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

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes" Organism="Homo sapiens"> <Comment Source="WikiPathways-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).&lt;br&gt;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).&lt;br&gt;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.&lt;br&gt;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.&lt;br&gt;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.&lt;br&gt;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).&lt;br&gt;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). 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<Graphics CenterX="100.0" CenterY="1529.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43524" /> </DataNode> <DataNode TextLabel="CAT gene " GraphId="c1055" Type="Protein" GroupRef="a3bb2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9622806" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1689.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000121691" /> </DataNode> <DataNode TextLabel="CORST " GraphId="c16f2" Type="Metabolite" GroupRef="d04a5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-879850" /> <Attribute Key="copies_num" Value="92" /> <Graphics CenterX="520.0" CenterY="1709.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16827" /> 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Database="Uniprot-TrEMBL" ID="Q9NTG7" /> </DataNode> <DataNode TextLabel="CAT gene" GraphId="d3f80" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1536.0" CenterY="745.5" Width="74.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000121691" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="d4cb8" Type="Protein" GroupRef="a30a9"> <BiopaxRef>e57</BiopaxRef> <BiopaxRef>bf0</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623250" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="1569.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="IGFPB1 gene " GraphId="d5e42" Type="Protein" GroupRef="f4366"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" 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Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:27584" /> </DataNode> <DataNode TextLabel="FBXO32" GraphId="d7aff" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1936.5" CenterY="379.0" Width="63.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q969P5" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="d7e67" Type="Protein" GroupRef="b8e3a"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625360" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1569.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="G6PC gene " GraphId="d8ce2" Type="Protein" GroupRef="a30a9"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623250" /> <Attribute 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TextLabel="FOXO4 " GraphId="dae58" Type="Protein" GroupRef="faa81"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9617987" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1509.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P98177" /> </DataNode> <DataNode TextLabel="FOXO4:ATXN3:SOD2&#xA;gene" GraphId="daf1d" Type="Complex"> <BiopaxRef>a6c</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="631.0" CenterY="527.5" Width="98.0" Height="33.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9617936" /> </DataNode> <DataNode TextLabel="PLXNA4 gene" GraphId="dbd0e" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1352.5" CenterY="298.5" Width="87.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000221866" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="dd1c7" Type="Protein" GroupRef="b1c9f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625082" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1229.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="dd6a7" Type="Protein" GroupRef="e13d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9622805" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1569.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="RETN gene " GraphId="ddb99" Type="Protein" GroupRef="debc3"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625827" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1509.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000104918" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="de1f3" Type="Protein" GroupRef="b3969"> <BiopaxRef>e57</BiopaxRef> <BiopaxRef>bf0</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623398" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1249.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="POMC gene " GraphId="de445" Type="Protein" GroupRef="e1ba1"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623080" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1249.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000115138" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="dec0e" Type="Protein" GroupRef="a3bb2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9622806" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1669.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="dfe6d" Type="Protein" GroupRef="de327"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623320" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1789.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="AGRP gene" GraphId="e0b4f" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="831.5" CenterY="900.5" Width="41.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000159723" /> </DataNode> <DataNode TextLabel="AGRP" GraphId="e1437" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="869.0" CenterY="1136.0" Width="42.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00253" /> </DataNode> <DataNode TextLabel="FOXO3 " GraphId="e28c0" Type="Protein" GroupRef="eecb6"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9620827" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1589.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43524" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="e367b" Type="Protein" GroupRef="f4366"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623423" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1369.