Circadian Clock (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Circadian Clock" Data-Source="Reactome - http://www.reactome.org" Version="54" Author="May, Bruce" Maintainer="May, Bruce" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning. &lt;br&gt;Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA (NR1D1), both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha (RORA) activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1. &lt;br&gt;BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening. &lt;br&gt;PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.&lt;br&gt;The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients. View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=400253 Reactome].</Comment> <BiopaxRef>c0c</BiopaxRef> <BiopaxRef>b41</BiopaxRef> <BiopaxRef>f84</BiopaxRef> <BiopaxRef>f8b</BiopaxRef> <Attribute Key="reactome_id" Value="400253" /> <Graphics BoardWidth="1832.0" BoardHeight="2131.0" /> <DataNode TextLabel="ARNTL" GraphId="c8dac" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="90.5" CenterY="183.5" Width="91.0" Height="21.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="NR1D1" GraphId="bca4b" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="610.0" CenterY="900.5" Width="64.0" Height="25.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P20393" /> </DataNode> <DataNode TextLabel="CLOCK,NPAS2" GraphId="c8767" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="624.5" CenterY="217.5" Width="103.0" Height="25.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-400343" /> </DataNode> <DataNode TextLabel="CLOCK " GraphId="ed810" Type="Protein" GroupRef="a84ce"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400343" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1371.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="NPAS2 " GraphId="b28b1" Type="Protein" GroupRef="a84ce"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400343" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1391.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="BMAL1:CLOCK,NPAS2" GraphId="ef414" Type="Complex"> <Comment Source="Reactome">BMAL1 (ARNTL) contains both a nuclear localization signal and a nuclear export signal. The shuttling of BMAL1 between the nucleus and cytoplasm is important for transactivation by BMAL1:CLOCK/NPAS2 and degradation of BMAL1:CLOCK/NPAS2. BMAL1 initially forms a heterodimer with CLOCK or NPAS2 in the cytosol. The heterodimer is then phosphorylated and translocated into the nucleus.</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="908.5" CenterY="227.0" Width="153.0" Height="26.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-400360" /> </DataNode> <DataNode TextLabel="CLOCK " GraphId="da866" Type="Protein" GroupRef="b8f20"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400360" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1451.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="NPAS2 " GraphId="d898b" Type="Protein" GroupRef="b8f20"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400360" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1471.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="ARNTL " GraphId="f9ce6" Type="Protein" GroupRef="b8f20"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400360" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1491.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2" GraphId="d5535" Type="Complex"> <BiopaxRef>bc8</BiopaxRef> <BiopaxRef>f17</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1090.5" CenterY="751.0" Width="195.0" Height="26.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-421315" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="e2029" Type="Protein" GroupRef="c6038"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-421315" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1551.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="cb152" Type="Protein" GroupRef="c6038"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-421315" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1571.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="b55a4" Type="Protein" GroupRef="c6038"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-421315" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1591.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="CRY1" GraphId="b38ba" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1266.0" CenterY="190.0" Width="62.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16526" /> </DataNode> <DataNode TextLabel="CRY2" GraphId="ad510" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1200.0" CenterY="158.5" Width="68.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q49AN0" /> </DataNode> <DataNode TextLabel="PER1" GraphId="d89d7" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1334.0" CenterY="218.0" Width="60.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15534" /> </DataNode> <DataNode TextLabel="PER2" GraphId="c7206" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1409.0" CenterY="235.5" Width="58.0" Height="27.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15055" /> </DataNode> <DataNode TextLabel="CRY1,2" GraphId="a901a" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1561.5" CenterY="172.5" Width="79.0" Height="21.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-400223" /> </DataNode> <DataNode TextLabel="CRY1 " GraphId="d26ab" Type="Protein" GroupRef="ead46"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400223" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1651.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16526" /> </DataNode> <DataNode TextLabel="CRY2 " GraphId="f3c02" Type="Protein" GroupRef="ead46"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-400223" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1671.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q49AN0" /> </DataNode> <DataNode TextLabel="BMAL1:CLOCK,NPAS2:CRY" GraphId="e4b6c" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1690.5" CenterY="107.5" Width="179.0" Height="27.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-549449" /> </DataNode> <DataNode TextLabel="CLOCK " GraphId="aeb29" Type="Protein" GroupRef="cae36"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-549449" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1731.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="NPAS2 " GraphId="a1a49" Type="Protein" GroupRef="cae36"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-549449" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1751.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="ARNTL " GraphId="c17b2" Type="Protein" GroupRef="cae36"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-549449" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1771.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="CRY1 " GraphId="f519e" Type="Protein" GroupRef="cae36"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-549449" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1791.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16526" /> </DataNode> <DataNode TextLabel="CRY2 " GraphId="e7d5b" Type="Protein" GroupRef="cae36"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-549449" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1811.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q49AN0" /> </DataNode> <DataNode TextLabel="CRY:PER:Kinase" GraphId="e0647" Type="Complex"> <Comment Source="Reactome">As inferred from mouse, PER proteins can form homodimers and CRY proteins can form heterodimers with PER proteins. CRY and PER proteins may therefore form trimers (PER:PER:CRY).</Comment> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1619.0" CenterY="715.0" Width="138.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-421287" /> </DataNode> <DataNode TextLabel="CRY1 " GraphId="f732b" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1871.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16526" /> </DataNode> <DataNode TextLabel="CRY2 " GraphId="a7e73" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1891.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q49AN0" /> </DataNode> <DataNode TextLabel="PER1 " GraphId="f69fe" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1911.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15534" /> </DataNode> <DataNode TextLabel="PER2 " GraphId="cec96" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1931.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15055" /> </DataNode> <DataNode TextLabel="CSNK1E " GraphId="ce2c8" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1951.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49674" /> </DataNode> <DataNode TextLabel="CSNK1D " GraphId="d03ed" Type="Protein" GroupRef="fce63"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421287" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1971.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48730" /> </DataNode> <DataNode TextLabel="p-CRY:p-PER:Kinase" GraphId="c58a2" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1694.0" CenterY="985.5" Width="146.0" Height="25.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-421296" /> </DataNode> <DataNode TextLabel="p-S-CRY1 " GraphId="a7996" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1371.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16526" /> </DataNode> <DataNode TextLabel="p-S-CRY2 " GraphId="f5759" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1391.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q49AN0" /> </DataNode> <DataNode TextLabel="p-S-PER1 " GraphId="f99b9" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="240.0" CenterY="1411.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15534" /> </DataNode> <DataNode TextLabel="p-S-PER2 " GraphId="ab698" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="240.0" CenterY="1431.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15055" /> </DataNode> <DataNode TextLabel="CSNK1E " GraphId="b2d8f" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="240.0" CenterY="1451.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49674" /> </DataNode> <DataNode TextLabel="CSNK1D " GraphId="fcd20" Type="Protein" GroupRef="ab1a2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421296" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="240.0" CenterY="1471.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48730" /> </DataNode> <DataNode TextLabel="CSNK1E,CSNK1D" GraphId="f701f" Type="Complex"> <BiopaxRef>e27</BiopaxRef> <BiopaxRef>f94</BiopaxRef> <BiopaxRef>ca3</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1719.0" CenterY="496.5" Width="112.0" Height="27.