FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (Homo sapiens)

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2-10, 12-25, 27...32323, 1727273, 17, 3771, 3, 5, 31, 357, 8, 15, 273, 313, 31343, 5, 31, 3534cytosolendoplasmic reticulum lumenmitochondrial matrixnucleoplasmFOXO1,FOXO3:ABCA6geneIGFPB1 geneATXN3 FOXO3 NPY geneFBXO32 geneFOXO1 FOXO1:SREBF1 geneHDAC2 FOXO1:NPY geneFOXO3 4xHC-INS(90-110) AGRP gene TRIM63PCK1 gene PPARGC1A FOXO1,FOXO3:p-2S-SMAD2/3:SMAD4:TRIM63 geneFOXO6POMC(138-150)PCK1FOXO1 FOXO1,FOXO3,FOXO4ABCA6 gene FOXO4 FOXO4 PPARGC1ACORT RETN gene FOXO1:AGRP geneNPYPPARGC1A TRIM63 geneSIN3A ATXN3NR3C1:(ALDO,11DCORST,CORST,CORT) dimerFOXO3 TRIM63 gene FOXO1:PPARGC1A,FOXO3,FOXO4:PCK1 geneG6PCFOXO3 SOD2FOXO1 FOXO1 HDAC1 p-S423,S425-SMAD3 FOXO4 FOXO4 2xHC-INS(25-54) InsulinFOXO6 ALDO FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6PPARGC1A FOXO6 CAT gene p-S465,S467-SMAD2 IGFPB1 gene FBXO32 gene FOXO1,FOXO3,(FOXO4)SIN3A ATXN3 PPARGC1A FOXO4 CAT geneFOXO1 FOXO1 HDAC1 FOXO1 FOXO6 CORT FOXO4 NR3C1 FOXO1 FOXO1 FOXO6 SMAD4 SOD2 gene FOXO3 FOXO3 FOXO3 NPY gene FOXO1 ABCA6FOXO3 FOXO1 SREBF1(1-1147)RETNFOXO1 FOXO4:ATXN3FOXO3,FOXO6,(FOXO1):CAT genePPARGC1A CORST ABCA6 geneFOXO1 G6PC gene p-2S-SMAD2/3:SMAD4GCK gene CORST p-S423,S425-SMAD3 FOXO1,FOXO3,FOXO4:IGFBP1 geneFOXO1 GCKFOXO4 FOXO3 FOXO3FOXO4:ATXN3:SOD2geneFOXO1:NR3C1:(ALDO,11DCORST,CORST,CORT):TRIM63 geneFOXO1,FOXO3,(FOXO4):FBXO32 geneFOXO1FOXO1 SOD2 geneFOXO1 SREBF1 gene FOXO6 FOXO3 FOXO1:PPARGC1A,FOXO3,FOXO4FOXO411DCORST PCK1 geneFOXO6:PLXNA4 geneG6PC geneFOXO1:POMC geneFOXO1 HDAC2 FOXO1 SREBF1 geneFOXO1 FOXO3 FOXO3 SIRT3PLXNA4 gene FOXO1:SIN3A:HDAC1.HDAC2 dimers:GCK geneFOXO4 FOXO1,FOXO3FBXO32POMC genep-S465,S467-SMAD2 FOXO1 FOXO4 AGRPALDO IGFBP1RETN geneFOXO3:SOD2 geneAGRP geneCATFOXO3 11DCORST PLXNA4FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6:G6PC genePLXNA4 genePOMC gene FOXO3 SIN3A:HDAC1,HDAC2dimersSMAD4 TRIM63 gene FOXO3,FOXO6,(FOXO1)FOXO4 GCK geneFOXO1:PPARGC1ASOD2 gene FOXO1 NR3C1 FOXO1:RETN gene26, 282726, 2826, 2826, 28711, 332726, 2826, 28


Description

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). View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 9615017
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Reactome version: 73
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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History

CompareRevisionActionTimeUserComment
113366view11:44, 2 November 2020ReactomeTeamReactome version 74
112817view18:23, 9 October 2020DeSlOntology Term : 'forkhead class O signaling pathway' added !