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO1:PPARGC1A,FOXO3,FOXO4:PCK1 gene" GraphId="e48eb" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="640.5" CenterY="287.0" Width="123.0" Height="48.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9623320" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="e4d5b" Type="Protein" GroupRef="cb29b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623234" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1309.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO1,FOXO3,FOXO4:IGFBP1 gene" GraphId="e4dc2" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="976.5" CenterY="162.5" Width="99.0" Height="47.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9623423" /> </DataNode> <DataNode TextLabel="POMC gene" GraphId="e54e0" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1051.5" CenterY="961.5" Width="77.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000115138" /> </DataNode> <DataNode TextLabel="SOD2 gene " GraphId="e6922" Type="Protein" GroupRef="fa059"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9617974" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1469.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000112096" /> </DataNode> <DataNode TextLabel="FOXO1:NPY gene" GraphId="e7453" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="745.0" CenterY="892.0" Width="64.0" Height="34.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9622979" /> </DataNode> <DataNode TextLabel="FOXO6 " GraphId="e75a2" Type="Protein" GroupRef="a30a9"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623250" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="1549.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="A8MYZ6" /> </DataNode> <DataNode TextLabel="AGRP gene " GraphId="e7ad6" Type="Protein" GroupRef="eb090"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623048" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1849.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000159723" /> </DataNode> <DataNode TextLabel="GCK gene" GraphId="e7ba7" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="509.5" CenterY="706.5" Width="45.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000106633" /> </DataNode> <DataNode TextLabel="FOXO6" GraphId="e8afe" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1220.5" CenterY="270.0" Width="49.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="A8MYZ6" /> </DataNode> <DataNode TextLabel="CORT " GraphId="e8d8e" Type="Metabolite" GroupRef="d04a5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-879850" /> <Attribute Key="copies_num" Value="122" /> <Graphics CenterX="520.0" CenterY="1729.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:17650" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="e8f13" Type="Protein" GroupRef="db5b3"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625735" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1789.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO4 " GraphId="e92b3" Type="Protein" GroupRef="de359"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623256" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="1469.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P98177" /> </DataNode> <DataNode TextLabel="ATXN3" GraphId="e93e8" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="976.0" CenterY="541.0" Width="50.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54252" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="e9fc8" Type="Protein" GroupRef="de359"> <BiopaxRef>e57</BiopaxRef> <BiopaxRef>bf0</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623256" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="1429.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="ABCA6 gene" GraphId="ea5ca" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1449.5" CenterY="301.5" Width="83.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000154262" /> </DataNode> <DataNode TextLabel="PLXNA4" GraphId="eb384" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="1446.5" CenterY="42.0" Width="55.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HCM2" /> </DataNode> <DataNode TextLabel="SMAD4 " GraphId="eb6eb" Type="Protein" GroupRef="ea550"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625757" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1369.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13485" /> </DataNode> <DataNode TextLabel="RETN" GraphId="ec49c" Type="Protein"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="752.0" CenterY="1142.0" Width="42.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HD89" /> </DataNode> <DataNode TextLabel="NPY gene" GraphId="ec6b9" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="608.0" CenterY="896.5" Width="66.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000122585" /> </DataNode> <DataNode TextLabel="FOXO1,FOXO3" GraphId="ec93e" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1414.0" CenterY="366.0" Width="62.0" Height="32.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9614686" /> </DataNode> <DataNode TextLabel="p-S465,S467-SMAD2 " GraphId="ece3d" Type="Protein" GroupRef="ea550"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625757" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="660.0" CenterY="1389.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15796" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="ed3c1" Type="Protein" GroupRef="debc3"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625827" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1489.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="FOXO1 " GraphId="ed7f9" Type="Protein" GroupRef="a99fa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9624643" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1669.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12778" /> </DataNode> <DataNode TextLabel="PCK1" GraphId="ed849" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="342.0" CenterY="359.0" Width="48.