJ, Lee JS, Im DS, Yu BP, Chung HY.; ''The essential role of FoxO6 phosphorylation in aging and calorie restriction.''; PubMedEurope PMCScholia
Guan XH, Liu XH, Hong X, Zhao N, Xiao YF, Wang LF, Tang L, Jiang K, Qian YS, Deng KY, Ji G, Fu M, Xin HB.; ''CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway.''; PubMedEurope PMCScholia
Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ, DiStefano PS, Chiang LW, Greenberg ME.; ''DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein.''; PubMedEurope PMCScholia
Dudgeon C, Wang P, Sun X, Peng R, Sun Q, Yu J, Zhang L.; ''PUMA induction by FoxO3a mediates the anticancer activities of the broad-range kinase inhibitor UCN-01.''; PubMedEurope PMCScholia
Bollinger LM, Witczak CA, Houmard JA, Brault JJ.; ''SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner.''; PubMedEurope PMCScholia
Bakker WJ, van Dijk TB, Parren-van Amelsvoort M, Kolbus A, Yamamoto K, Steinlein P, Verhaak RG, Mak TW, Beug H, Löwenberg B, von Lindern M.; ''Differential regulation of Foxo3a target genes in erythropoiesis.''; PubMedEurope PMCScholia
Tinkum KL, White LS, Marpegan L, Herzog E, Piwnica-Worms D, Piwnica-Worms H.; ''Forkhead box O1 (FOXO1) protein, but not p53, contributes to robust induction of p21 expression in fasted mice.''; PubMedEurope PMCScholia
Kitamura T, Feng Y, Kitamura YI, Chua SC, Xu AW, Barsh GS, Rossetti L, Accili D.; ''Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake.''; PubMedEurope PMCScholia
Matsuzaki H, Ichino A, Hayashi T, Yamamoto T, Kikkawa U.; ''Regulation of intracellular localization and transcriptional activity of FOXO4 by protein kinase B through phosphorylation at the motif sites conserved among the FOXO family.''; PubMedEurope PMCScholia
Liao L, Su X, Yang X, Hu C, Li B, Lv Y, Shuai Y, Jing H, Deng Z, Jin Y.; ''TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis.''; PubMedEurope PMCScholia
Yusuf I, Kharas MG, Chen J, Peralta RQ, Maruniak A, Sareen P, Yang VW, Kaestner KH, Fruman DA.; ''KLF4 is a FOXO target gene that suppresses B cell proliferation.''; PubMedEurope PMCScholia
Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, Pfeifer A, Klockgether T, Wuellner U, Evert BO.; ''FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.''; PubMedEurope PMCScholia
Chen L, Tang Y, Wang J, Yan Z, Xu R.; ''miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4.''; PubMedEurope PMCScholia
Silhan J, Vacha P, Strnadova P, Vecer J, Herman P, Sulc M, Teisinger J, Obsilova V, Obsil T.; ''14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4.''; PubMedEurope PMCScholia
Liu ZQ, Shen M, Wu WJ, Li BJ, Weng QN, Li M, Liu HL.; ''Expression of PUMA in Follicular Granulosa Cells Regulated by FoxO1 Activation During Oxidative Stress.''; PubMedEurope PMCScholia
Rangarajan P, Karthikeyan A, Lu J, Ling EA, Dheen ST.; ''Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.''; PubMedEurope PMCScholia
Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O'Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A.; ''Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover.''; PubMedEurope PMCScholia
Hori YS, Kuno A, Hosoda R, Horio Y.; ''Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress.''; PubMedEurope PMCScholia
Guo F, Wang Q, Zhou Y, Wu L, Ma X, Liu F, Huang F, Qin G.; ''Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells.''; PubMedEurope PMCScholia
Liu T, Chen X, Li T, Li X, Lyu Y, Fan X, Zhang P, Zeng W.; ''Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.''; PubMedEurope PMCScholia
Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J, Kimura A, Takahashi K, Nishio Y, Sakata M, Kurachi H, Tasaka K, Murata Y.; ''Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin.''; PubMedEurope PMCScholia
Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.''; PubMedEurope PMCScholia
Li J, Hu L, Tian C, Lu F, Wu J, Liu L.; ''microRNA-150 promotes cervical cancer cell growth and survival by targeting FOXO4.''; PubMedEurope PMCScholia
Gilley J, Coffer PJ, Ham J.; ''FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.''; PubMedEurope PMCScholia
Awad H, Nolette N, Hinton M, Dakshinamurti S.; ''AMPK and FoxO1 regulate catalase expression in hypoxic pulmonary arterial smooth muscle.''; PubMedEurope PMCScholia
Yang Z, Whelan J, Babb R, Bowen BR.; ''An mRNA splice variant of the AFX gene with altered transcriptional activity.''; PubMedEurope PMCScholia
Chuang PY, Yu Q, Fang W, Uribarri J, He JC.; ''Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor.''; PubMedEurope PMCScholia
Liu CW, Yang SY, Lin CK, Liu HS, Ho LT, Wu LY, Lee MJ, Ku HC, Chang HH, Huang RN, Kao YH.; ''The forkhead transcription factor FOXO1 stimulates the expression of the adipocyte resistin gene.''; PubMedEurope PMCScholia
Tang ED, Nuñez G, Barr FG, Guan KL.; ''Negative regulation of the forkhead transcription factor FKHR by Akt.''; PubMedEurope PMCScholia
Ciechomska I, Pyrzynska B, Kazmierczak P, Kaminska B.; ''Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells.''; PubMedEurope PMCScholia
Song C, Peng W, Yin S, Zhao J, Fu B, Zhang J, Mao T, Wu H, Zhang Y.; ''Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice.''; PubMedEurope PMCScholia