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-421289" /> </DataNode> <DataNode TextLabel="CSNK1E " GraphId="aa93e" Type="Protein" GroupRef="fe085"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421289" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1531.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49674" /> </DataNode> <DataNode TextLabel="CSNK1D " GraphId="fd1ff" Type="Protein" GroupRef="fe085"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-421289" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="240.0" CenterY="1551.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48730" /> </DataNode> <DataNode TextLabel="p-CRY:p-PER:Kinase" GraphId="fa720" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1253.5" CenterY="902.5" Width="147.0" 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Database="Uniprot-TrEMBL" ID="P62987" /> </DataNode> <DataNode TextLabel="UBB(1-76) " GraphId="fab7b" Type="Protein" GroupRef="cb100"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-68524" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1591.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="UBB(77-152) " GraphId="dfbf2" Type="Protein" GroupRef="cb100"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-68524" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1611.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="UBB(153-228) " GraphId="d15a7" Type="Protein" GroupRef="cb100"> <Attribute Key="cellular_location" 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Database="Uniprot-TrEMBL" ID="O15379" /> </DataNode> <DataNode TextLabel="NCOR1" GraphId="dbfb7" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="452.5" CenterY="962.0" Width="65.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75376" /> </DataNode> <DataNode TextLabel="EP300" GraphId="a58b9" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="700.5" CenterY="639.0" Width="51.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q09472" /> </DataNode> <DataNode TextLabel="PPARGC1A" GraphId="f1d11" Type="Protein"> <BiopaxRef>f83</BiopaxRef> <BiopaxRef>c2d</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="129.0" CenterY="764.0" Width="78.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="CLOCK" GraphId="b05e9" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="329.5" CenterY="218.0" Width="49.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-T69,T71-ATF2" GraphId="e23bf" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="118.5" CenterY="896.0" Width="121.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P15336" /> </DataNode> <DataNode TextLabel="p-S133-CREB1" GraphId="d75b8" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="113.0" CenterY="950.0" Width="110.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16220" /> </DataNode> <DataNode TextLabel="MEF2C,D:PPARGC1A" GraphId="a3a10" Type="Complex"> <Attribute 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Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q14814" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="fadc9" Type="Protein" GroupRef="bed3c"> <BiopaxRef>f83</BiopaxRef> <BiopaxRef>c2d</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-1605560" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1411.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="p-PPARGC1A" GraphId="d973f" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="112.5" CenterY="923.0" Width="95.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1592227" /> </DataNode> <DataNode TextLabel="p-T178,S539-PPARGC1A " GraphId="d505c" Type="Protein" GroupRef="ed9e8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-1592227" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1491.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="p-T263,S266,T299-PPARGC1A " GraphId="ee23c" Type="Protein" GroupRef="ed9e8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-1592227" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1531.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="HIF1A" GraphId="e648d" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="771.5" CenterY="563.0" Width="43.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q16665" /> </DataNode> <DataNode TextLabel="PPARGC1A gene" GraphId="b6f4e" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="157.0" CenterY="1002.5" Width="110.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000109189" /> </DataNode> <DataNode TextLabel="RORA gene" GraphId="e1d0f" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="837.0" CenterY="615.5" Width="78.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000069667" /> </DataNode> <DataNode TextLabel="PP1 catalytic&#xA;subunit" GraphId="b3d9b" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1611.0" CenterY="810.0" Width="152.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-163538" /> </DataNode> <DataNode TextLabel="PPP1CA " GraphId="e8440" Type="Protein" GroupRef="dac71"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-163538" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1591.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62136" /> </DataNode> <DataNode TextLabel="PPP1CB " GraphId="be788" Type="Protein" GroupRef="dac71"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-163538" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1611.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62140" /> </DataNode> <DataNode TextLabel="PPP1CC " GraphId="b10fe" Type="Protein" GroupRef="dac71"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-163538" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1631.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P36873" /> </DataNode> <DataNode TextLabel="ARNTL gene" GraphId="e2bf9" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="106.5" CenterY="592.5" Width="83.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000133794" /> </DataNode> <DataNode TextLabel="SIRT1" GraphId="e8aa4" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="199.5" CenterY="328.0" Width="45.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96EB6" /> </DataNode> <DataNode TextLabel="CLOCK gene" GraphId="a329c" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="284.5" CenterY="585.5" Width="85.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000134852" /> </DataNode> <DataNode TextLabel="RAI1" GraphId="d805e" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="286.5" CenterY="297.0" Width="37.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q7Z5J4" /> </DataNode> <DataNode TextLabel="NPAS2 gene" GraphId="f0957" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="468.5" CenterY="585.5" Width="85.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170485" /> </DataNode> <DataNode TextLabel="PPARA:RXRA&#xA;Coactivator complex" GraphId="e57b7" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="595.5" CenterY="381.0" Width="89.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-400154" /> </DataNode> <DataNode TextLabel="CREBBP " GraphId="fe608" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1691.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q92793" /> </DataNode> <DataNode TextLabel="CARM1 " GraphId="fbefd" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1711.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q86X55" /> </DataNode> <DataNode TextLabel="MED1 " GraphId="f66fd" Type="Protein" GroupRef="db7b8"> <Comment Source="Reactome">MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.</Comment> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1731.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15648" /> </DataNode> <DataNode TextLabel="NCOA1 " GraphId="d67d7" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1751.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15788" /> </DataNode> <DataNode TextLabel="NCOA2 " GraphId="c704d" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1771.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15596" /> </DataNode> <DataNode TextLabel="NCOA6 " GraphId="dc6d6" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1791.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q14686" /> </DataNode> <DataNode TextLabel="HELZ2 " GraphId="bd4af" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1811.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9BYK8" /> </DataNode> <DataNode TextLabel="SMARCD3 " GraphId="e026a" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1831.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q6STE5" /> </DataNode> <DataNode TextLabel="TGS1 " GraphId="b8e90" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1851.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96RS0" /> </DataNode> <DataNode TextLabel="CHD9 " GraphId="fcb1c" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1871.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q3L8U1" /> </DataNode> <DataNode TextLabel="TBL1X " GraphId="c064a" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1891.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60907" /> </DataNode> <DataNode TextLabel="TBL1XR1 " GraphId="e9163" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1911.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9BZK7" /> </DataNode> <DataNode TextLabel="Peroxisome Proliferator Receptor Element (PPRE) " GraphId="f6015" GroupRef="db7b8"> <Comment Source="Reactome">Peroxisome proliferator receptor elements bind heterodimers containing a peroxisome proliferator receptor and a retinoic acid receptor. The consensus sequence is TGAMCTTTGNCCTAGWTYYG.</Comment> <BiopaxRef>ce0</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1951.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-NUL-422139" /> </DataNode> <DataNode TextLabel="ALA " GraphId="c959f" Type="Metabolite" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1971.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:27432" /> </DataNode> <DataNode TextLabel="AA " GraphId="ae177" Type="Metabolite" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1991.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15843" /> </DataNode> <DataNode TextLabel="EPA " GraphId="cac58" Type="Metabolite" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2011.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:28364" /> </DataNode> <DataNode TextLabel="LINA " GraphId="a0677" Type="Metabolite" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2031.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:17351" /> </DataNode> <DataNode TextLabel="Palm " GraphId="a32f1" Type="Metabolite" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2051.