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P35558" /> </DataNode> <DataNode TextLabel="FOXO3,FOXO6,(FOXO1):CAT gene" GraphId="ed9db" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1467.0" CenterY="822.5" Width="120.0" Height="33.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9622806" /> </DataNode> <DataNode TextLabel="FOXO1:NR3C1:(ALDO,11DCORST,CORST,CORT):TRIM63 gene" GraphId="eda50" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1319.5" CenterY="775.5" Width="119.0" Height="61.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9625735" /> </DataNode> <DataNode TextLabel="FOXO4 " GraphId="ee325" Type="Protein" GroupRef="a99fa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9624643" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="380.0" CenterY="1709.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P98177" /> </DataNode> <DataNode TextLabel="RETN gene" GraphId="eef37" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="711.0" CenterY="952.5" Width="44.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000104918" /> </DataNode> <DataNode TextLabel="TRIM63 gene " GraphId="ef720" Type="Protein" GroupRef="ea550"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625757" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="1429.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000158022" /> </DataNode> <DataNode TextLabel="FOXO3 " GraphId="efe18" Type="Protein" GroupRef="a7705"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9614686" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1809.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43524" /> </DataNode> <DataNode TextLabel="FOXO4 " GraphId="f0169" Type="Protein" GroupRef="f4366"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9623423" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1409.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P98177" /> </DataNode> <DataNode TextLabel="FOXO6 " GraphId="f15db" Type="Protein" GroupRef="e13d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9622805" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1549.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="A8MYZ6" /> </DataNode> <DataNode TextLabel="FOXO3 " GraphId="f2099" Type="Protein" GroupRef="fa059"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9617974" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1449.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43524" /> </DataNode> <DataNode TextLabel="FOXO1,FOXO1:PPARGC1A,FOXO3,FOXO4,FOXO6" GraphId="f24f7" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1006.5" CenterY="417.5" Width="165.0" Height="29.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9623256" /> </DataNode> <DataNode TextLabel="FOXO1,FOXO3,FOXO4" GraphId="f2f93" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1082.5" CenterY="303.0" Width="97.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9617987" /> </DataNode> <DataNode TextLabel="FOXO3 " GraphId="f32a8" Type="Protein" GroupRef="b1c9f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-9625082" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1249.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43524" /> </DataNode> <DataNode TextLabel="FOXO1:AGRP gene" GraphId="f353a" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="978.5" CenterY="907.5" Width="75.0" Height="37.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9623048" /> </DataNode> <DataNode TextLabel="FOXO4:ATXN3" GraphId="f399d" Type="Complex"> <BiopaxRef>a6c</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="801.0" CenterY="489.0" Width="94.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-9617923" /> </DataNode> <DataNode 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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.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1311.0" Y="264.0" /> <Point X="1314.0" Y="179.0" /> <Anchor Position="0.0" Shape="None" GraphId="fba05" /> <Anchor Position="0.99" Shape="None" GraphId="aa6b2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9615015" /> </Interaction> <Interaction GraphId="aaf82"> <Comment Source="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).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="548.0" Y="564.0" /> <Point X="517.0" Y="417.0" /> <Anchor Position="0.0" Shape="None" GraphId="bc123" /> <Anchor Position="0.99" Shape="None" GraphId="da2b4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625324" /> </Interaction> <Interaction GraphId="ab112"> <Comment Source="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). 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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). </Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1405.0" Y="275.0" /> <Point X="1446.0" Y="56.0" /> <Anchor Position="0.0" Shape="None" GraphId="c57bd" /> <Anchor Position="0.99" Shape="None" GraphId="cd396" /> <Anchor Position="0.5" Shape="None" GraphId="d179a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9615023" /> </Interaction> <Interaction GraphId="afbdb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1176.0" Y="956.0" GraphRef="b213f" RelX="-1.0" RelY="0.0" /> <Point X="1124.0" Y="972.0" GraphRef="a2270" RelX="-0.5" RelY="-65.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623072" /> </Interaction> <Interaction GraphId="b1f13"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="951.0" Y="541.0" GraphRef="e93e8" RelX="-1.0" RelY="0.0" /> <Point X="938.0" Y="511.0" GraphRef="f8639" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9617927" /> </Interaction> <Interaction GraphId="b4b53"> <Comment Source="Reactome">Based on studies in mice, FOXO1 binds the promoter of the RESTN gene, encoding resistin (Liu et al. 2014).