Rena G, Prescott AR, Guo S, Cohen P, Unterman TG.; ''Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting.''; PubMedEurope PMCScholia
Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM.; ''Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.''; PubMedEurope PMCScholia
Roy UK, Henkhaus RS, Ignatenko NA, Mora J, Fultz KE, Gerner EW.; ''Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc.''; PubMedEurope PMCScholia
Wang W, Zhou PH, Hu W.; ''Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim.''; PubMedEurope PMCScholia
Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, Kwon OY, Song WJ, Tatar M, Yu K.; ''Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals.''; PubMedEurope PMCScholia
Mei Y, Zhang Y, Yamamoto K, Xie W, Mak TW, You H.; ''FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation.''; PubMedEurope PMCScholia
Ju Y, Xu T, Zhang H, Yu A.; ''FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells.''; PubMedEurope PMCScholia
Shore AM, White PC, Hui RC, Essafi A, Lam EW, Rowe M, Brennan P.; ''Epstein-Barr virus represses the FoxO1 transcription factor through latent membrane protein 1 and latent membrane protein 2A.''; PubMedEurope PMCScholia
van der Heide LP, Jacobs FM, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.''; PubMedEurope PMCScholia
Accili D, Arden KC.; ''FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.''; PubMedEurope PMCScholia
Sengupta A, Molkentin JD, Paik JH, DePinho RA, Yutzey KE.; ''FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress.''; PubMedEurope PMCScholia
Raffaello A, Milan G, Masiero E, Carnio S, Lee D, Lanfranchi G, Goldberg AL, Sandri M.; ''JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy.''; PubMedEurope PMCScholia
Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM.; ''Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.''; PubMedEurope PMCScholia
FOXO transcription factors induce expression of several genes that negatively regulate proliferation of different cell types, such as erythroid progenitors (Bakker et al. 2004, Wang et al. 2015) and neuroepithelial progenitor cells in the telencephalon (Seoane et al. 2004). Transcription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004). FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008). FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014). Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006). Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015). Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013). FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008). FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007).
FOXO transcription factors promote expression of several pro-apoptotic genes, such as FASLG (Brunet et al. 1999, Ciechomska et al. 2003, Chen et al. 2013, Li et al. 2015), PINK1 (Mei et al. 2009, Sengupta et al. 2011), BCL2L11 (BIM) (Gilley et al. 2003, Urbich et al. 2005, Chuang et al. 2007, Hughes et al. 2011, Chen et al. 2013, Wang et al. 2016), BCL6 (Tang et al. 2002, Fernandez de Mattos et al. 2004, Shore et al. 2006) and BBC3 (PUMA) (Dudgeon et al. 2010, Hughes et al. 2011, Liu et al. 2015, Wu et al. 2016, Liu et al. 2017, Fitzwalter et al. 2018). FOXO-mediated induction of cell death genes is important during development, for example during nervous system development, where FOXO promotes neuronal death upon NGF withdrawal (Gilley et al. 2003), and also contributes to the tumor-suppressive role of FOXO factors (Arimoto Ishida et al. 2004). FOXO1 transcriptional activity is implicated in the cell death of enteric nervous system (ENS) precursors. RET signaling, which activates PI3K/AKT signaling, leading to inhibition of FOXO mediated transcription, ensures survival of ENS precursors (Srinivasan et al. 2005). Transcription of the STK11 (LKB1) gene, encoding Serine/threonine-protein kinase STK11 (also known as Liver kinase B1), which regulates diverse cellular processes, including apoptosis, is directly stimulated by FOXO3 and FOXO4 (Lutzner et al. 2012).
FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016). FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016). FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity. In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling. FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin. FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014). Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999). Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005). Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017).
AKT-mediated phosphorylation results in exclusion of FOXO1 (Rena et al. 2001), FOXO3 (Brunet et al. 1999) and FOXO4 (Obslova et al. 2005) from the nucleus. In the absence of PI3K/AKT signaling, FOXO1 (Rena et al. 2001), FOXO3 (Brunet et al. 1999) and FOXO4 (Matsuzaki et al. 2005) are mainly nuclear, but after activation of PI3K/AKT signaling, they become cytoplasmic. One of the conserved AKT phosphorylation sites is within the nuclear localization signal (NLS) of FOXO1, FOXO3 and FOXO4. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of FOXO6 phosphorylated on putative AKT sites may shuttle to the nucleus (Jacobs et al. 2003, van der Heide et al. 2005).
Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO1 is promoted by binding of FOXO1 to 14-3-3 proteins: YWHAZ (14-3-3 zeta), YWHAQ (14-3-3 theta), YWHAB (14-3-3 beta) and YWHAG (14-3-3 gamma) (Rena et al. 2001).
Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO3 is promoted by binding of FOXO3 to 14-3-3 proteins: YWHAZ (14-3-3 zeta), YWHAQ (14-3-3 theta), and SFN (14-3-3 sigma) (Brunet et al. 1999, Arimoto-Ishida et al. 2004).
Nuclear exclusion and cytoplasmic retention of AKT-phosphorylated FOXO4 is promoted by binding of FOXO4 to 14-3-3 zeta (YWHAZ) (Obsilova et al. 2005, Boura et al. 2007, Silhan et al. 2009).
Reactive oxygen species (ROS) oxidize cysteine residue(s) of FOXO4. There are five cysteine residues in FOXO4, of which two residues, C31 (corresponds to C27 in mouse Foxo4) and C481 (corresponds to C477 of mouse Foxo4) are conserved in other FOXO family members. Oxidation of C481 of FOXO4 has the most significant functional implications (Dansen et al. 2009).
After oxidation of FOXO4 cysteine residues by reactive oxygen species (ROS), FOXO4 forms a complex with a protein acetyltransferase EP300 (p300) or CREBBP (CBP). A covalent disulfide bond between FOXO4 and EP300 or CREBBP facilitates complex formation (Dansen et al. 2009).
Thioredoxin (TXN) reduces oxidized FOXO4 and disrupts interaction between FOXO4 and EP300 (p300). TXN-mediated disruption of FOXO4:EP300 complexes is negatively regulated by TXNIP (TBP-2), a TXN binding protein (Dansen et al. 2009).
SIRT1, an NAD-dependent histone deacetylase, deacetylates FOXO3. SIRT1-mediated deacetylation of FOXO3 inhibits FOXO3-mediated cell death induced by oxidative stress while promoting FOXO3-mediated cell cycle arrest, which increases resistance to oxidative stress (Brunet et al. 2004). FOXO3 can similarly be deacetylated by SIRT3, also an NAD-dependent histone deacetylase. Deacetylation of FOXO3 by SIRT3 in response to oxidative stress increases FOXO3 nuclear localization by interfering with AKT-mediated phosphorylation of FOXO3. SIRT3-mediated deacetylation of FOXO3 positively regulates FOXO3-mediated transcription of SOD2 and CAT genes which encode enzymes that process reactive oxygen species and reduce oxidative stress to the cell (Kim et al. 2010, Tseng et al. 2013).
Endogenous human histone acetyltransferase CREBBP (CBP) binds to endogenous human FOXO1. The C-terminus of FOXO1 is needed for this interaction (Daitoku et al. 2004).
Based on experiments using recombinant human CREBBP and recombinant mouse Foxo1, CREBBP phosphorylates FOXO1 on conserved lysine residues K245, K248 and K265 (these residues correspond to K242, K245 and K262, respectively, in mouse Foxo1) (Daitoku et al. 2004).
A histone deacetylase SIRT1 deacetylates FOXO1. Deacetylation increases FOXO1-mediated upregulation of SOD2 and CDKN1B (Diatoku et al. 2004). SIRT-dependent deacetylation leads to retention of FOXO1 in the nucleus (Frescas et al. 2005).
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transcription of
cell cycle genesTranscription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004).
FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008).
FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014).
Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006).
Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015).
Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013).
FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008).
FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007).
transcription of
cell death genesTranscription of the STK11 (LKB1) gene, encoding Serine/threonine-protein kinase STK11 (also known as Liver kinase B1), which regulates diverse cellular processes, including apoptosis, is directly stimulated by FOXO3 and FOXO4 (Lutzner et al. 2012).
transcription of oxidative stress, metabolic and
neuronal genesFOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).
dimer,YWHAG
dimer,YWHAB dimerAnnotated Interactions
Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).
Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017).
In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of FOXO6 phosphorylated on putative AKT sites may shuttle to the nucleus (Jacobs et al. 2003, van der Heide et al. 2005).
FOXO3 can similarly be deacetylated by SIRT3, also an NAD-dependent histone deacetylase. Deacetylation of FOXO3 by SIRT3 in response to oxidative stress increases FOXO3 nuclear localization by interfering with AKT-mediated phosphorylation of FOXO3. SIRT3-mediated deacetylation of FOXO3 positively regulates FOXO3-mediated transcription of SOD2 and CAT genes which encode enzymes that process reactive oxygen species and reduce oxidative stress to the cell (Kim et al. 2010, Tseng et al. 2013).
dimer,YWHAG
dimer,YWHAB dimer