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15756" /> </DataNode> <DataNode TextLabel="PPARA " GraphId="a4c64" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2071.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q07869" /> </DataNode> <DataNode TextLabel="RXRA " GraphId="ffe72" Type="Protein" GroupRef="db7b8"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-400154" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2091.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P19793" /> </DataNode> <DataNode TextLabel="BMAL1:CLOCK,NPAS2&#xA;activates circadian&#xA;gene expression" GraphId="b7c2f" Type="Pathway"> <Comment Source="Reactome">As inferred from mouse, BMAL1:CLOCK (ARNTL:CLOCK) and BMAL1:NPAS2 (ARNTL:NPAS2) heterodimers bind to sequence elements (E boxes) in the promoters of target genes and enhance transcription (Gekakis et al. 1998, reviewed in Munoz and Baler 2003).</Comment> <BiopaxRef>eae</BiopaxRef> <BiopaxRef>b15</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="1336.5" CenterY="741.0" Width="231.0" Height="66.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-1368108" /> </DataNode> <DataNode TextLabel="CRY1 gene" GraphId="fe449" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1103.0" CenterY="612.5" Width="90.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000008405" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2:CRY1 gene" GraphId="a4e13" Type="Complex"> <BiopaxRef>d09</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1087.5" CenterY="485.0" Width="113.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663148" /> </DataNode> <DataNode TextLabel="CRY1 gene " GraphId="c01f9" Type="Protein" GroupRef="ee912"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663148" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1371.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000008405" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="cafc7" Type="Protein" GroupRef="ee912"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663148" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1391.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="f2834" Type="Protein" GroupRef="ee912"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663148" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1411.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="bf109" Type="Protein" GroupRef="ee912"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663148" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1431.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="CRY2 gene" GraphId="b91f7" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1043.0" CenterY="391.5" Width="90.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000121671" /> </DataNode> <DataNode TextLabel="PER1 gene" GraphId="e8275" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1270.0" CenterY="618.5" Width="90.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000179094" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2:PER1 gene" GraphId="ace38" Type="Complex"> <BiopaxRef>fae</BiopaxRef> <BiopaxRef>bc2</BiopaxRef> <BiopaxRef>c68</BiopaxRef> <BiopaxRef>f4a</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1255.5" CenterY="488.0" Width="113.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663110" /> </DataNode> <DataNode TextLabel="PER1 gene " GraphId="f981e" Type="Protein" GroupRef="ae9e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663110" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1491.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000179094" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="edfe9" Type="Protein" GroupRef="ae9e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663110" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1511.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="a81c6" Type="Protein" GroupRef="ae9e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663110" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1531.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="fa417" Type="Protein" GroupRef="ae9e4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663110" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1551.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="p-CREB:CRTC1:PER1&#xA;gene" GraphId="b5abc" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1232.0" CenterY="351.0" Width="116.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5656495" /> </DataNode> <DataNode TextLabel="CRTC1 " GraphId="ed1fd" Type="Protein" GroupRef="f665b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5656495" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1611.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q6UUV9" /> </DataNode> <DataNode TextLabel="p-S133-CREB1 " GraphId="c37a4" Type="Protein" GroupRef="f665b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5656495" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1631.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16220" /> </DataNode> <DataNode TextLabel="PER1 gene " GraphId="ec90f" Type="Protein" GroupRef="f665b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5656495" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1651.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000179094" /> </DataNode> <DataNode TextLabel="SIK1" GraphId="f686c" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1254.5" CenterY="399.0" Width="41.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P57059" /> </DataNode> <DataNode TextLabel="PER2 gene" GraphId="c99ba" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1421.5" CenterY="619.5" Width="91.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000132326" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2:PER2 gene" GraphId="f2ca5" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1408.0" CenterY="487.0" Width="114.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663176" /> </DataNode> <DataNode TextLabel="PER2 gene " GraphId="de47b" Type="Protein" GroupRef="e1c4f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663176" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1711.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000132326" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="b271d" Type="Protein" GroupRef="e1c4f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663176" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1731.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="c42eb" Type="Protein" GroupRef="e1c4f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663176" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1751.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="bf64c" Type="Protein" GroupRef="e1c4f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663176" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1771.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="NR3C1:Dexamethasone" GraphId="bd4bf" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1385.5" CenterY="362.5" Width="77.0" Height="47.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-879850" /> </DataNode> <DataNode TextLabel="NR3C1 " GraphId="f76b6" Type="Protein" GroupRef="effcb"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-879850" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1831.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P04150" /> </DataNode> <DataNode TextLabel="DEXA " GraphId="c1883" Type="Metabolite" GroupRef="effcb"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-879850" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1851.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:41879" /> </DataNode> <DataNode TextLabel="NR1D1 gene" GraphId="d4a3c" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="881.5" CenterY="858.5" Width="101.0" Height="51.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000126368" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2:NR1D1 gene" GraphId="e8a26" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="924.0" CenterY="917.0" Width="192.0" Height="32.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663173" /> </DataNode> <DataNode TextLabel="NR1D1 gene " GraphId="b97b2" Type="Protein" GroupRef="ef997"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663173" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1911.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000126368" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="fd262" Type="Protein" GroupRef="ef997"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663173" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1931.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="dabb1" Type="Protein" GroupRef="ef997"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663173" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1951.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="c7c0d" Type="Protein" GroupRef="ef997"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663173" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1971.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <DataNode TextLabel="RORA:Coactivator:ARNTL gene" GraphId="ad4d8" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="161.5" CenterY="375.0" Width="89.0" Height="46.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663268" /> </DataNode> <DataNode TextLabel="RORA " GraphId="b11d6" Type="Protein" GroupRef="a7198"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663268" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1371.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P35398" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="b551b" Type="Protein" GroupRef="a7198"> <BiopaxRef>f83</BiopaxRef> <BiopaxRef>c2d</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663268" /> 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Database="Uniprot-TrEMBL" ID="P48552" /> </DataNode> <DataNode TextLabel="ARNTL gene " GraphId="cdb40" Type="Protein" GroupRef="a7198"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663268" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1451.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000133794" /> </DataNode> <DataNode TextLabel="NR1D1:heme:Corepressors:ARNTL gene" GraphId="e8c55" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="151.5" CenterY="447.0" Width="97.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663269" /> </DataNode> <DataNode TextLabel="ARNTL gene " GraphId="d965e" Type="Protein" GroupRef="eb6e5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" 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Type="Protein" GroupRef="ae002"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663272" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1731.