112765view16:16, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
11DCORST MetaboliteCHEBI:16973 (ChEBI)
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
ABCA6 gene ProteinENSG00000154262 (Ensembl)
ABCA6 geneGeneProductENSG00000154262 (Ensembl)
ABCA6ProteinQ8N139 (Uniprot-TrEMBL)
AGRP gene ProteinENSG00000159723 (Ensembl)
AGRP geneGeneProductENSG00000159723 (Ensembl)
AGRPProteinO00253 (Uniprot-TrEMBL)
ALDO MetaboliteCHEBI:27584 (ChEBI)
ATXN3 ProteinP54252 (Uniprot-TrEMBL)
ATXN3ProteinP54252 (Uniprot-TrEMBL)
CAT gene ProteinENSG00000121691 (Ensembl)
CAT geneGeneProductENSG00000121691 (Ensembl)
CATProteinP04040 (Uniprot-TrEMBL)
CORST MetaboliteCHEBI:16827 (ChEBI)
CORT MetaboliteCHEBI:17650 (ChEBI)
FBXO32 gene ProteinENSG00000156804 (Ensembl)
FBXO32 geneGeneProductENSG00000156804 (Ensembl)
FBXO32ProteinQ969P5 (Uniprot-TrEMBL)
FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6:G6PC geneComplexR-HSA-9623250 (Reactome)
FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6ComplexR-HSA-9623256 (Reactome)
FOXO1,FOXO3,(FOXO4):FBXO32 geneComplexR-HSA-9624643 (Reactome)
FOXO1,FOXO3,(FOXO4)ComplexR-HSA-9620827 (Reactome)
FOXO1,FOXO3,FOXO4:IGFBP1 geneComplexR-HSA-9623423 (Reactome)
FOXO1,FOXO3,FOXO4ComplexR-HSA-9617987 (Reactome)
FOXO1,FOXO3:ABCA6 geneComplexR-HSA-9625082 (Reactome)
FOXO1,FOXO3:p-2S-SMAD2/3:SMAD4:TRIM63 geneComplexR-HSA-9625757 (Reactome)
FOXO1,FOXO3ComplexR-HSA-9614686 (Reactome)
FOXO1:AGRP geneComplexR-HSA-9623048 (Reactome)
FOXO1:NPY geneComplexR-HSA-9622979 (Reactome)
FOXO1:NR3C1:(ALDO,11DCORST,CORST,CORT):TRIM63 geneComplexR-HSA-9625735 (Reactome)
FOXO1:POMC geneComplexR-HSA-9623080 (Reactome)
FOXO1:PPARGC1A,FOXO3,FOXO4:PCK1 geneComplexR-HSA-9623320 (Reactome)
FOXO1:PPARGC1A,FOXO3,FOXO4ComplexR-HSA-9623398 (Reactome)
FOXO1:PPARGC1AComplexR-HSA-9623234 (Reactome)
FOXO1:RETN geneComplexR-HSA-9625827 (Reactome)
FOXO1:SIN3A:HDAC1.HDAC2 dimers:GCK geneComplexR-HSA-9625107 (Reactome)
FOXO1:SREBF1 geneComplexR-HSA-9625360 (Reactome)
FOXO1ProteinQ12778 (Uniprot-TrEMBL)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO3,FOXO6,(FOXO1):CAT geneComplexR-HSA-9622806 (Reactome)
FOXO3,FOXO6,(FOXO1)ComplexR-HSA-9622805 (Reactome)
FOXO3:SOD2 geneComplexR-HSA-9617974 (Reactome)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
FOXO4 ProteinP98177 (Uniprot-TrEMBL)
FOXO4:ATXN3:SOD2 geneComplexR-HSA-9617936 (Reactome)
FOXO4:ATXN3ComplexR-HSA-9617923 (Reactome)
FOXO4ProteinP98177 (Uniprot-TrEMBL)
FOXO6 ProteinA8MYZ6 (Uniprot-TrEMBL)
FOXO6:PLXNA4 geneComplexR-HSA-9615222 (Reactome)
FOXO6ProteinA8MYZ6 (Uniprot-TrEMBL)
G6PC gene ProteinENSG00000131482 (Ensembl)
G6PC geneGeneProductENSG00000131482 (Ensembl)
G6PCProteinP35575 (Uniprot-TrEMBL)
GCK gene ProteinENSG00000106633 (Ensembl)
GCK geneGeneProductENSG00000106633 (Ensembl)
GCKProteinP35557 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
IGFBP1ProteinP08833 (Uniprot-TrEMBL)