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="794.0" Y="906.0" /> <Point X="803.0" Y="969.0" /> <Anchor Position="0.0" Shape="None" GraphId="ad1b1" /> <Anchor Position="0.99" Shape="None" GraphId="a80d2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625828" /> </Interaction> <Interaction GraphId="b5142"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1416.0" Y="462.0" GraphRef="ffbdb" RelX="0.0" RelY="0.9607843137254902" /> <Point X="1467.0" Y="515.0" GraphRef="f969c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624611" /> </Interaction> <Interaction GraphId="b5632"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="736.0" Y="170.0" GraphRef="aceb6" RelX="1.0" RelY="-0.02040816326530612" /> <Point X="651.0" Y="242.0" GraphRef="fd860" RelX="28.5" RelY="-18.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623192" /> </Interaction> <Interaction GraphId="b676d"> <Comment Source="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. 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FOXO1 binding interferes with recruitment of SREBF1 transcriptional activator NR1H3 (LXRA) to the SREBF1 promoter (Liu et al. 2010). 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<Interaction GraphId="bc442"> <Comment Source="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).&lt;br&gt;FOXO3 (Hall et al. 2000) and FOXO4 (Yang et al. 2002) also directly stimulates PCK1 gene transcription .</Comment> <BiopaxRef>a73</BiopaxRef> <BiopaxRef>a95</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="750.0" Y="353.0" /> <Point X="369.0" Y="358.0" /> <Anchor Position="0.0" Shape="None" GraphId="acabf" /> <Anchor Position="0.99" Shape="None" GraphId="a283b" /> <Anchor Position="0.5" Shape="None" GraphId="ad9ca" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623280" /> </Interaction> <Interaction GraphId="bd956"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1458.0" Y="1049.0" GraphRef="e81b8" RelX="3.5" RelY="2.599999999999909" /> 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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.</Comment> <BiopaxRef>fa9</BiopaxRef> <BiopaxRef>eb3</BiopaxRef> <BiopaxRef>a73</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="867.0" Y="229.0" /> <Point X="739.0" Y="194.0" /> <Anchor Position="0.0" Shape="None" GraphId="e9d9e" /> <Anchor Position="0.99" Shape="None" GraphId="c0608" /> <Anchor Position="0.5" Shape="None" GraphId="f6410" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623168" /> </Interaction> <Interaction GraphId="c2417"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1180.0" Y="868.0" GraphRef="d0878" RelX="0.9809523809523809" RelY="0.0" /> <Point X="1210.0" Y="847.0" GraphRef="bc01e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625749" /> </Interaction> <Interaction GraphId="c367d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="517.0" Y="417.0" GraphRef="da2b4" RelX="-0.30999999999994543" RelY="-1.4700000000000273" /> <Point X="511.0" Y="413.0" GraphRef="fe5a8" RelX="-0.012048192771084338" RelY="0.9393939393939394" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625324" /> </Interaction> <Interaction GraphId="c3a7e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="785.0" Y="615.0" GraphRef="a4166" RelX="0.9746835443037974" RelY="-0.0196078431372549" /> <Point X="807.0" Y="641.0" GraphRef="a71eb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9617972" /> </Interaction> <Interaction GraphId="c3ddb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1499.0" Y="745.0" GraphRef="d3f80" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="1455.0" Y="725.0" GraphRef="e00e3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9622737" /> </Interaction> <Interaction GraphId="c3fa1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1527.0" Y="822.0" GraphRef="ed9db" RelX="1.0" RelY="-0.030303030303030304" /> <Point X="1575.0" Y="848.0" GraphRef="f66f7" RelX="-12.5" RelY="-37.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9622738" /> </Interaction> <Interaction GraphId="c4538"> <Comment Source="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). 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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).&lt;br&gt;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.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1108.0" Y="789.0" /> <Point X="1458.0" Y="1049.0" /> <Anchor Position="0.0" Shape="None" GraphId="dd6fb" /> <Anchor Position="0.99" Shape="None" GraphId="e81b8" /> <Anchor Position="0.5" Shape="None" GraphId="cadc3" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625693" /> </Interaction> <Interaction GraphId="d0203"> <Comment Source="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).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1047.0" Y="892.0" /> <Point X="1173.0" Y="943.0" /> <Anchor Position="0.0" Shape="None" GraphId="f333f" /> <Anchor Position="0.99" Shape="None" GraphId="cc04f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623059" /> </Interaction> <Interaction GraphId="d2e62"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="740.0" Y="376.0" GraphRef="cbf3b" RelX="0.9726027397260274" RelY="-0.0196078431372549" /> <Point X="749.0" Y="337.0" GraphRef="d272a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623281" /> </Interaction> <Interaction GraphId="d3c90"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="746.0" Y="590.0" GraphRef="a4166" RelX="-0.012658227848101266" RelY="-1.0" /> <Point X="783.0" Y="540.0" GraphRef="b2652" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9617832" /> </Interaction> <Interaction GraphId="d3e14"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1257.0" Y="767.0" GraphRef="b9c91" RelX="2.5599999999999454" RelY="0.2300000000000182" /> <Point X="1260.0" Y="775.0" GraphRef="eda50" RelX="-1.0" RelY="-0.01639344262295082" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625699" /> </Interaction> <Interaction GraphId="d4807"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="962.0" Y="767.0" GraphRef="ae8ee" RelX="-0.008403361344537815" RelY="-1.0" /> <Point X="1001.0" Y="744.0" GraphRef="aa673" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625699" /> </Interaction> <Interaction GraphId="d4da6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="924.0" Y="417.0" GraphRef="f24f7" RelX="-1.0" RelY="-0.034482758620689655" /> <Point X="867.0" Y="229.0" GraphRef="e9d9e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623168" /> </Interaction> <Interaction GraphId="d6a32"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="771.0" Y="989.0" GraphRef="ff1a6" RelX="-1.0" RelY="-0.02857142857142857" /> <Point X="735.0" Y="998.0" GraphRef="b5d2a" RelX="-11.0" RelY="-30.