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000109189" /> </DataNode> <DataNode TextLabel="NR1D1:heme:Corepressors:CLOCK gene" GraphId="e9824" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="385.5" CenterY="434.0" Width="97.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663248" /> </DataNode> <DataNode TextLabel="NR1D1 " GraphId="e084c" Type="Protein" GroupRef="f97b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663248" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1791.0" 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GraphId="ed853" Type="Protein" GroupRef="f97b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663248" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1851.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75376" /> </DataNode> <DataNode TextLabel="CLOCK gene " GraphId="afd5b" Type="Protein" GroupRef="f97b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663248" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1871.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000134852" /> </DataNode> <DataNode TextLabel="RORA:EP300:NPAS2&#xA;gene" GraphId="de8db" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="609.5" CenterY="312.0" Width="95.0" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663257" /> </DataNode> <DataNode TextLabel="NPAS2 gene " GraphId="f4a7a" Type="Protein" GroupRef="d56d2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663257" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1371.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170485" /> </DataNode> <DataNode TextLabel="EP300 " GraphId="f1c20" Type="Protein" GroupRef="d56d2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663257" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1391.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q09472" /> </DataNode> <DataNode TextLabel="RORA " GraphId="d273d" Type="Protein" GroupRef="d56d2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663257" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1411.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P35398" /> </DataNode> <DataNode TextLabel="NR1D1:heme:Corepressors:NPAS2 gene" GraphId="a4ec9" Type="Complex"> <BiopaxRef>d90</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="576.5" CenterY="457.0" Width="97.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663274" /> </DataNode> <DataNode TextLabel="NR1D1 " GraphId="ba800" Type="Protein" GroupRef="de41b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663274" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1471.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P20393" /> </DataNode> <DataNode TextLabel="ferriheme b " GraphId="aa093" Type="Metabolite" GroupRef="de41b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663274" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1491.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:36144" /> </DataNode> <DataNode TextLabel="HDAC3 " GraphId="a681a" Type="Protein" GroupRef="de41b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663274" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1511.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15379" /> </DataNode> <DataNode TextLabel="NCOR1 " GraphId="df7fb" Type="Protein" GroupRef="de41b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663274" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1531.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75376" /> </DataNode> <DataNode TextLabel="NPAS2 gene " GraphId="ff2fe" Type="Protein" GroupRef="de41b"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663274" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1551.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170485" /> </DataNode> <DataNode TextLabel="RORA:Coactivator:NR1D1 gene" GraphId="c4186" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="771.5" CenterY="810.0" Width="121.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663260" /> </DataNode> <DataNode TextLabel="NR1D1 gene " GraphId="f087f" Type="Protein" GroupRef="af6d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663260" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1611.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000126368" /> </DataNode> <DataNode TextLabel="RORA " GraphId="e2ec7" Type="Protein" GroupRef="af6d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663260" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1631.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P35398" /> </DataNode> <DataNode TextLabel="PPARGC1A " GraphId="b13e9" Type="Protein" GroupRef="af6d4"> <BiopaxRef>f83</BiopaxRef> <BiopaxRef>c2d</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663260" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1651.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBK2" /> </DataNode> <DataNode TextLabel="EP300 " GraphId="f3f8f" Type="Protein" GroupRef="af6d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663260" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1671.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q09472" /> </DataNode> <DataNode TextLabel="NRIP1 " GraphId="d8b0a" Type="Protein" GroupRef="af6d4"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663260" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1691.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48552" /> </DataNode> <DataNode TextLabel="NR1D1:heme:Corepressors:NR1D1 gene" GraphId="b736b" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="706.5" CenterY="859.5" Width="107.0" Height="45.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5663262" /> </DataNode> <DataNode TextLabel="NR1D1 gene " GraphId="e791f" Type="Protein" GroupRef="ec03e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663262" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1751.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000126368" /> </DataNode> <DataNode TextLabel="NR1D1 " GraphId="a7c40" Type="Protein" GroupRef="ec03e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663262" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1771.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P20393" /> </DataNode> <DataNode TextLabel="ferriheme b " GraphId="d3636" Type="Metabolite" GroupRef="ec03e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663262" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1791.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:36144" /> </DataNode> <DataNode TextLabel="HDAC3 " GraphId="ad798" Type="Protein" GroupRef="ec03e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663262" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1811.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15379" /> </DataNode> <DataNode TextLabel="NCOR1 " GraphId="e1e4b" Type="Protein" GroupRef="ec03e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5663262" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1831.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75376" /> </DataNode> <DataNode TextLabel="ferriheme b" GraphId="bc423" Type="Metabolite"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="604.5" CenterY="973.0" Width="89.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:36144" /> </DataNode> <DataNode TextLabel="RORA activates gene&#xA;expression" GraphId="f0ddc" Type="Pathway"> <Comment Source="Reactome">As inferred from mouse, RORA binds ROR elements (ROREs) in DNA and recruits the coactivators PPARGC1A (PGC-1alpha) and p300 (EP300, a histone acetylase) to activate transcription.</Comment> <BiopaxRef>b21</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="725.0" CenterY="721.0" Width="138.0" Height="58.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-1368082" /> </DataNode> <DataNode TextLabel="NR1D1 (REV-ERBA)&#xA;represses gene&#xA;expression" GraphId="fea1f" Type="Pathway"> <Comment Source="Reactome">REV-ERBA binds DNA elements very similar to those bound by the transcription activator RORA. RORAREV-ERBA bound to DNA and heme recruits the corepressors NCoR and HDAC3 to repress transcription. Thus REV-ERBA and RORA appear to compete to repress or activate genes, repectively.</Comment> <BiopaxRef>e83</BiopaxRef> <BiopaxRef>df9</BiopaxRef> <BiopaxRef>cd1</BiopaxRef> <BiopaxRef>bbb</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="349.5" CenterY="903.5" Width="209.0" Height="57.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-1368071" /> </DataNode> <DataNode TextLabel="NRIP1" GraphId="d51cf" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="698.5" CenterY="668.0" Width="55.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48552" /> </DataNode> <DataNode TextLabel="p-BMAL1:p-CLOCK,NPAS2:RORA gene" GraphId="e16f0" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="803.5" CenterY="657.0" Width="123.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5669290" /> </DataNode> <DataNode TextLabel="RORA gene " GraphId="ba467" Type="Protein" GroupRef="a84f2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5669290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1891.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000069667" /> </DataNode> <DataNode TextLabel="p-S-ARNTL " GraphId="da5e4" Type="Protein" GroupRef="a84f2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5669290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1911.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O00327" /> </DataNode> <DataNode TextLabel="p-S-CLOCK " GraphId="d4b39" Type="Protein" GroupRef="a84f2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5669290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1931.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15516" /> </DataNode> <DataNode TextLabel="p-S-NPAS2 " GraphId="e3691" Type="Protein" GroupRef="a84f2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5669290" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1951.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99743" /> </DataNode> <Interaction GraphId="fa0e2"> <Comment Source="Reactome">BMAL1 (ARNTL), CLOCK, and NPAS2 are basic helix-loop-helix transcription factors. In humans BMAL1 has been demonstrated to form a heterodimer with CLOCK. In mouse, BMAL1 can form a heterodimer with either CLOCK or NPAS2. By analogy with other basic helix-loop-helix proteins the basic domain binds DNA, in this case the E-box motif, and the helix-loop-helix domains interact to form the heterodimer. BMAL1 and CLOCK/NPAS2 are codependently phosphorylated by unknown kinases after dimerization. The phosphorylation enhances transactivation activity and is inhibited by PER:CRY complexes. Both CLOCK and NPAS2 are expressed in the suprachiasmatic nucleus of the hypothalamus and act redundantly there. The tissue distributions of CLOCK and NPAS2 do not entirely overlap, however. For example, NPAS2 but not CLOCK is found in forebrain.