IGFPB1 gene ProteinENSG00000146678 (Ensembl)
IGFPB1 geneGeneProductENSG00000146678 (Ensembl)
InsulinComplexR-HSA-74674 (Reactome)
NPY gene ProteinENSG00000122585 (Ensembl)
NPY geneGeneProductENSG00000122585 (Ensembl)
NPYProteinP01303 (Uniprot-TrEMBL)
NR3C1 ProteinP04150 (Uniprot-TrEMBL)
NR3C1:(ALDO,11DCORST,CORST,CORT) dimerComplexR-HSA-879850 (Reactome)
PCK1 gene ProteinENSG00000124253 (Ensembl)
PCK1 geneGeneProductENSG00000124253 (Ensembl)
PCK1ProteinP35558 (Uniprot-TrEMBL)
PLXNA4 gene ProteinENSG00000221866 (Ensembl)
PLXNA4 geneGeneProductENSG00000221866 (Ensembl)
PLXNA4ProteinQ9HCM2 (Uniprot-TrEMBL)
POMC gene ProteinENSG00000115138 (Ensembl)
POMC geneGeneProductENSG00000115138 (Ensembl)
POMC(138-150)ProteinP01189 (Uniprot-TrEMBL)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
RETN gene ProteinENSG00000104918 (Ensembl)
RETN geneGeneProductENSG00000104918 (Ensembl)
RETNProteinQ9HD89 (Uniprot-TrEMBL)
SIN3A ProteinQ96ST3 (Uniprot-TrEMBL)
SIN3A:HDAC1,HDAC2 dimersComplexR-HSA-9022431 (Reactome)
SIRT3ProteinQ9NTG7 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SOD2 gene ProteinENSG00000112096 (Ensembl)
SOD2 geneGeneProductENSG00000112096 (Ensembl)
SOD2ProteinP04179 (Uniprot-TrEMBL)
SREBF1 gene ProteinENSG00000072310 (Ensembl)
SREBF1 geneGeneProductENSG00000072310 (Ensembl)
SREBF1(1-1147)ProteinP36956 (Uniprot-TrEMBL)
TRIM63 gene ProteinENSG00000158022 (Ensembl)
TRIM63 geneGeneProductENSG00000158022 (Ensembl)
TRIM63ProteinQ969Q1 (Uniprot-TrEMBL)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-173511 (Reactome)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABCA6 geneR-HSA-9625091 (Reactome)
ABCA6 geneR-HSA-9625092 (Reactome)
ABCA6ArrowR-HSA-9625092 (Reactome)
AGRP geneR-HSA-9623018 (Reactome)
AGRP geneR-HSA-9623023 (Reactome)
AGRPArrowR-HSA-9623023 (Reactome)
ATXN3R-HSA-9617927 (Reactome)
CAT geneR-HSA-9622737 (Reactome)
CAT geneR-HSA-9622738 (Reactome)
CATArrowR-HSA-9622738 (Reactome)
FBXO32 geneR-HSA-9624611 (Reactome)
FBXO32 geneR-HSA-9624624 (Reactome)
FBXO32ArrowR-HSA-9624624 (Reactome)
FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6:G6PC geneArrowR-HSA-9623168 (Reactome)
FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6:G6PC geneArrowR-HSA-9623192 (Reactome)
FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6R-HSA-9623168 (Reactome)
FOXO1,FOXO3,(FOXO4):FBXO32 geneArrowR-HSA-9624611 (Reactome)
FOXO1,FOXO3,(FOXO4):FBXO32 geneArrowR-HSA-9624624 (Reactome)
FOXO1,FOXO3,(FOXO4)R-HSA-9624611 (Reactome)
FOXO1,FOXO3,FOXO4:IGFBP1 geneArrowR-HSA-9623415 (Reactome)
FOXO1,FOXO3,FOXO4:IGFBP1 geneArrowR-HSA-9623427 (Reactome)
FOXO1,FOXO3,FOXO4R-HSA-9623415 (Reactome)
FOXO1,FOXO3:ABCA6 geneArrowR-HSA-9625091 (Reactome)
FOXO1,FOXO3:ABCA6 geneArrowR-HSA-9625092 (Reactome)
FOXO1,FOXO3:p-2S-SMAD2/3:SMAD4:TRIM63 geneArrowR-HSA-9625693 (Reactome)
FOXO1,FOXO3:p-2S-SMAD2/3:SMAD4:TRIM63 geneArrowR-HSA-9625749 (Reactome)