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625863" /> </Interaction> <Interaction GraphId="d6e10"> <Comment Source="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). 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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).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1454.0" Y="414.0" /> <Point X="1902.0" Y="380.0" /> <Anchor Position="0.0" Shape="None" GraphId="f1bd2" /> <Anchor Position="0.99" Shape="None" GraphId="ee475" /> <Anchor Position="0.5" Shape="None" GraphId="d9ae5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624624" /> </Interaction> <Interaction GraphId="d8efb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="531.0" Y="706.0" GraphRef="e7ba7" RelX="0.9555555555555556" RelY="-0.0196078431372549" /> <Point X="621.0" Y="757.0" GraphRef="f4d38" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625101" /> </Interaction> <Interaction GraphId="d9bbb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1099.0" Y="812.0" GraphRef="b554d" RelX="1.0" 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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. 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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. 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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).&lt;br&gt;FOXO3 (Hall et al. 2000) and FOXO4 (Yang et al. 2002) also bind the promoter of the PCK1 gene.</Comment> <BiopaxRef>a73</BiopaxRef> <BiopaxRef>a95</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="749.0" Y="337.0" /> <Point X="697.0" Y="314.0" /> <Anchor Position="0.0" Shape="None" GraphId="d272a" /> <Anchor Position="0.99" Shape="None" GraphId="c2037" /> <Anchor Position="0.5" Shape="None" GraphId="d0ca9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623281" /> </Interaction> <Interaction GraphId="f87c1"> <Comment Source="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.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1467.0" Y="515.0" /> <Point X="1547.0" Y="507.0" /> <Anchor Position="0.0" Shape="None" GraphId="f969c" /> <Anchor Position="0.99" Shape="None" GraphId="c8dc9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9624611" /> </Interaction> <Interaction GraphId="f9106"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="966.0" Y="693.0" GraphRef="c6eea" RelX="1.5900000000000318" RelY="0.5199999999999818" /> <Point X="963.0" Y="714.0" GraphRef="bac67" RelX="-1.0" RelY="-0.02702702702702703" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9617972" /> </Interaction> <Interaction GraphId="faa89"> <Comment Source="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). </Comment> <BiopaxRef>e59</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="807.0" Y="641.0" /> <Point X="966.0" Y="693.0" /> <Anchor Position="0.0" Shape="None" GraphId="a71eb" /> <Anchor Position="0.99" Shape="None" GraphId="c6eea" /> <Anchor Position="0.5" Shape="None" GraphId="ca737" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9617972" /> </Interaction> <Interaction GraphId="fadc8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="513.0" Y="499.0" GraphRef="d9355" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="522.0" Y="476.0" GraphRef="f3d14" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625346" /> </Interaction> <Interaction GraphId="fb980"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="733.0" Y="952.0" GraphRef="eef37" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="742.0" Y="929.0" GraphRef="a8a27" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625863" /> </Interaction> <Interaction GraphId="fc642"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="623.0" Y="681.0" GraphRef="b8e45" RelX="0.0" RelY="-1.0" /> <Point X="567.0" Y="423.0" GraphRef="b3d84" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9623240" /> </Interaction> <Interaction GraphId="fd740"> <Comment Source="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). 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Catalase converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress. 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Onuma H, Vander Kooi BT, Boustead JN, Oeser JK, O'Brien RM.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c13"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">24920680</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bollinger LM, Witczak CA, Houmard JA, Brault JJ.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c62"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">26700816</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liao L, Su X, Yang X, Hu C, Li B, Lv Y, Shuai Y, Jing H, Deng Z, Jin Y.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="a63"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">20921137</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy.</bp:TITLE> <bp:AUTHORS 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rdf:id="de7"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">27869526</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PGC-1α over-expression suppresses the skeletal muscle atrophy and myofiber-type composition during hindlimb unloading.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang J, Wang F, Zhang P, Liu H, He J, Zhang C, Fan M, Chen X.</bp:AUTHORS> </bp:PublicationXref> <bp:openControlledVocabulary xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#"> <bp:TERM xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">forkhead class O signaling pathway</bp:TERM> <bp:ID xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PW:0000717</bp:ID> <bp:Ontology xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pathway Ontology</bp:Ontology> </bp:openControlledVocabulary> </Biopax> </Pathway>

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