</Comment> <BiopaxRef>cb3</BiopaxRef> <BiopaxRef>b15</BiopaxRef> <BiopaxRef>f37</BiopaxRef> <BiopaxRef>a2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="778.0" Y="225.0" /> <Point X="829.0" Y="224.0" /> <Anchor Position="0.0" Shape="None" GraphId="cc6eb" /> <Anchor Position="0.99" Shape="None" GraphId="a373e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400228" /> </Interaction> <Interaction GraphId="c5924"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="675.0" Y="217.0" GraphRef="c8767" RelX="0.9805825242718447" RelY="-0.04" /> <Point X="778.0" Y="225.0" GraphRef="cc6eb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400228" /> </Interaction> <Interaction GraphId="df027"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="135.0" Y="183.0" GraphRef="c8dac" RelX="0.978021978021978" RelY="-0.047619047619047616" /> <Point X="778.0" Y="225.0" GraphRef="cc6eb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400228" /> </Interaction> <Interaction GraphId="ab7ac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="829.0" Y="224.0" GraphRef="a373e" RelX="0.5099999999999909" RelY="-0.009999999999990905" /> <Point X="832.0" Y="227.0" GraphRef="ef414" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400228" /> </Interaction> <Interaction GraphId="bbb1b"> <Comment Source="Reactome">As inferred from mouse, BMAL1 (ARNTL), CLOCK, and NPAS2 are phosphorylated by unknown kinases. The phosphorylation is dependent on the heterodimerization of BMAL1 with CLOCK or NPAS2. Phosphorylated BMAL1:CLOCK/NPAS2 is a much stronger transactivator of gene expression than is unphosphorylated BMAL1:CLOCK/NPAS2.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="908.0" Y="243.0" /> <Point X="1077.0" Y="735.0" /> <Anchor Position="0.0" Shape="None" GraphId="e406e" /> <Anchor Position="0.99" Shape="None" GraphId="b1def" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-421320" /> </Interaction> <Interaction GraphId="f8167"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="908.0" Y="240.0" GraphRef="ef414" RelX="-0.006535947712418301" RelY="1.0" /> <Point X="908.0" Y="243.0" GraphRef="e406e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-421320" /> </Interaction> <Interaction GraphId="c4b90"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1077.0" Y="735.0" GraphRef="b1def" RelX="1.6900000000000546" RelY="4.920000000000073" /> <Point X="1090.0" Y="738.0" GraphRef="d5535" RelX="-0.005128205128205128" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-421320" /> </Interaction> <Interaction GraphId="ca6a5"> <Comment Source="Reactome">CRY1 and CRY2 bind the unphosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and by homology the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer) and prolong its half-life. The unphosphorylated BMAL1:CLOCK heterodimer only weakly activates transcription and is therefore believed to competitively reduce transcription by phosphorylated BMAL1:CLOCK heterodimer. The complex of unphosphorylated BMAL1:CLOCK with CRY may contain additional components and may traffic into the nucleus.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1551.0" Y="112.0" /> <Point X="1598.0" Y="110.0" /> <Anchor Position="0.0" Shape="None" GraphId="e15bc" /> <Anchor Position="0.99" Shape="None" GraphId="fb5de" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549355" /> </Interaction> <Interaction GraphId="f84bb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="984.0" Y="227.0" GraphRef="ef414" RelX="0.9869281045751634" RelY="0.0" /> <Point X="1551.0" Y="112.0" GraphRef="e15bc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549355" /> </Interaction> <Interaction GraphId="edb4c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1561.0" Y="162.0" GraphRef="a901a" RelX="-0.012658227848101266" RelY="-1.0" /> <Point X="1551.0" Y="112.0" GraphRef="e15bc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549355" /> </Interaction> <Interaction GraphId="ef04e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1598.0" Y="110.0" GraphRef="fb5de" RelX="0.4700000000000273" RelY="-0.01999999999999602" /> <Point X="1601.0" Y="107.0" GraphRef="e4b6c" RelX="-1.0" RelY="-0.037037037037037035" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549355" /> </Interaction> <Interaction GraphId="bcf13"> <Comment Source="Reactome">In the cytosol the kinases CSNK1D (casein kinase I delta) and CSNK1E (casein kinase I epsilon) phosphorylate PER1, PER2, CRY1, and CRY2 at multiple sites. Evidence indicates that PER:CRY complexes form a stable ternary complex with either CSNK1E or CSNK1D. Both kinases are able to bind and phosphorylate PER proteins. CSNK1E has been shown to phosphorylate CRY proteins only when they are complexed with PER proteins.&lt;br&gt;PER proteins contain a nuclear localization sequence and a nuclear export sequence allowing their movement into and out of the nucleus. Phosphorylation is required for transit of PER:CRY:kinase complexes into the nucleus and for interaction of PER proteins with the ubiquitin-mediated degradation process in the cytoplasm.&lt;br&gt;A mutation at Serine662 of PER2 is responsible for familial advanced phase sleep syndrome, however the particular kinase responsible for phosphorylating Serine662 is unknown.</Comment> <BiopaxRef>bc2</BiopaxRef> <BiopaxRef>cdd</BiopaxRef> <BiopaxRef>a21</BiopaxRef> <BiopaxRef>afe</BiopaxRef> <BiopaxRef>e62</BiopaxRef> <BiopaxRef>e96</BiopaxRef> <BiopaxRef>f80</BiopaxRef> <BiopaxRef>afd</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1634.0" Y="729.0" /> <Point X="1695.0" Y="970.0" /> <Anchor Position="0.0" Shape="None" GraphId="e0730" /> <Anchor Position="0.99" Shape="None" GraphId="f23b6" /> <Anchor Position="0.5" Shape="None" GraphId="a9c24" /> <Anchor Position="0.5" Shape="None" GraphId="ca866" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400382" /> </Interaction> <Interaction GraphId="b4d40"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1619.0" Y="726.0" GraphRef="e0647" RelX="0.0" RelY="1.0" /> <Point X="1634.0" Y="729.0" GraphRef="e0730" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400382" /> </Interaction> <Interaction GraphId="e3865"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1695.0" Y="970.0" GraphRef="f23b6" RelX="0.6099999999999" RelY="2.409999999999968" /> <Point X="1694.0" Y="973.0" GraphRef="c58a2" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400382" /> </Interaction> <Interaction GraphId="f24eb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1663.0" Y="496.0" GraphRef="f701f" RelX="-1.0" RelY="-0.037037037037037035" /> <Point X="1720.0" Y="785.0" GraphRef="a9c24" RelX="55.5" RelY="-64.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400382" /> </Interaction> <Interaction GraphId="d2439"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1611.0" Y="799.0" GraphRef="b3d9b" RelX="0.0" RelY="-1.0" /> <Point X="1720.0" Y="785.0" GraphRef="ca866" RelX="55.5" RelY="-64.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400382" /> </Interaction> <Interaction GraphId="bf954"> <Comment Source="Reactome">The ternary complex containing phosphorylated CRY and PER proteins with a kinase (CSNK1D or CSNK1E) is translocated to the nucleus. Phosphorylation controls transfer to the nucleus and retention in the nucleus.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1618.0" Y="985.0" /> <Point X="1282.0" Y="918.0" /> <Anchor Position="0.0" Shape="None" GraphId="d2a15" /> <Anchor Position="0.99" Shape="None" GraphId="e2dbf" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549385" /> </Interaction> <Interaction GraphId="dc0eb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1621.0" Y="985.0" GraphRef="c58a2" RelX="-1.0" RelY="-0.04" /> <Point X="1618.0" Y="985.0" GraphRef="d2a15" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549385" /> </Interaction> <Interaction GraphId="dabdf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1282.0" Y="918.0" GraphRef="e2dbf" RelX="-3.3600000000001273" RelY="-0.6699999999999591" /> <Point X="1253.0" Y="914.0" GraphRef="fa720" RelX="-0.006802721088435374" RelY="0.92" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549385" /> </Interaction> <Interaction GraphId="cf176"> <Comment Source="Reactome">CRY (CRY1 and CRY2) and PER (PER1, PER2, PER3) proteins form complex in the cytoplasm where they are phosphorylated by CSNK1D and CSNK1E kinases. CRY:PER complexes appear to form stable complexes with a kinase. Because of the nuclear localization signals of PER and CRY, the complexes are translocated to the nucleus where they bind BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) heterodimers and inhibit the transactivation activity of BMAL1:CLOCK/NPAS2.&lt;br&gt;CRY and PER proteins are themselves transcriptionally activated by BMAL1:CLOCK/NPAS2 thus they participate in a negative loop inhibiting their own synthesis and the synthesis of other targets of BMAL1:CLOCK/NPAS2.&lt;br&gt;Experiments with two-hybrid interactions and in vitro associations show that CRY1, CRY2, and PER2 bind BMAL1 at two different sites on BMAL1. PER2 but not CRY1 or CRY2 binds CLOCK. Different combinations of PER and CRY proteins in PER:CRY complexes have different inhibitory activities.</Comment> <BiopaxRef>ced</BiopaxRef> <BiopaxRef>f8a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1089.0" Y="912.0" /> <Point X="1080.0" Y="1006.0" /> <Anchor Position="0.0" Shape="None" GraphId="b26ef" /> <Anchor Position="0.99" Shape="None" GraphId="cbad1" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400256" /> </Interaction> <Interaction GraphId="c46ec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1180.0" Y="902.0" GraphRef="fa720" RelX="-1.0" RelY="-0.04" /> <Point X="1089.0" Y="912.0" GraphRef="b26ef" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400256" /> </Interaction> <Interaction GraphId="e3f02"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1090.0" Y="764.0" GraphRef="d5535" RelX="-0.005128205128205128" RelY="1.0" /> <Point X="1089.0" Y="912.0" GraphRef="b26ef" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400256" /> </Interaction> <Interaction GraphId="f1128"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1080.0" Y="1006.0" GraphRef="cbad1" RelX="-0.08999999999991815" RelY="0.9400000000000546" /> <Point X="1078.0" Y="1009.0" GraphRef="a10cb" RelX="-0.005076142131979695" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400256" /> </Interaction> <Interaction GraphId="ca0a9"> <Comment Source="Reactome">Beta-TrCP1 is an F-box type component of a particular SKP/CUL/F-Box (SCF) E3 ubiquitin ligase. Beta-TrCP1 interacts specifically with phosphorylated PER proteins and directs their polyubiquitination.