FOXO1,FOXO3R-HSA-9625091 (Reactome)
FOXO1,FOXO3R-HSA-9625749 (Reactome)
FOXO1:AGRP geneArrowR-HSA-9623018 (Reactome)
FOXO1:AGRP geneArrowR-HSA-9623023 (Reactome)
FOXO1:NPY geneArrowR-HSA-9622980 (Reactome)
FOXO1:NPY geneArrowR-HSA-9622981 (Reactome)
FOXO1:NR3C1:(ALDO,11DCORST,CORST,CORT):TRIM63 geneArrowR-HSA-9625693 (Reactome)
FOXO1:NR3C1:(ALDO,11DCORST,CORST,CORT):TRIM63 geneArrowR-HSA-9625699 (Reactome)
FOXO1:POMC geneArrowR-HSA-9623059 (Reactome)
FOXO1:POMC geneTBarR-HSA-9623072 (Reactome)
FOXO1:PPARGC1A,FOXO3,FOXO4:PCK1 geneArrowR-HSA-9623280 (Reactome)
FOXO1:PPARGC1A,FOXO3,FOXO4:PCK1 geneArrowR-HSA-9623281 (Reactome)
FOXO1:PPARGC1A,FOXO3,FOXO4R-HSA-9623281 (Reactome)
FOXO1:PPARGC1AArrowR-HSA-9623240 (Reactome)
FOXO1:RETN geneArrowR-HSA-9625828 (Reactome)
FOXO1:RETN geneArrowR-HSA-9625863 (Reactome)
FOXO1:SIN3A:HDAC1.HDAC2 dimers:GCK geneArrowR-HSA-9625101 (Reactome)
FOXO1:SIN3A:HDAC1.HDAC2 dimers:GCK geneTBarR-HSA-9625124 (Reactome)
FOXO1:SREBF1 geneArrowR-HSA-9625324 (Reactome)
FOXO1:SREBF1 geneTBarR-HSA-9625346 (Reactome)
FOXO1ArrowR-HSA-9617833 (Reactome)
FOXO1R-HSA-9622980 (Reactome)
FOXO1R-HSA-9623018 (Reactome)
FOXO1R-HSA-9623059 (Reactome)
FOXO1R-HSA-9623240 (Reactome)
FOXO1R-HSA-9625101 (Reactome)
FOXO1R-HSA-9625324 (Reactome)
FOXO1R-HSA-9625699 (Reactome)
FOXO1R-HSA-9625828 (Reactome)
FOXO3,FOXO6,(FOXO1):CAT geneArrowR-HSA-9622737 (Reactome)
FOXO3,FOXO6,(FOXO1):CAT geneArrowR-HSA-9622738 (Reactome)
FOXO3,FOXO6,(FOXO1)R-HSA-9622737 (Reactome)
FOXO3:SOD2 geneArrowR-HSA-9617833 (Reactome)
FOXO3:SOD2 geneArrowR-HSA-9617972 (Reactome)
FOXO3R-HSA-9617972 (Reactome)
FOXO4:ATXN3:SOD2 geneArrowR-HSA-9617832 (Reactome)
FOXO4:ATXN3:SOD2 geneArrowR-HSA-9617833 (Reactome)
FOXO4:ATXN3ArrowR-HSA-9617927 (Reactome)
FOXO4:ATXN3R-HSA-9617832 (Reactome)
FOXO4R-HSA-9617927 (Reactome)
FOXO6:PLXNA4 geneArrowR-HSA-9615015 (Reactome)
FOXO6:PLXNA4 geneArrowR-HSA-9615023 (Reactome)
FOXO6R-HSA-9615015 (Reactome)
G6PC geneR-HSA-9623168 (Reactome)
G6PC geneR-HSA-9623192 (Reactome)
G6PCArrowR-HSA-9623192 (Reactome)
GCK geneR-HSA-9625101 (Reactome)
GCK geneR-HSA-9625124 (Reactome)
GCKArrowR-HSA-9625124 (Reactome)
IGFBP1ArrowR-HSA-9623427 (Reactome)
IGFPB1 geneR-HSA-9623415 (Reactome)
IGFPB1 geneR-HSA-9623427 (Reactome)
InsulinTBarR-HSA-9623168 (Reactome)
InsulinTBarR-HSA-9623281 (Reactome)
InsulinTBarR-HSA-9623415 (Reactome)
NPY geneR-HSA-9622980 (Reactome)
NPY geneR-HSA-9622981 (Reactome)
NPYArrowR-HSA-9622981 (Reactome)
NR3C1:(ALDO,11DCORST,CORST,CORT) dimerR-HSA-9625699 (Reactome)
PCK1 geneR-HSA-9623280 (Reactome)
PCK1 geneR-HSA-9623281 (Reactome)
PCK1ArrowR-HSA-9623280 (Reactome)
PLXNA4 geneR-HSA-9615015 (Reactome)
PLXNA4 geneR-HSA-9615023 (Reactome)
PLXNA4ArrowR-HSA-9615023 (Reactome)
POMC geneR-HSA-9623059 (Reactome)
POMC geneR-HSA-9623072 (Reactome)
POMC(138-150)ArrowR-HSA-9623072 (Reactome)
PPARGC1AR-HSA-9623240 (Reactome)
R-HSA-9615015 (Reactome) Based on studies in mice, FOXO6 binds FOXO response elements in the PLXNA4 gene locus, encoding the semaphorin SEMA3A co-receptor PLXNA4. FOXO response elements are found in the promoter and the first intron of the mouse Plxna4 gene (Paap et al. 2016). The first intron of the human PLXNA4 gene contains several predicted FOXO response elements.
R-HSA-9615023 (Reactome) Based on studies in mice, FOXO6 directly stimulates transcription of the semaphorin SEMA3A co-receptor PLXNA4 (Plexin A4). Defects in migration of the radial glia during cortical development observed in Foxo6 knockout mice can be restored by ectopic overexpression of Plxna4 (Paap et al. 2016).
R-HSA-9617832 (Reactome) Endogenous human FOXO4 and ATXN3 form a complex that binds to adjacent FOXO- and ATXN3- binding sites in the promoter of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase (Araujo et al. 2011).
R-HSA-9617833 (Reactome) FOXO3 directly stimulates transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase (Kops et al. 2002). FOXO4 and ATXN3, which form a complex, also directly stimulate SOD2 gene transcription (Araujo et al. 2011). Acetylation of FOXO4 by EP300 (p300) or CREBBP (CBP) in response to oxidative stress does not affect FOXO4-mediated induction of SOD2 gene transcription (Dansen et al. 2009). FOXO1 positively regulates SOD2 transcription (Hori et al. 2013, Guan et al. 2016), but direct binding of FOXO1 to the SOD2 gene promoter has not been demonstrated.
R-HSA-9617927 (Reactome) Endogenous human FOXO4 forms a complex with endogenous human ATXN3 (Araujo et al. 2011), a deubiquitinase involved in protein homeostasis, transcription, cytoskeleton regulation and myogenesis (reviewed in Matos et al. 2018). ATXN3, however, does not deubiquitinate FOXO4. FOXO4 is not recruited to ATXN3-containing nuclear inclusions in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011).
R-HSA-9617972 (Reactome) FOXO3 binds forkhead box elements in the promoter region of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase (Kops et al. 2002). FOXO3-mediated upregulation of the SOD2 gene transcription is positively regulated by SIRT3 histone deacetylase, which deacetylates FOXO3 under conditions of oxidative stress and increases nuclear localization of FOXO3 (Sundaresan et al. 2009, Rangarajan et al. 2015, Yang et al. 2016).
R-HSA-9622737 (Reactome) Based on studies with mouse FOXO proteins, FOXO3 (Rangarajan et al. 2015, Song et al. 2016) and FOXO6 (Kim et al. 2014) bind forkhead box elements in the promoter of the CAT gene, encoding the enzyme catalase. Catalase converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress. FOXO1 positively regulates CAT gene transcription (Awad et al. 2014, Liao et al. 2016, Guo et al. 2016) and is probably able to bind to forkhead box elements in the CAT gene promoter.