</Comment> <BiopaxRef>afd</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1352.0" Y="1154.0" /> <Point X="1273.0" Y="1230.0" /> <Anchor Position="0.0" Shape="None" GraphId="a3be5" /> <Anchor Position="0.99" Shape="None" GraphId="aee6d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400219" /> </Interaction> <Interaction GraphId="fa284"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1231.0" Y="1154.0" GraphRef="c0553" RelX="0.9809523809523809" RelY="-0.047619047619047616" /> <Point X="1352.0" Y="1154.0" GraphRef="a3be5" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400219" /> </Interaction> <Interaction GraphId="c5ac4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1628.0" Y="1022.0" GraphRef="b2715" RelX="-1.0" RelY="0.0" /> <Point X="1352.0" Y="1154.0" GraphRef="a3be5" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400219" /> </Interaction> <Interaction GraphId="ea149"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1273.0" Y="1230.0" GraphRef="aee6d" RelX="-0.7899999999999636" RelY="0.7599999999999909" /> <Point X="1270.0" Y="1233.0" GraphRef="ebcdf" RelX="1.0" RelY="-0.043478260869565216" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400219" /> </Interaction> <Interaction GraphId="df8fc"> <Comment Source="Reactome">FBXL3 is an F-box type component of a particular SKP/CUL/F-Box E3 ubiquitin ligase. FBXL3 interacts specifically with CRY1 and CRY2 in the cytosol to direct the polyubiquitination of CRY1 and CRY2. It is unknown if FBXL3 requires phosphorylation or other modification of CRY proteins in order to bind and ubiquitinate them. Phosphorylation of CRY by Adenosine monophosphate-dependent kinase increases degradation of CRY, apparently by increasing association of CRY with FBXL3 Polyubiquitination of CRY proteins directs them to the 26S proteasome for degradation.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="788.0" Y="1065.0" /> <Point X="718.0" Y="1077.0" /> <Anchor Position="0.0" Shape="None" GraphId="c3be3" /> <Anchor Position="0.99" Shape="None" GraphId="b49bf" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400272" /> </Interaction> <Interaction GraphId="f51b4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="814.0" Y="1041.0" GraphRef="f6ec4" RelX="0.0" RelY="0.9047619047619048" /> <Point X="788.0" Y="1065.0" GraphRef="c3be3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400272" /> </Interaction> <Interaction GraphId="adbec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1017.0" Y="1053.0" GraphRef="a7ff0" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="788.0" Y="1065.0" GraphRef="c3be3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400272" /> </Interaction> <Interaction GraphId="e426c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="718.0" Y="1077.0" GraphRef="b49bf" RelX="-0.7000000000000455" RelY="0.11999999999989086" /> <Point X="715.0" Y="1078.0" GraphRef="e8501" RelX="1.0" RelY="-0.043478260869565216" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400272" /> </Interaction> <Interaction GraphId="de32c"> <Comment Source="Reactome">Polyubiquitination of CRY proteins is directed by the FBXL3 component of SCF E3 ubiquitin ligase. The polyubiquitinated CRY proteins are recognized and degraded by the 26S proteasome. 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The polyubiquitinated PER proteins are recognized and degraded by the 26S proteasome. 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The NR1D1:heme complex is then able to recruit the corepressors NCoR and HDAC3. Corepressors do not bind NR1D1 in the absence of heme. NR1D1:heme binds a RRE element in the promoter of the ARNTL (BMAL1) gene, recruits corepressors, and represses transcription.</Comment> <BiopaxRef>e83</BiopaxRef> <BiopaxRef>df9</BiopaxRef> <BiopaxRef>c9e</BiopaxRef> <BiopaxRef>bbb</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="506.0" Y="838.0" /> <Point X="171.0" Y="475.0" /> <Anchor Position="0.0" Shape="None" GraphId="b6e7c" /> <Anchor Position="0.99" Shape="None" GraphId="d82b6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="df3f5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="578.0" Y="900.0" GraphRef="bca4b" RelX="-1.0" RelY="-0.04" /> <Point X="506.0" Y="838.0" GraphRef="b6e7c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="a4ceb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="147.0" Y="592.0" GraphRef="e2bf9" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="506.0" Y="838.0" GraphRef="b6e7c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="f9a91"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="560.0" Y="973.0" GraphRef="bc423" RelX="-1.0" RelY="0.0" /> <Point X="506.0" Y="838.0" GraphRef="b6e7c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="d7947"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="452.0" Y="951.0" GraphRef="dbfb7" RelX="-0.015384615384615385" RelY="-1.0" /> <Point X="506.0" Y="838.0" GraphRef="b6e7c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="bf95d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="515.0" Y="952.0" GraphRef="badbe" RelX="0.0" RelY="-1.0" /> <Point X="506.0" Y="838.0" GraphRef="b6e7c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="b50c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="171.0" Y="475.0" GraphRef="d82b6" RelX="-3.3500000000000227" RelY="-3.6299999999999955" /> <Point X="151.0" Y="472.0" GraphRef="e8c55" RelX="-0.010309278350515464" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368069" /> </Interaction> <Interaction GraphId="e36a2"> <Comment Source="Reactome">As inferred from mouse, RORA binds RRE DNA elements and recruits the coactivators PGC-1alpha (PPARGC1A), p300 (EP300, a histone acetylase), and NRIP1. Activation of BMAL1 (ARNTL) expression by ROR-alpha (RORA) is inferred from mouse. In mouse, Rora together with coactivators Ep300 and Ppargc1a bind the promoter of Bmal1 and activate transcription.</Comment> <BiopaxRef>dc7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="214.0" Y="647.0" /> <Point X="185.0" Y="401.0" /> <Anchor Position="0.0" Shape="None" GraphId="a1516" /> <Anchor Position="0.99" Shape="None" GraphId="d9e3e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="e2ef4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="671.0" Y="668.0" GraphRef="d51cf" RelX="-1.0" RelY="0.0" /> <Point X="214.0" Y="647.0" GraphRef="a1516" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="f9509"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="147.0" Y="592.0" GraphRef="e2bf9" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="214.0" Y="647.0" GraphRef="a1516" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="e55d8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="675.0" Y="639.0" GraphRef="a58b9" RelX="-1.0" RelY="0.0" /> <Point X="214.0" Y="647.0" GraphRef="a1516" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="d2be6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="663.0" Y="608.0" GraphRef="e911a" RelX="-1.0" RelY="0.0" /> <Point X="214.0" Y="647.0" GraphRef="a1516" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="a77e5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="168.0" Y="764.0" GraphRef="f1d11" RelX="1.0" RelY="0.0" /> <Point X="214.0" Y="647.0" GraphRef="a1516" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="ea637"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="185.0" Y="401.0" GraphRef="d9e3e" RelX="-0.28999999999999204" RelY="-2.4600000000000364" /> <Point X="161.0" Y="398.0" GraphRef="ad4d8" RelX="-0.011235955056179775" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368087" /> </Interaction> <Interaction GraphId="ae79d"> <Comment Source="Reactome">The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. 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The ROR-alpha transcription factor binds the RORE element of the BMAL1 (ARNTL) promoter and activates transcription of the BMAL1 gene. The REV-ERBA transcription factor binds the same RORE element and represses transcription of the BMAL1 gene.</Comment> <BiopaxRef>f09</BiopaxRef> <BiopaxRef>b80</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="157.0" Y="569.0" /> <Point X="90.0" Y="197.0" /> <Anchor Position="0.0" Shape="None" GraphId="dda79" /> <Anchor Position="0.99" Shape="None" GraphId="d23b9" /> <Anchor Position="0.5" Shape="None" GraphId="e2f33" /> <Anchor Position="0.5" Shape="None" GraphId="b67e1" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="d9dec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="147.0" Y="592.0" GraphRef="e2bf9" RelX="0.9759036144578314" RelY="-0.0196078431372549" /> <Point X="157.0" Y="569.0" GraphRef="dda79" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="deebf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="90.0" Y="197.0" GraphRef="d23b9" RelX="-0.6700000000000017" RelY="-3.7200000000000273" /> <Point X="90.0" Y="193.0" GraphRef="c8dac" RelX="-0.01098901098901099" RelY="0.9047619047619048" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="d75e9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="151.0" Y="472.0" GraphRef="e8c55" RelX="-0.010309278350515464" RelY="1.0" /> <Point X="93.0" Y="323.0" GraphRef="e2f33" RelX="-30.5" RelY="-60.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="bfed8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="199.0" Y="339.0" GraphRef="e8aa4" RelX="-0.022222222222222223" RelY="1.0" /> <Point X="93.0" Y="323.0" GraphRef="b67e1" RelX="-30.5" RelY="-60.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="c410f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="199.0" Y="339.0" GraphRef="ad4d8" RelX="0.8426966292134831" RelY="-1.565217391304348" /> <Point X="93.0" Y="323.0" GraphRef="b67e1" RelX="-30.5" RelY="-60.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-400342" /> </Interaction> <Interaction GraphId="c9d7a"> <Comment Source="Reactome">The CLOCK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of CLOCK is repressed by REV-ERBA. The promoter of CLOCK contains an RRE element that may bind REV-ERBA and RORA.