FOXO3-mediated upregulation of the CAT gene transcription is positively regulated by SIRT3 histone deacetylase, which deacetylates FOXO3 under conditions of oxidative stress and increases nuclear localization of FOXO3 (Sundaresan et al. 2009, Rangarajan et al. 2015, Yang et al. 2016).
R-HSA-9622738 (Reactome) Transcription of the CAT gene is directly stimulated by FOXO3 (Rangarajan et al. 2015, Song et al. 2016) and FOXO6 (Kim et al. 2014), and is positively regulated by FOXO1 (Awad et al. 2014, Liao et al. 2016, Guo et al. 2016), although direct regulation by FOXO1 has not been demonstrated. CAT encodes the enzyme catalase, which converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress.
R-HSA-9622980 (Reactome) In the hypothalamic orexigenic neurons FOXO1 binds to the insulin responsive elements (IREs) in the promoter of the NPY gene (Kim et al. 2006), encoding neuropeptide-Y .
R-HSA-9622981 (Reactome) FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y, in hypothalamic orexigenic neurons. NPY stimulates food intake and weight gain. Insulin and leptin, through PI3K/AKT signaling, inhibit FOXO1-mediated upregulation of NPY expression (Kim et al. 2006). NPY may act through a positive feedback loop to increase the transcriptional activity of FOXO1 through the PKA/CREB pathway (Hong et al. 2012).
R-HSA-9623018 (Reactome) Based on studies in mouse hypothalamic neurons, FOXO1 binds the promoter of the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006).
R-HSA-9623023 (Reactome) Based on studies in mice, FOXO1 directly promotes transcription of the AGRP gene, encoding Agouti-related protein, in orexigenic neurons of the hypothalamus. AGRP promotes food intake and weight gain. FOXO1-mediated upregulation of AGRP gene transcription involves recruitment of histone actyltransferases to the AGRP gene promoter and displacement of the NcoR transcriptional repressor complex. Leptin inhibits FOXO1-mediated upregulation of AGRP, probably acting through STAT3 (Kitamura et al. 2006, Kim et al. 2006).
R-HSA-9623059 (Reactome) Based on studies in mice, FOXO1 binds the promoter of the POMC gene, encoding Pro-opiomelanocortin (Kitamura et al. 2006). FOXO1-mediated repression of the POMC gene is positively regulated by SIRT1-mediated deacetylation of FOXO1 (Cakir et al. 2009).
R-HSA-9623072 (Reactome) Based on studies in mice, FOXO1 represses transcription of the POMC gene, encoding Pro-opiomelanocortin, in hypothalamic anorexigenic neurons. FOXO1-mediated repression of the POMC gene involves the recruitment of histone deacetylases and the NcoR repressor complex to the POMC gene promoter. Leptin inhibits binding of FOXO1 and promotes binding of STAT3 to the POMC gene promoter, thus stimulating POMC gene transcription. One of the cleavage products of Pro-opiomelanocortin is melanocyte-stimulating hormone alpha, which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006).
R-HSA-9623168 (Reactome) FOXO1 (Ayala et al. 1999, Onuma et al. 2006, Puigserver et al. 2003), FOXO3 (Onuma et al. 2006), FOXO4 (Yang et al. 2002) and FOXO6 (Kim et al. 2011) bind insulin response elements in the promoter of the G6PC gene, encoding Glucose-6-phosphatase. Formation of the complex between FOXO1 and PPARGC1A (PGC-1alpha) may be required for FOXO1 to bind the G6PC gene promoter (Puigserver et al. 2003). Binding of FOXO transcription factors to the G6PC gene promoter is negatively regulated by insulin.
R-HSA-9623192 (Reactome) FOXO1 (Onuma et al. 2006), which can function in collaboration with PPARGC1A (PGC-1alpha) (Puigserver et al. 2003), FOXO3 (Onuma et al. 2006), FOXO4 (Yang et al. 2002) and FOXO6 (Kim et al. 2011) directly stimulate transcription of the G6PC gene, encoding Glucose-6-phosphatase. G6PC generates glucose and enables maintenance of steady glucose blood levels during fasting. FOXO6 mRNA levels increase in liver cells during fasting (Kim et al. 2011). Upregulation of G6PC expression by FOXO1 and FOXO6 is inhibited by insulin. FOXO-mediated induction of G6PC is involved in excessive endogenous glucose production and fasting hyperglycemia in diabetes (Kim et al. 2011).
R-HSA-9623240 (Reactome) Based on experiments in a mouse model system, FOXO1 forms a complex with the transcriptional co-activator PPARGC1A (PGC-1alpha). The interaction between FOXO1 and PPARGC1A is disrupted by AKT-mediated phosphorylation of FOXO1 (Puigserver et al. 2003).
R-HSA-9623280 (Reactome) Based on studies in mice, FOXO1 and PPARGC1A (PGC-1alpha) directly stimulate transcription of the PCK1 gene, encoding a gluconeogenesis enzyme Phosphoenolpyruvate carboxykinase (Puigserver et al. 2003).
FOXO3 (Hall et al. 2000) and FOXO4 (Yang et al. 2002) also directly stimulates PCK1 gene transcription .
R-HSA-9623281 (Reactome) Based on studies in mice, FOXO1, in complex with PPARGC1A (PGC-1alpha), binds the promoter of the PCK1 gene, encoding Phosphoenolpyruvate carboxykinase, an enzyme in the gluconeogenesis pathway. Interaction of FOXO1 with PPARGC1A is inhibited by AKT-mediated phosphorylation of FOXO1, and binding of FOXO1 and PPARGC1A to the PKC1 promoter is inhibited by insulin (Puigserver et al. 2003).
FOXO3 (Hall et al. 2000) and FOXO4 (Yang et al. 2002) also bind the promoter of the PCK1 gene.
R-HSA-9623415 (Reactome) FOXO1 (Tang et al. 1999), FOXO3 (Brunet et al. 1999, Hall et al. 2000) and FOXO4 (Kops et al. 1999, Yang et al. 2002) bind insulin response elements in the promoter of the IGFBP1 gene, encoding Insulin-like growth factor-binding protein 1. FOXO-mediated regulation of IGFBP1 gene expression is negatively regulated by insulin.
R-HSA-9623427 (Reactome) FOXO1 (Tang et al. 1999), FOXO3 (Hall et al. 2000) and FOXO4 (Kops et al. 1999, Yang et al. 2002) directly stimulate transcription of IGFBP1 gene, encoding Insulin-like growth factor-binding protein 1.
R-HSA-9624611 (Reactome) Based on studies with recombinant human proteins and the mouse Fbxo32 (Atrogin-1) promoter, FOXO1 (Sandri et al. 2004), FOXO3 (Raffaello et al. 2010), and possibly FOXO4 bind the promoter of the FBXO32 gene.
R-HSA-9624624 (Reactome) Transcription of the FBXO32 gene, encoding Atrogin-1, is positively regulated by FOXO1, FOXO3 and FOXO4 (Senf et al. 2011). Direct binding to the FBXO32 gene promoter has been demonstrated for FOXO1 (Sandri et al. 2004) and FOXO3 (Raffaello et al. 2010), but not FOXO4. Atrogin-1 is a component of an SCF ubiquitin ligase complex that promotes degradation of muscle cell proteins during muscle atrophy (Tintignac et al. 2005). The ability of the Insulin-like growth factor 1 (IGF1) to prevent muscle atrophy depends on PI3K/AKT-mediated inactivation of FOXO transcription factors (Stitt et al. 2004). Acetylation of FOXO3 negatively regulates FOXO3-mediated upregulation of FBXO32 (Bertaggia et al. 2012).
R-HSA-9625091 (Reactome) FOXO1 and FOXO3 bind forkhead box response elements in the promoter of the ABCA6 gene, encoding ATP-binding cassette sub-family A member 6, a putative transporter protein involved in lipid homeostasis (Gai et al. 2013).
R-HSA-9625092 (Reactome) FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein responsive to cholesterol and thought to be involved in lipid homeostasis (Gai et al. 2013).
R-HSA-9625101 (Reactome) Based on studies in mice, FOXO1 recruits transcriptional repressor SIN3A and histone deacetylases (HDACs) of the I class to the promoter of the GCK gene, encoding glucokinase (Langlet et al. 2017).