</Comment> <BiopaxRef>aa7</BiopaxRef> <BiopaxRef>b4e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="336.0" Y="562.0" /> <Point X="329.0" Y="232.0" /> <Anchor Position="0.0" Shape="None" GraphId="ccb74" /> <Anchor Position="0.99" Shape="None" GraphId="e18bc" /> <Anchor Position="0.5" Shape="None" GraphId="fd064" /> <Anchor Position="0.5" Shape="None" GraphId="a75f5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="aeb1c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="326.0" Y="585.0" GraphRef="a329c" RelX="0.9764705882352941" RelY="-0.0196078431372549" /> <Point X="336.0" Y="562.0" GraphRef="ccb74" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="f67fa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="329.0" Y="232.0" GraphRef="e18bc" RelX="-0.06999999999999318" RelY="-3.3000000000000114" /> <Point X="329.0" Y="229.0" GraphRef="b05e9" RelX="-0.02040816326530612" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="c728f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="385.0" Y="459.0" GraphRef="e9824" RelX="-0.010309278350515464" RelY="1.0" /> <Point X="330.0" Y="332.0" GraphRef="fd064" RelX="-2.5" RelY="-65.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="bf940"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="221.0" Y="328.0" GraphRef="e8aa4" RelX="0.9555555555555556" RelY="0.0" /> <Point X="330.0" Y="332.0" GraphRef="a75f5" RelX="-2.5" RelY="-65.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="ead83"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="221.0" Y="328.0" GraphRef="d805e" RelX="-3.5405405405405403" RelY="2.8181818181818183" /> <Point X="330.0" Y="332.0" GraphRef="a75f5" RelX="-2.5" RelY="-65.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368119" /> </Interaction> <Interaction GraphId="a49b7"> <Comment Source="Reactome">The NPAS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of NPAS2 is enhanced by the RORA:Coactivator complex and repressed by the REV-ERBA:Corepressor complex.</Comment> <BiopaxRef>cab</BiopaxRef> <BiopaxRef>f6e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="520.0" Y="562.0" /> <Point X="521.0" Y="254.0" /> <Anchor Position="0.0" Shape="None" GraphId="c0376" /> <Anchor Position="0.99" Shape="None" GraphId="b7d74" /> <Anchor Position="0.5" Shape="None" GraphId="b4787" /> <Anchor Position="0.5" Shape="None" GraphId="f207d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="f7cdc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="510.0" Y="585.0" GraphRef="f0957" RelX="0.9764705882352941" RelY="-0.0196078431372549" /> <Point X="520.0" Y="562.0" GraphRef="c0376" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="dd132"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="521.0" Y="254.0" GraphRef="b7d74" RelX="0.009999999999990905" RelY="-3.079999999999984" /> <Point X="522.0" Y="251.0" GraphRef="b120d" RelX="-0.01818181818181818" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="fa3f4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="576.0" Y="482.0" GraphRef="a4ec9" RelX="-0.010309278350515464" RelY="1.0" /> <Point X="520.0" Y="326.0" GraphRef="b4787" RelX="-0.5" RelY="-82.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="b2d3c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="595.0" Y="406.0" GraphRef="e57b7" RelX="-0.011235955056179775" RelY="1.0" /> <Point X="520.0" Y="326.0" GraphRef="f207d" RelX="-0.5" RelY="-82.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="db0bf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="595.0" Y="406.0" GraphRef="de8db" RelX="-0.30526315789473685" RelY="4.947368421052632" /> <Point X="520.0" Y="326.0" GraphRef="f207d" RelX="-0.5" RelY="-82.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1368065" /> </Interaction> <Interaction GraphId="ae7bc"> <Comment Source="Reactome">The phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds an E-box in the promoter of the CRY1 gene and activates transcription of CRY1. NPAS2 is predicted to act redundantly with CLOCK.</Comment> <BiopaxRef>d09</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1085.0" Y="580.0" /> <Point X="1085.0" Y="513.0" /> <Anchor Position="0.0" Shape="None" GraphId="e882f" /> <Anchor Position="0.99" Shape="None" GraphId="e011c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663120" /> </Interaction> <Interaction GraphId="a2a84"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1103.0" Y="587.0" GraphRef="fe449" RelX="0.0" RelY="-1.0" /> <Point X="1085.0" Y="580.0" GraphRef="e882f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663120" /> </Interaction> <Interaction GraphId="fe9e9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1090.0" Y="738.0" GraphRef="d5535" RelX="-0.005128205128205128" RelY="-1.0" /> <Point X="1085.0" Y="580.0" GraphRef="e882f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663120" /> </Interaction> <Interaction GraphId="eaac6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1085.0" Y="513.0" GraphRef="e011c" RelX="0.0" RelY="-0.6699999999999591" /> <Point X="1087.0" Y="510.0" GraphRef="a4e13" RelX="-0.008849557522123894" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663120" /> </Interaction> <Interaction GraphId="dcdae"> <Comment Source="Reactome">The CRYPTOCHROME-1 (CRY1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CRY1 mRNA and protein show circadian expression. The promoter of the CRY1 gene contains an E-box which is bound by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 heterodimer), which activates transcription of CRY1.</Comment> <BiopaxRef>b43</BiopaxRef> <BiopaxRef>c08</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1157.0" Y="589.0" /> <Point X="1257.0" Y="205.0" /> <Anchor Position="0.0" Shape="None" GraphId="f9edc" /> <Anchor Position="0.99" Shape="None" GraphId="bc982" /> <Anchor Position="0.5" Shape="None" GraphId="fc289" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549467" /> </Interaction> <Interaction GraphId="b4861"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1148.0" Y="612.0" GraphRef="fe449" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1157.0" Y="589.0" GraphRef="f9edc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549467" /> </Interaction> <Interaction GraphId="bb9e1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1257.0" Y="205.0" GraphRef="bc982" RelX="1.0" RelY="-3.839999999999975" /> <Point X="1266.0" Y="202.0" GraphRef="b38ba" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549467" /> </Interaction> <Interaction GraphId="c55bb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1143.0" Y="485.0" GraphRef="a4e13" RelX="0.9823008849557522" RelY="0.0" /> <Point X="1149.0" Y="353.0" GraphRef="fc289" RelX="-58.0" RelY="-44.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549467" /> </Interaction> <Interaction GraphId="d395c"> <Comment Source="Reactome">The CRYPTOCHROME-2 (CRY2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the CRY2 protein shows circadian rhythm in the suprachiasmatic nucleus (SCN) and in peripheral tissues. The mRNA shows circadian rhythm in muscle but not in the SCN. Expression is dependent on CLOCK.</Comment> <BiopaxRef>a8a</BiopaxRef> <BiopaxRef>c08</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1097.0" Y="368.0" /> <Point X="1193.0" Y="173.0" /> <Anchor Position="0.0" Shape="None" GraphId="a455e" /> <Anchor Position="0.99" Shape="None" GraphId="ede74" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549470" /> </Interaction> <Interaction GraphId="c6570"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1088.0" Y="391.0" GraphRef="b91f7" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1097.0" Y="368.0" GraphRef="a455e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549470" /> </Interaction> <Interaction GraphId="d643d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1193.0" Y="173.0" GraphRef="ede74" RelX="0.9600000000000364" RelY="-1.950000000000017" /> <Point X="1200.0" Y="169.0" GraphRef="ad510" RelX="0.0" RelY="0.9130434782608695" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549470" /> </Interaction> <Interaction GraphId="f2fcb"> <Comment Source="Reactome">The phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds E-boxes in the promoter of the PER1 gene and activates transcription of PER1. NPAS2 is predicted to act redundantly with CLOCK.</Comment> <BiopaxRef>fae</BiopaxRef> <BiopaxRef>bc2</BiopaxRef> <BiopaxRef>c68</BiopaxRef> <BiopaxRef>f4a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1240.0" Y="584.0" /> <Point X="1253.0" Y="516.0" /> <Anchor Position="0.0" Shape="None" GraphId="d93d6" /> <Anchor Position="0.99" Shape="None" GraphId="e3ede" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663174" /> </Interaction> <Interaction GraphId="db7ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1187.0" Y="751.0" GraphRef="d5535" RelX="0.9897435897435898" RelY="0.0" /> <Point X="1240.0" Y="584.0" GraphRef="d93d6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663174" /> </Interaction> <Interaction GraphId="f8ed3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1270.0" Y="593.0" GraphRef="e8275" RelX="0.0" RelY="-1.0" /> <Point X="1240.0" Y="584.0" GraphRef="d93d6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663174" /> </Interaction> <Interaction GraphId="f6262"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1253.0" Y="516.0" GraphRef="e3ede" RelX="0.13000000000010914" RelY="-0.6800000000000637" /> <Point X="1255.0" Y="513.0" GraphRef="ace38" RelX="-0.008849557522123894" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663174" /> </Interaction> <Interaction GraphId="d84ce"> <Comment Source="Reactome">The PERIOD-1 (PER1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER1 gene contains E-boxes which are bound by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER1.</Comment> <BiopaxRef>fae</BiopaxRef> <BiopaxRef>bc2</BiopaxRef> <BiopaxRef>c68</BiopaxRef> <BiopaxRef>f4a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1324.0" Y="595.0" /> <Point X="1332.0" Y="233.0" /> <Anchor Position="0.0" Shape="None" GraphId="bb702" /> <Anchor Position="0.99" Shape="None" GraphId="f23b8" /> <Anchor Position="0.5" Shape="None" GraphId="ba69e" /> <Anchor Position="0.5" Shape="None" GraphId="f88a5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="aa065"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1315.0" Y="618.0" GraphRef="e8275" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1324.0" Y="595.0" GraphRef="bb702" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="bc1c2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1332.0" Y="233.0" GraphRef="f23b8" RelX="0.07999999999992724" RelY="-3.6200000000000045" /> <Point X="1334.0" Y="230.0" GraphRef="d89d7" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="dd4a4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1254.0" Y="410.0" GraphRef="f686c" RelX="-0.024390243902439025" RelY="1.0" /> <Point X="1318.0" Y="364.0" GraphRef="ba69e" RelX="-10.0" RelY="-50.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="f4fcf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1255.0" Y="513.0" GraphRef="ace38" RelX="-0.008849557522123894" RelY="1.0" /> <Point X="1318.0" Y="364.0" GraphRef="f88a5" RelX="-10.0" RelY="-50.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="cae7b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1255.0" Y="513.0" GraphRef="b5abc" RelX="0.39655172413793105" RelY="9.0" /> <Point X="1318.0" Y="364.0" GraphRef="f88a5" RelX="-10.0" RelY="-50.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549533" /> </Interaction> <Interaction GraphId="c722d"> <Comment Source="Reactome">As inferred from mouse, the phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds a noncanonical E-box in the promoter of the PER2 gene and activates transcription of PER2. NPAS2 is predicted to act redundantly with CLOCK.</Comment> <BiopaxRef>d09</BiopaxRef> <BiopaxRef>c68</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1386.0" Y="575.0" /> <Point X="1406.0" Y="515.0" /> <Anchor Position="0.0" Shape="None" GraphId="a119f" /> <Anchor Position="0.99" Shape="None" GraphId="e4471" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663118" /> </Interaction> <Interaction GraphId="b60b1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1421.0" Y="594.0" GraphRef="c99ba" RelX="-0.01098901098901099" RelY="-1.0" /> <Point X="1386.0" Y="575.0" GraphRef="a119f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663118" /> </Interaction> <Interaction GraphId="f6456"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1187.0" Y="751.0" GraphRef="d5535" RelX="0.9897435897435898" RelY="0.0" /> <Point X="1386.0" Y="575.0" GraphRef="a119f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663118" /> </Interaction> <Interaction GraphId="e0092"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1406.0" Y="515.0" GraphRef="e4471" RelX="0.20000000000004547" RelY="-0.6000000000000227" /> <Point X="1408.0" Y="512.0" GraphRef="f2ca5" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663118" /> </Interaction> <Interaction GraphId="e3205"> <Comment Source="Reactome">The PERIOD-2 (PER2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER2 gene contains an E-box which binds the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER2.</Comment> <BiopaxRef>d09</BiopaxRef> <BiopaxRef>c68</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1476.0" Y="596.0" /> <Point X="1415.0" Y="252.0" /> <Anchor Position="0.0" Shape="None" GraphId="b3607" /> <Anchor Position="0.99" Shape="None" GraphId="dee8a" /> <Anchor Position="0.5" Shape="None" GraphId="da5c0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549493" /> </Interaction> <Interaction GraphId="d65e3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1466.0" Y="619.0" GraphRef="c99ba" RelX="0.978021978021978" RelY="-0.0196078431372549" /> <Point X="1476.0" Y="596.0" GraphRef="b3607" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549493" /> </Interaction> <Interaction GraphId="bcba6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1415.0" Y="252.0" GraphRef="dee8a" RelX="-0.6099999999999" RelY="-3.4399999999999977" /> <Point X="1409.0" Y="248.0" GraphRef="c7206" RelX="0.0" RelY="0.9259259259259259" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549493" /> </Interaction> <Interaction GraphId="e9d6e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1385.0" Y="385.0" GraphRef="bd4bf" RelX="-0.012987012987012988" RelY="0.9574468085106383" /> <Point X="1466.0" Y="360.0" GraphRef="da5c0" RelX="20.5" RelY="-64.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549493" /> </Interaction> <Interaction GraphId="b1078"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1385.0" Y="385.0" GraphRef="f2ca5" RelX="-0.40350877192982454" RelY="-4.08" /> <Point X="1466.0" Y="360.0" GraphRef="da5c0" RelX="20.5" RelY="-64.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-549493" /> </Interaction> <Interaction GraphId="ba14e"> <Comment Source="Reactome">Activation of NR1D1 (REV-ERBA) expression by phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) is inferred from mouse. NPAS2 is predicted to act redundantly with CLOCK.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="995.0" Y="830.0" /> <Point X="940.0" Y="898.0" /> <Anchor Position="0.0" Shape="None" GraphId="a3988" /> <Anchor Position="0.99" Shape="None" GraphId="e373e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663155" /> </Interaction> <Interaction GraphId="b788c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="931.0" Y="858.0" GraphRef="d4a3c" RelX="0.9801980198019802" RelY="-0.0196078431372549" /> <Point X="995.0" Y="830.0" GraphRef="a3988" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663155" /> </Interaction> <Interaction GraphId="e46d2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="993.0" Y="751.0" GraphRef="d5535" RelX="-1.0" RelY="0.0" /> <Point X="995.0" Y="830.0" GraphRef="a3988" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663155" /> </Interaction> <Interaction GraphId="d3b80"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="940.0" Y="898.0" GraphRef="e373e" RelX="-0.5499999999999545" RelY="0.67999999999995" /> <Point X="924.0" Y="901.0" GraphRef="e8a26" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663155" /> </Interaction> <Interaction GraphId="d9ad6"> <Comment Source="Reactome">The NR1D1 (REV-ERBA) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the Rev-erba gene shows circadian expression due to transactivation by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer. 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RORA binds the NR1D1 (REV-ERBA) promoter and activates transcription.</Comment> <BiopaxRef>c62</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="620.0" Y="768.0" /> <Point X="708.0" Y="810.0" /> <Anchor Position="0.0" Shape="None" GraphId="b4c36" /> <Anchor Position="0.99" Shape="None" GraphId="b1212" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="c579b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="831.0" Y="858.0" GraphRef="d4a3c" RelX="-1.0" RelY="-0.0196078431372549" /> <Point X="620.0" Y="768.0" GraphRef="b4c36" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="b281f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="671.0" Y="668.0" GraphRef="d51cf" RelX="-1.0" RelY="0.0" /> <Point X="620.0" Y="768.0" GraphRef="b4c36" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="a3f41"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="690.0" Y="618.0" GraphRef="e911a" RelX="0.0" RelY="1.0" /> <Point X="620.0" Y="768.0" GraphRef="b4c36" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="f9752"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="675.0" Y="639.0" GraphRef="a58b9" RelX="-1.0" RelY="0.0" /> <Point X="620.0" Y="768.0" GraphRef="b4c36" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="a8a5b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="168.0" Y="764.0" GraphRef="f1d11" RelX="1.0" RelY="0.0" /> <Point X="620.0" Y="768.0" GraphRef="b4c36" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="baa43"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="708.0" Y="810.0" GraphRef="b1212" RelX="0.8799999999999955" RelY="0.4199999999999591" /> <Point X="711.0" Y="810.0" GraphRef="c4186" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663273" /> </Interaction> <Interaction GraphId="c804c"> <Comment Source="Reactome">NR1D1 (REV-ERBA) binds the promoter of the CLOCK gene and recruits corepressors to repress transcription. Recruitment of repressors appears to depend on the binding of heme by NR1D1.</Comment> <BiopaxRef>b9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="538.0" Y="834.0" /> <Point X="385.0" Y="462.0" /> <Anchor Position="0.0" Shape="None" GraphId="f7fbe" /> <Anchor Position="0.99" Shape="None" GraphId="fe6c8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="d8649"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="578.0" Y="900.0" GraphRef="bca4b" RelX="-1.0" RelY="-0.04" /> <Point X="538.0" Y="834.0" GraphRef="f7fbe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="c538e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="484.0" Y="962.0" GraphRef="dbfb7" RelX="0.9692307692307692" RelY="0.0" /> <Point X="538.0" Y="834.0" GraphRef="f7fbe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="aca75"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="326.0" Y="585.0" GraphRef="a329c" RelX="0.9764705882352941" RelY="-0.0196078431372549" /> <Point X="538.0" Y="834.0" GraphRef="f7fbe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="b59ba"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="515.0" Y="952.0" GraphRef="badbe" RelX="0.0" RelY="-1.0" /> <Point X="538.0" Y="834.0" GraphRef="f7fbe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="fc408"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="604.0" Y="958.0" GraphRef="bc423" RelX="-0.011235955056179775" RelY="-1.0" /> <Point X="538.0" Y="834.0" GraphRef="f7fbe" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="d18fe"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="385.0" Y="462.0" GraphRef="fe6c8" RelX="-1.5299999999999727" RelY="-3.7199999999999704" /> <Point X="385.0" Y="459.0" GraphRef="e9824" RelX="-0.010309278350515464" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663271" /> </Interaction> <Interaction GraphId="c9af8"> <Comment Source="Reactome">NR1D1 (REV-ERBA) binds the promoter of the NPAS2 gene and recruits corepressors to repress transcription. Recruitment of repressors appears to depend on the binding of heme by NR1D1.</Comment> <BiopaxRef>d90</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="563.0" Y="828.0" /> <Point X="576.0" Y="485.0" /> <Anchor Position="0.0" Shape="None" GraphId="b64a5" /> <Anchor Position="0.99" Shape="None" GraphId="c0ed3" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663245" /> </Interaction> <Interaction GraphId="d1349"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="578.0" Y="900.0" GraphRef="bca4b" RelX="-1.0" RelY="-0.04" /> <Point X="563.0" Y="828.0" GraphRef="b64a5" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5663245" /> </Interaction> <Interaction GraphId="a3e37"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="468.0" Y="610.0" GraphRef="f0957" RelX="-0.011764705882352941" RelY="0.9607843137254902" /> <Point X="563.0" Y="828.0" GraphRef="b64a5" 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