R-HSA-9625124 (Reactome) Based on studies in mice, FOXO1, together with SIN3A and histone deacetylases (HDACs), directly represses transcription of the GCK gene, encoding glucokinase. Insulin interferes with FOXO1-mediated repression of GCK expression, resulting in upregulation of GCK and stimulation of lipogenesis (Langlet et al. 2017).
R-HSA-9625324 (Reactome) FOXO1 binds to the promoter of the SREBF1 (SREBP1) gene, encoding Sterol regulatory element-binding protein 1, a transcriptional activator required for lipid homeostasis. Binding of FOXO1 to the SREBF1 promoter is inhibited by insulin (Deng et al. 2012).
R-HSA-9625346 (Reactome) FOXO1 directly represses transcription of the SREBF1 (SREBP1) gene, encoding Sterol regulatory element-binding protein 1, a transcriptional activator required for lipid homeostasis (Deng et al. 2012). FOXO1 binding interferes with recruitment of SREBF1 transcriptional activator NR1H3 (LXRA) to the SREBF1 promoter (Liu et al. 2010). CRY1, a transcriptional target of SREBF1, downregulates FOXO1 protein levels by promoting MDM2-mediated polyubiquitination and degradation of FOXO1 (Jang et al. 2016).
R-HSA-9625693 (Reactome) FOXO1 and activated glucocorticoid receptor (NR3C1) directly activate transcription of the TRIM63 gene, acting synergistically. TRIM63 (MuRF1) is an E3 ubiquitin ligase involved in degradation of muscle proteins and muscle atrophy during starvation, similar to FBXO31 (atrogin-1) (Waddell et al. 2008).
FOXO1 and FOXO3 directly activate TRIM63 gene transcription acting synergistically with SMAD3 (Bollinger et al. 2014, Wang et al. 2017). SMAD3 in the nucleus exist as a heterotrimer composed of two molecules of SMAD2 or SMAD3 and one molecule of SMAD4.
R-HSA-9625699 (Reactome) Glucocorticoid receptor elements (GREs) and forkhead box elements are conserved in the promoter of the mouse, rat and human TRIM63 gene, encoding an E3 ubiquitin ligase TRIM63 (MuRF1) (Waddell et al. 2008).
R-HSA-9625749 (Reactome) FOXO1 and FOXO3 can bind to the promoter of the TRIM63 gene, encoding an E3 ubiquitin ligase MURF1, together with SMAD3 (Bollinger et al. 2014, Wang et al. 2017). SMAD3 in the nucleus exist as a heterotrimer composed of two molecules of SMAD2 or SMAD3 and one molecule of SMAD4.
R-HSA-9625828 (Reactome) Based on studies in mice, FOXO1 binds the promoter of the RESTN gene, encoding resistin (Liu et al. 2014).
R-HSA-9625863 (Reactome) Based on studies in mice, transcription of the RETN gene, encoding resistin, is directly stimulated by FOXO1 (Liu et al. 2014). Resistin is an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells (Steppan et al. 2001).
RETN geneR-HSA-9625828 (Reactome)
RETN geneR-HSA-9625863 (Reactome)
RETNArrowR-HSA-9625863 (Reactome)
SIN3A:HDAC1,HDAC2 dimersR-HSA-9625101 (Reactome)
SIRT3ArrowR-HSA-9617972 (Reactome)
SIRT3ArrowR-HSA-9622737 (Reactome)
SOD2 geneR-HSA-9617832 (Reactome)
SOD2 geneR-HSA-9617833 (Reactome)
SOD2 geneR-HSA-9617972 (Reactome)
SOD2ArrowR-HSA-9617833 (Reactome)
SREBF1 geneR-HSA-9625324 (Reactome)
SREBF1 geneR-HSA-9625346 (Reactome)
SREBF1(1-1147)ArrowR-HSA-9625346 (Reactome)
TRIM63 geneR-HSA-9625693 (Reactome)
TRIM63 geneR-HSA-9625699 (Reactome)
TRIM63 geneR-HSA-9625749 (Reactome)
TRIM63ArrowR-HSA-9625693 (Reactome)
p-2S-SMAD2/3:SMAD4R-HSA-9625749 (Reactome)
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